Adult-Onset Myasthenia Gravis

Autoimmune MONDO:0018324 Pathograph 56 Show in embeddings browser Myasthenia Gravis Neuromuscular Disease Autoimmune Disease

Adult-onset myasthenia gravis is acquired autoimmune disease beginning in adulthood, with fluctuating, fatigable skeletal-muscle weakness caused by impaired postsynaptic neuromuscular transmission. Onset-age groups overlap with antibody-defined and thymic subgroups. Early-onset AChR-positive disease often has thymic follicular hyperplasia, whereas late-onset disease more often accompanies an involuted thymus and striational antibodies. These are population patterns, not obligatory features or established distinct initiating mechanisms. AChR antibodies can activate complement, accelerate receptor loss, or interfere with receptor function; predominantly IgG4 MuSK antibodies impair receptor-clustering signals through a different mechanism. Treatment depends on antibody status, clinical activity, thymic pathology, comorbidity, and age.

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Mappings

MONDO

MONDO:0018324 adult-onset myasthenia gravis

Orphanet lists MONDO:0018324 as an exact cross-reference for ORPHA:391490.

MONDO:0009688 myasthenia gravis DisMech

Orphanet classes ORPHA:391490 as a clinical subtype of a disorder, and MONDO asserts MONDO:0018324 is_a MONDO:0009688; the general myasthenia gravis concept is therefore broader than this entry. Curated as `skos:broadMatch` so it is not mistaken for a mapping that would retire MONDO:0009688 from the curation queue — that concept is curated separately in `Myasthenia_Gravis.yaml`.

ICD-10-CM

ICD10CM:G70.0 Myasthenia gravis

Orphanet records ICD-10 G70.0 as a *narrower* cross-reference direction for ORPHA:391490 — i.e. the ORPHA subtype is narrower than the ICD code — so from this entry's perspective the ICD code is the broader concept.

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Definitions

Orphanet disease definition

Orphanet defines adult-onset myasthenia gravis as a rare autoimmune disorder of the neuromuscular junction with fatigable muscle weakness, frequent ocular signs and/or generalized weakness, and occasional thymoma association.

CASE_DEFINITION

Show evidence (1 reference)

ORPHA:391490 SUPPORT DIRECT BACKGROUND Other

"A rare autoimmune disorder of the neuromuscular junction characterized by fatigable muscle weakness with frequent ocular signs and/or generalized muscle weakness, and occasionally associated with thymoma."

Orphanet's definition for the adult-onset subtype anchors the scope of this entry.

◆

Subtypes

Early-Onset MG (onset before ~50 years)

Adult-onset disease before the study-specific late-onset boundary, commonly 50 years. Female predominance and follicular thymic hyperplasia are especially associated with AChR-positive early-onset cohorts. Research labeled EOMG may include juvenile cases, so its results are not automatically adult-specific.

Show evidence (1 reference)

PMID:40675735 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"EOMG often presents with distinct immunological and genetic profiles, a predominance of female patients, and a higher incidence of thymic hyperplasia."

Defines the early-onset subgroup by its immunogenetic profile, sex skew, and thymic pathology.

Late-Onset MG (onset at or after ~50 years)

Disease beginning at or beyond the study-specific late-onset boundary, commonly 50 years. AChR-positive disease, male predominance, ocular presentation, and anti-titin antibodies are relatively enriched in several cohorts. An atrophic thymus is common but does not prove immunological inactivity or an exclusively extrathymic origin.

Show evidence (2 references)

PMID:33458590 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"LOMG with onset ≥ 50 years of age is more common in men and ocular onset is common. Frequency of anti-AChR and anti-titin antibodies are high."

Gives the conventional ≥50-year onset boundary together with the male skew and antibody profile that define the subgroup.

PMID:40675735 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"In contrast, LOMG and VLOMG are characterized by thymic atrophy, differing genetic associations, and milder long-term disease courses with variable treatment responses."

Contrasts late-onset thymic and genetic biology with the early-onset subgroup.

Very Late-Onset MG (onset after ~65 years)

A further age stratum within late-onset disease, often defined as onset at or beyond 65 years. Focal ocular or bulbar presentations can occur; comorbidity, diagnostic alternatives, and treatment tolerability warrant particular attention. The threshold varies between reports.

Show evidence (2 references)

PMID:23893883 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"We define late-onset myasthenia gravis (LOMG) when symptoms appear at ≥65 years of age. There has been a continuous increase in the incidence of LOMG with a clear male predominance."

Documents the ≥65-year boundary used for the very-late-onset tier — and, by differing from the ≥50-year boundary used elsewhere, shows that the cut-point itself is a convention rather than a measured discontinuity.

PMID:23893883 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Commonly, patients present with focal (ocular or bulbar) weakness. A high index of suspicion required to achieve early diagnosis and to improve prognosis."

Supports focal presentation and diagnostic delay as characteristic of the oldest-onset group.

Discussions and Knowledge Gaps

Onset-associated genetic architecture and ascertainment

INTERPRETATION OPEN adult-mg-interpretation-1

Onset-age strata show differing HLA and non-HLA associations, with shared susceptibility and substantial ascertainment limits. Older studies were enriched for European AChR-positive, nonthymomatous disease and early-onset cohorts could include adolescents. The 2024 discovery analysis included 5,708 cases and 432,028 controls and reused prior European cohorts; replication used 3,989 self-reported cases and 226,643 controls. Its early-onset replication used age below 50 at participation, while late-onset replication used all cases because onset age was unavailable. These results do not prove that the age strata are distinct diseases or establish clinical diagnostic use of polygenic scores.

Show evidence (3 references)

PMID:39537604 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"We defined EOMG cases as those under 50 years old at participation."

The replication proxy differs from measured onset age.

PMID:39537604 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"As no age of onset information was available, we replicated the LOMG discovery GWAS loci using the full 23andMe MG dataset."

The late-onset replication was not restricted to verified late-onset cases.

PMID:34400559 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"MG onset-specific analysis reveals differences in the genetic architecture of early-onset MG (EOMG) versus late-onset MG (LOMG)."

The abstract supports differences, not complete genetic separation.

Striational antibodies and associated muscle or cardiac inflammation

INTERPRETATION OPEN adult-mg-interpretation-2

Myositis and myocarditis can accompany MG, particularly in selected thymoma-associated or late-onset series. A 2019 study analyzed stored sera from 30 patients selected for MG with myositis and/or myocarditis; it was not a population-incidence study. Titin and Kv1.4 antibodies were common in that selected group, while RyR reactivity lacked specificity. These assays do not establish that the antibodies caused muscle or cardiac injury, and myocarditis mortality must not be presented as the mortality of myasthenic crisis.

Show evidence (1 reference)

PMID:30918333 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"MG patients with myositis and/or myocarditis as well as late-onset and thymoma-associated MG had anti-titin, anti-ryanodine receptor, and anti-Kv1.4 antibodies."

Primary selected-sample assay findings; no general frequency or pathogenic function is inferred.

Emerging thymic cell-interaction hypotheses

EMERGING HYPOTHESIS OPEN adult-mg-interpretation-3

Single-cell and BCR profiling of untreated early-onset MG thymi identified clonal expansion and inferred cell-state trajectories and MIF–CD74 communication. Spatial proximity and protein staining support the tissue context but do not demonstrate signaling necessity, lineage ancestry, or response to MIF blockade. Serum MIF associations are exploratory and are not a validated diagnostic or disease-activity test.

Show evidence (2 references)

PMID:40117520 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Clonally expanded sequences were most enriched in the GC and cycling B-cell subsets"

Measured clonal enrichment in the primary dataset; antigen specificity and proposed communication require further validation.

PMID:40117520 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Cell-cell interactome predictions identified strong interactions between T cells and GC-associated and memory B cells, dominated by B-cell prosurvival signaling through the MIF-CD74 axis."

The MIF-CD74 communication is a computational interactome prediction, which is why the discussion treats it as an emerging hypothesis rather than a demonstrated signaling requirement.

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Pathophysiology

Thymic Chemokine Overexpression

CXCL13 and CCL21 overexpression in hyperplastic AChR-positive MG thymus is associated with recruitment of peripheral lymphocytes. This is an early-onset-enriched pathway; its initiating stimulus is unresolved.

thymus UBERON:0002370

Downstream

Thymic Lymphocyte Recruitment Chemokines favor peripheral lymphocyte recruitment into the inflammatory thymus.

Show evidence (1 reference)

PMID:39105625 SUPPORT DIRECT REVIEW SYNTHESIS Other

"B cell infiltration and germinal center formation is associated with overexpression of CXCL13, CCL21, and B cell–activating factor (BAFF) in thymic epithelial cells"

Review synthesis of thymic chemokine findings.

Thymic Lymphocyte Recruitment

Peripheral B cells and helper T cells accumulate in the hyperplastic thymus, with vascular changes that support cellular entry.

B cell CL:0000236

thymus UBERON:0002370

Downstream

Ectopic Thymic Germinal Center Formation Recruited lymphocytes support ectopic germinal-center organization.

Show evidence (1 reference)

PMID:29125185 SUPPORT DIRECT REVIEW SYNTHESIS Other

"The hyperplastic MG thymus displays all the characteristics of tertiary lymphoid organs (TLOs): neoangiogenic processes with high endothelial venule and lymphatic vessel development, chemokine overexpression favoring peripheral cell recruitment, and ectopic germinal center development."

Thymic cellular recruitment described in a mechanistic review.

Ectopic Thymic Germinal Center Formation

Ectopic thymic follicles provide a niche for B-cell clonal expansion and maturation, particularly in AChR-positive early-onset disease. A 2025 single-cell study analyzed 11 immunotherapy-naive thymi after one of 12 recruited samples failed quality control; inferred trajectories are not lineage tracing.

B cell CL:0000236

germinal center formation GO:0002467

thymus UBERON:0002370

Downstream

AChR Autoantibody Production The thymic germinal-center environment can sustain AChR-reactive B-lineage cells; circulating antibody-producing cells also maintain disease after thymectomy.

Thymic Follicular Hyperplasia Ectopic follicles contribute to the histological hyperplasia.

Show evidence (2 references)

PMID:40117520 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Clonally expanded sequences were most enriched in the GC and cycling B-cell subsets"

Primary BCR sequencing supports local clonal expansion, not antigen specificity of every expanded clone.

PMID:38886398 SUPPORT DIRECT BACKGROUND Human Clinical

"EOMG is often characterized by B cells infiltrating the thymus, leading to ectopic germinal center (GC) development (lymphofollicular hyperplasia) for AChR+ MG"

The introduction of this thymic-histology cohort study restates the established association of AChR-positive early-onset MG with B-cell thymic infiltration and ectopic germinal-center formation.

Thymoma-Associated Loss of Immune Tolerance

In thymoma-associated disease, abnormal T-cell selection and export of autoreactive T cells can support AChR autoimmunity. Tumor histology and immune changes vary; no single molecular lesion is asserted for every thymoma.

thymus UBERON:0002370

Downstream

AChR Autoantibody Production Autoreactive T-cell help can support antibody-producing B cells outside the tumor, permitting persistent or delayed disease after resection.

Show evidence (1 reference)

PMID:39105625 SUPPORT DIRECT REVIEW SYNTHESIS Other

"Development of MG requires the generation of autoreactive T cells within the tumor and subsequent exit of these T cells to the periphery and is further associated with a reduction of Tregs"

Review synthesis of the thymoma-associated mechanism.

AChR Autoantibody Production

Autoreactive B-lineage cells produce AChR-directed antibodies in the thymus and peripheral compartments. Antibody titer alone does not determine pathogenic activity or clinical severity.

plasma cell CL:0000786

immunoglobulin production GO:0002377

Downstream

AChR Autoantibody Binding Circulating antibodies with accessible extracellular epitopes bind the muscle receptor; not every detected antibody is pathogenic.

Show evidence (1 reference)

PMID:39105625 SUPPORT DIRECT REVIEW SYNTHESIS Other

"Thymocytes produce AChR antibodies, as do circulating plasma cells"

Review identifies intrathymic and circulating sources.

AChR Autoantibody Binding

AChR-reactive antibodies bind the postsynaptic receptor. Isotype, epitope, combinations of antibodies, and tissue access affect their ability to cause injury.

neuromuscular junction GO:0031594

skeletal muscle tissue UBERON:0001134

Downstream

Complement Activation at the Endplate Complement-fixing antibody combinations recruit the complement cascade.

AChR Crosslinking Bivalent antibodies and complementary epitope specificities can crosslink receptors.

AChR Functional Blockade Some antibodies interfere with receptor activation independently of complement-mediated injury.

Show evidence (1 reference)

PMID:36074148 SUPPORT DIRECT PRIMARY RESULT In Vitro

"All AChR-specific antibodies were hypermutated, including isotypes IgG1, IgG3, and IgG4, and recognized different subunits of the AChR."

Patient-derived monoclonal antibodies characterize binding specificity in experimental assays.

Complement Activation at the Endplate

Complement-fixing AChR antibodies promote terminal complement activation and membrane attack complex formation at the postsynaptic membrane. This is distinct from the predominant IgG4 MuSK mechanism.

complement activation GO:0006956

neuromuscular junction GO:0031594

skeletal muscle tissue UBERON:0001134

Experimental models

AChR-Transfected HEK Antibody-Combination Assays CELL LINE Selected antibody combinations increased C3 deposition on receptor-expressing cells.

Animal models

Patient-Derived AChR Antibody Passive Transfer in Lewis Rats Rattus norvegicus partially recapitulates The antibody combination increased junctional C3 staining beyond either control or aG101 alone.

Downstream

Postsynaptic Membrane Injury Membrane attack complex formation injures receptor-rich membrane and synaptic folds.

Show evidence (1 reference)

PMID:39105625 SUPPORT DIRECT REVIEW SYNTHESIS Other

"Upon binding of AChR antibody, the membrane attack complex is formed on the postsynaptic surface and leads to the shedding of AChR-rich membrane resulting in the loss of synaptic folding as well as Na+ channels"

Established complement mechanism, with variable contribution between patients.

Postsynaptic Membrane Injury

Complement-associated injury removes receptor-rich postsynaptic membrane and simplifies junctional architecture. Loss of sodium channels also reduces the transmission safety factor.

neuromuscular junction GO:0031594

skeletal muscle tissue UBERON:0001134

Downstream

Reduced Surface AChR Availability Loss of receptor-bearing membrane reduces available postsynaptic AChRs.

Reduced Endplate Potential Safety Margin Postsynaptic structural and sodium-channel loss make generation of a muscle action potential less reliable.

Show evidence (1 reference)

PMID:39105625 SUPPORT DIRECT REVIEW SYNTHESIS Other

Review describes receptor-rich membrane shedding and channel loss.

AChR Crosslinking

Antibodies can crosslink AChR molecules into abnormal surface assemblies, distinct from physiological receptor clustering. Patient-derived antibody combinations showed greater clustering than individual antibodies in transfected cells.

neuromuscular junction GO:0031594

skeletal muscle tissue UBERON:0001134

Experimental models

AChR-Transfected HEK Antibody-Combination Assays CELL LINE Antibody pairs increased visible receptor clustering.

Downstream

Accelerated AChR Internalization Crosslinking can accelerate receptor endocytosis and degradation, the antigenic-modulation pathway.

Show evidence (1 reference)

PMID:36074148 SUPPORT DIRECT PRIMARY RESULT In Vitro

"None of the single antibodies had any significant effect on the distribution of the receptor. Combinations of antibodies such as aG112 and bG402, on the other hand, mediated strong clustering"

Live-cell experiments support antibody-combination-dependent clustering in the tested panel.

Accelerated AChR Internalization

Antigenic modulation accelerates endocytosis and degradation of antibody-crosslinked receptors.

endocytosis GO:0006897

neuromuscular junction GO:0031594

skeletal muscle tissue UBERON:0001134

Downstream

Reduced Surface AChR Availability Accelerated removal lowers the available surface receptor pool.

Show evidence (1 reference)

PMID:39105625 SUPPORT DIRECT REVIEW SYNTHESIS Other

"This refers to the capacity of an antibody against link two antigen molecules, instigating a cellular signal that expedites the process of endocytosis and subsequent degradation of the complex"

Mechanistic review summarizes receptor internalization and degradation.

Reduced Surface AChR Availability

Loss of receptor-bearing membrane, enhanced internalization, and impaired clustering reduce receptor availability at functional postsynaptic sites.

neuromuscular junction GO:0031594

skeletal muscle tissue UBERON:0001134

Animal models

Patient-Derived AChR Antibody Passive Transfer in Lewis Rats Rattus norvegicus partially recapitulates The combination reduced receptor-associated alpha-bungarotoxin signal at endplates.

Downstream

Reduced Endplate Potential Safety Margin Fewer functional receptors reduce the evoked endplate depolarization.

Show evidence (1 reference)

PMID:39105625 SUPPORT DIRECT REVIEW SYNTHESIS Other

"Neuromuscular transmission failure occurs owing to a reduction in the number or activity of AChR molecules at the NMJ, leading to a decrease in the end-plate potential (EPP)."

Review connects receptor number/activity to reduced endplate potential.

AChR Functional Blockade

Some AChR antibodies inhibit receptor activation without requiring complement. Patient sera inhibited neurotransmission in an iPSC-derived system after heat inactivation, but the six cloned antibodies in that study did not reproduce blockade, either individually or in tested combinations.

neuromuscular junction GO:0031594

skeletal muscle tissue UBERON:0001134

Experimental models

Human iPSC-Derived Neuromuscular Coculture with MG Sera IPSC DERIVED MODEL Patient sera reduced the stimulation-evoked myotube response independently of active complement.

Downstream

Reduced Endplate Potential Safety Margin Receptor blockade reduces effective cholinergic activation.

Show evidence (2 references)

PMID:39105625 SUPPORT DIRECT REVIEW SYNTHESIS Other

"This occurs when antibodies bind to the ACh binding site"

Review summarizes the established blockade mechanism.

PMID:36074148 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Direct AChR antagonism by serum constituents was independent of complement, because heat-inactivated sera showed the same results as fresh sera"

Serum perturbation supports a complement-independent effect; it does not map every serum effect to a particular epitope.

MuSK Autoantibody Binding

Predominantly IgG4 MuSK antibodies bind extracellular MuSK epitopes. This serologic branch is not confined to one adult age group and does not require complement activation as its principal mechanism.

neuromuscular junction GO:0031594

skeletal muscle tissue UBERON:0001134

Downstream

Impaired LRP4-MuSK Interaction Patient IgG4 antibodies block association between LRP4 and MuSK.

Show evidence (1 reference)

PMID:24297891 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Here we show that pathogenic IgG4 antibodies to MuSK bind to a structural epitope in the first Ig-like domain of MuSK, prevent binding between MuSK and Lrp4, and inhibit Agrin-stimulated MuSK phosphorylation."

Purified human patient antibodies were tested with recombinant proteins and cultured cells.

Impaired LRP4-MuSK Interaction

MuSK IgG4 binding impedes the agrin-dependent interaction between LRP4 and MuSK. The 2013 experiments did not show a direct effect on MuSK homodimerization or surface abundance in the engineered fibroblast context.

neuromuscular junction GO:0031594

skeletal muscle tissue UBERON:0001134

Experimental models

Patient MuSK IgG4 in Recombinant Binding and Myotube Assays OTHER Patient IgG4 reduced binding in a solid-phase recombinant-protein assay.

Downstream

Reduced Agrin-Stimulated MuSK Phosphorylation Loss of LRP4 engagement impairs agrin-induced activation of MuSK.

Show evidence (1 reference)

PMID:24297891 SUPPORT DIRECT PRIMARY RESULT In Vitro

Direct recombinant-protein binding assay.

Reduced Agrin-Stimulated MuSK Phosphorylation

MuSK-directed IgG4 reduces agrin-stimulated MuSK phosphorylation in cultured myotubes, impairing the signaling that organizes the postsynaptic receptor apparatus.

neuromuscular junction GO:0031594

skeletal muscle tissue UBERON:0001134

Experimental models

Patient MuSK IgG4 in Recombinant Binding and Myotube Assays OTHER Patient IgG4 suppressed agrin-induced MuSK phosphorylation.

Engineered MuSK Activation in 3T3 Fibroblasts CELL LINE IgG4 did not suppress LRP4-independent phosphorylation in this engineered context.

Downstream

Impaired Postsynaptic AChR Clustering Reduced MuSK signaling compromises receptor clustering through downstream postsynaptic signaling and scaffolding.

Show evidence (1 reference)

PMID:24297891 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Patient IgG4 antibodies to MuSK blocked MuSK phosphorylation"

Measured signaling response in C2 myotubes.

Impaired Postsynaptic AChR Clustering

MuSK-pathway disruption reduces proper accumulation of AChRs at the postsynaptic muscle membrane. This differs from antibody-induced crosslinking of receptors in AChR-positive disease.

neuromuscular junction GO:0031594

skeletal muscle tissue UBERON:0001134

Downstream

Reduced Surface AChR Availability Failure of physiological synaptic clustering reduces the receptor pool available at the junction.

Show evidence (1 reference)

PMID:39105625 SUPPORT DIRECT REVIEW SYNTHESIS Other

"MuSK antibodies interfere with clustering of AChR on the postsynaptic muscle surface directly opposed to the nerve terminal."

Review-supported MuSK pathway effect.

Reduced Endplate Potential Safety Margin

The margin between endplate depolarization and the threshold for a muscle action potential is reduced. Repetitive activation can then make transmission fail in individual fibers.

neuromuscular junction GO:0031594

skeletal muscle tissue UBERON:0001134

Downstream

Impaired Neuromuscular Transmission During repetitive activity, endplate depolarization can fall below the action-potential threshold.

Show evidence (1 reference)

PMID:39105625 SUPPORT DIRECT REVIEW SYNTHESIS Other

"Neuromuscular transmission failure occurs owing to a reduction in the number or activity of AChR molecules at the NMJ, leading to a decrease in the end-plate potential (EPP)."

Review connects reduced receptor number/activity to endplate potential.

Impaired Neuromuscular Transmission

Motor-nerve activation increasingly fails to elicit muscle-fiber action potentials and contraction, producing fatigable weakness in variably affected skeletal-muscle groups.

neuromuscular synaptic transmission GO:0007274

neuromuscular junction GO:0031594

skeletal muscle tissue UBERON:0001134

Animal models

Patient-Derived AChR Antibody Passive Transfer in Lewis Rats Rattus norvegicus partially recapitulates The combination caused a weakness phenotype, providing an indirect functional readout of junction injury.

Downstream

Fatigable Muscle Weakness Failure of transmission in the affected muscle group produces this clinical manifestation.

Ptosis Failure of transmission in the affected muscle group produces this clinical manifestation.

Diplopia Failure of transmission in the affected muscle group produces this clinical manifestation.

Dysphagia Failure of transmission in the affected muscle group produces this clinical manifestation.

Dysarthria Failure of transmission in the affected muscle group produces this clinical manifestation.

Generalized Muscle Weakness Failure of transmission in the affected muscle group produces this clinical manifestation.

Neck Muscle Weakness Failure of transmission in the affected muscle group produces this clinical manifestation.

Myasthenic Crisis Failure of transmission in the affected muscle group produces this clinical manifestation.

Show evidence (1 reference)

PMID:39105625 SUPPORT DIRECT REVIEW SYNTHESIS Other

"Neuromuscular fatigue, characterized by a progressive loss of force generation, occurs as increasing numbers of muscle fibers become incapable of contracting."

Shared downstream physiology of antibody-mediated MG.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

Cardiovascular 2

Thymic Follicular Hyperplasia Thymus hyperplasia HP:0010516

Show evidence (1 reference)

PMID:27273086 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"We show that among patients presenting a thymic hyperplasia with germinal centers (GC), 80 % are females"

Primary histological result; the denominator is those with hyperplasia, not all women with MG.

Thymoma HP:0100522

Show evidence (1 reference)

ORPHA:391490 SUPPORT DIRECT BACKGROUND Other

"generalized muscle weakness, and occasionally associated with thymoma."

Structured adult-onset disease record.

Digestive 1

Dysphagia HP:0002015

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK559331/ SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"causes symptoms like difficulty chewing or frequent choking, dysphagia, hoarseness, and dysarthria."

General clinical MG synthesis supports the specific bulbar symptom, without an adult-specific frequency.

Eye 2

Ptosis HP:0000508

Show evidence (1 reference)

PMID:33458590 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Ocular MG (OMG) refers to patients whose symptoms are confined to ocular muscles (levator palpebrae superioris and extraocular muscles), resulting in ptosis and diplopia; orbicularis oculi muscles are variably weak."

Names the ocular findings explicitly.

Diplopia HP:0000651

Show evidence (1 reference)

PMID:33458590 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

Names the ocular findings explicitly.

Musculoskeletal 3

Fatigable Muscle Weakness Fatigable weakness HP:0003473

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK559331/ SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"The distinguishing clinical feature of MG is the fluctuating muscle weakness that varies in severity, worsens with physical activity, and improves with rest."

Defines clinical fatigability.

Generalized Muscle Weakness HP:0003324

Show evidence (1 reference)

PMID:39105625 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"generalized MG, which involves weakness of any voluntary muscle. Generalized weakness can range from highly isolated manifestations, particularly bulbar muscles, to widespread muscle weakness"

Clarifies the clinical category.

Neck Muscle Weakness HP:0000467

Show evidence (1 reference)

PMID:33458590 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Bulbar, neck and respiratory muscles are involved with fast progression of the disease to life-threatening symptoms"

Review describes the MuSK-associated distribution.

Nervous System 1

Dysarthria HP:0001260

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK559331/ SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"causes symptoms like difficulty chewing or frequent choking, dysphagia, hoarseness, and dysarthria."

General clinical MG synthesis supports the specific bulbar symptom, without an adult-specific frequency.

Respiratory 1

Myasthenic Crisis Respiratory failure HP:0002878

Show evidence (2 references)

PMID:22476514 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Myasthenic crisis was equally common in generalized EOMG and LOMG (13 %)."

Source-specific observation; no general population frequency is assigned.

PMID:39105625 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Generalized weakness can range from highly isolated manifestations, particularly bulbar muscles, to widespread muscle weakness, including respiratory insufficiency producing respiratory failure"

Supports the respiratory-failure manifestation; the cohort quote separately supports only its source-specific crisis frequency.

Constitutional 1

Fatigue HP:0012378

Show evidence (1 reference)

PMID:39105625 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Despite resolution of manifest weakness with treatment, many patients complain of general fatigue"

Review distinguishes fatigue from manifest weakness.

Other 1

Ocular-Restricted Disease

This is a disease-distribution category, not the sign of ophthalmoplegia. It remains unbound pending a suitable distribution term.

Show evidence (1 reference)

PMID:22476514 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Ocular MG was more common in LOMG compared to EOMG (40 vs. 18 %, p = 0.021)."

Quantifies the excess of ocular-restricted disease in the late-onset subgroup.

🧬

Genetic Associations

HLA-B*08

Gene: HLA-B hgnc:4932 gene page relationship_type: SUSCEPTIBILITY

Show evidence (3 references)

PMID:23055271 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"We observed the strongest association in the HLA class I region at rs7750641"

Locates the strongest early-onset genome-wide signal in the HLA class I region.

PMID:23055271 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"By imputation and conditional analyses, HLA-B*08 proves to be the major associated allele (p = 2.87 × 10(-113) ; OR, 6.41)."

Imputation and conditional analysis support the association, without a functional antigen-presentation assay.

PMID:23055271 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"All EOMG cases included in these studies were North European and met the following criteria: 1) clinical diagnostic criteria for MG; 2) anti-AChR antibody positive; 3) no evidence of thymoma; 4) onset-age >10 years and either <40 years or <45 years with hyperplastic thymic histology."

Defines the ancestry, serotype, thymoma exclusion, and juvenile inclusion.

HLA-DRB1

Gene: HLA-DRB1 hgnc:4948 gene page relationship_type: SUSCEPTIBILITY

Show evidence (2 references)

PMID:28495048 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"HLA-DRB1*03 allele was overrepresented in the global MG. When the early-onset subgroup was considered, this association became even stronger."

Shows the class II risk allele concentrating in the early-onset subgroup.

PMID:28495048 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Regarding the late-onset subgroup, the frequency of HLA-DRB1*01 allele was higher than in the CP."

Shows a different class II allele associating with the late-onset subgroup in the same cohort.

HLA-DQA1

Gene: HLA-DQA1 hgnc:4942 gene page relationship_type: SUSCEPTIBILITY

Show evidence (3 references)

PMID:26562150 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Moreover, the strongest associations were in opposite directions from EOMG, including an OR of 0.54 for DQA1*05:01 in LOMG (P = 5.9 × 10-12) versus 2.82 in EOMG (P = 3.86 × 10-45)."

States the onset-direction reversal directly, with both effect sizes: DQA1*05:01 is protective in late-onset and predisposing in early-onset disease.

PMID:26562150 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Association and conditioning studies for the MHC region showed three distinct and largely independent association peaks for LOMG corresponding to (a) MHC class II (highest attenuation when conditioning on DQA1), (b) HLA-A and (c) MHC class III SNPs."

Three conditional association peaks were observed. Attenuation with DQA1 conditioning does not uniquely identify the causal allele or mechanism.

PMID:26562150 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"we conducted a genome-wide association study imputation of>6 million single nucleotide polymorphisms (SNPs) in 532 LOMG cases (anti-acetylcholine receptor ... antibody positive; onset age≥50 years) and 2,128 controls matched for sex and population substructure."

Defines the primary study population, AChR-antibody-positive late-onset cases with onset at age 50 or later.

TNIP1

Gene: TNIP1 hgnc:16903 relationship_type: SUSCEPTIBILITY

Show evidence (2 references)

PMID:23055271 SUPPORT INDIRECT PRIMARY RESULT Human Clinical

"These data thus implicate the TNIP1 151Ala replacement itself in EOMG pathogenesis, although without direct functional data, this remains a hypothesis to be proven."

The authors explicitly distinguish association from untested function.

PMID:26562150 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"In contrast, EOMG-associated SNPs in TNIP1 showed no association in LOMG, nor did other loci suggested for EOMG."

Absence of a detected association in this cohort is not evidence of absence in every late-onset population.

PTPN22

Gene: PTPN22 hgnc:9652 gene page relationship_type: SUSCEPTIBILITY

Show evidence (1 reference)

PMID:26562150 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Several other SNPs showed suggestive significance including rs2476601 (P = 6.5 × 10-6, OR 1.62) encoding the PTPN22 R620W variant noted in early-onset myasthenia gravis (EOMG) and other autoimmune diseases."

The late-onset association was suggestive in this study.

TNFRSF11A

Gene: TNFRSF11A hgnc:11908 gene page relationship_type: SUSCEPTIBILITY

Show evidence (2 references)

PMID:26562150 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The data confirm reported TNFRSF11A associations (rs4574025, P = 3.9 × 10-7, odds ratio [OR] 1.42)"

Supports the reported association at P=3.9×10^-7, short of the conventional 5×10^-8 threshold in this study.

PMID:34400559 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"We confirmed the previously reported MG association with TNFRSF11A (rs4369774; p=1.09×10-13, OR=1.4)."

The later meta-analysis supports the locus while not constituting an independent replication of every earlier cohort.

ZBTB10

Gene: ZBTB10 hgnc:30953 relationship_type: SUSCEPTIBILITY

Show evidence (1 reference)

PMID:26562150 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"identify a novel candidate gene, ZBTB10, achieving genome-wide significance (rs6998967, P = 8.9 × 10-10, OR 0.53)"

Genome-wide association nominates the nearby gene; the odds ratio denotes lower odds for the tested allele.

CHRNA1

Gene: CHRNA1 hgnc:1955 gene page relationship_type: SUSCEPTIBILITY

Show evidence (2 references)

PMID:39537604 SUPPORT DIRECT PRIMARY RESULT Computational

"To link loci implicated by the GWAS to protein-coding genes, we applied positional mapping, expression quantitative trait loci (eQTL), and chromatin interaction gene mapping."

Describes the gene-nomination method.

PMID:39537604 SUPPORT DIRECT PRIMARY RESULT Computational

"Four of these loci (rs6433501, rs231779, rs6861227, rs215918) only contained a single protein-coding gene (CHRNA1,CTLA4,TNIP1, TBX18)."

Names the nominated single-gene loci.

CTLA4

Gene: CTLA4 hgnc:2505 gene page relationship_type: SUSCEPTIBILITY

Show evidence (2 references)

PMID:39537604 SUPPORT DIRECT PRIMARY RESULT Computational

"To link loci implicated by the GWAS to protein-coding genes, we applied positional mapping, expression quantitative trait loci (eQTL), and chromatin interaction gene mapping."

Describes the gene-nomination method.

PMID:39537604 SUPPORT DIRECT PRIMARY RESULT Computational

"Four of these loci (rs6433501, rs231779, rs6861227, rs215918) only contained a single protein-coding gene (CHRNA1,CTLA4,TNIP1, TBX18)."

Names the nominated single-gene loci.

TBX18

Gene: TBX18 hgnc:11595 relationship_type: SUSCEPTIBILITY

Show evidence (2 references)

PMID:39537604 SUPPORT DIRECT PRIMARY RESULT Computational

"To link loci implicated by the GWAS to protein-coding genes, we applied positional mapping, expression quantitative trait loci (eQTL), and chromatin interaction gene mapping."

Describes the gene-nomination method.

PMID:39537604 SUPPORT DIRECT PRIMARY RESULT Computational

"Four of these loci (rs6433501, rs231779, rs6861227, rs215918) only contained a single protein-coding gene (CHRNA1,CTLA4,TNIP1, TBX18)."

Names the nominated single-gene loci.

AGRN

Gene: AGRN hgnc:329 gene page relationship_type: SUSCEPTIBILITY

Show evidence (1 reference)

PMID:34400559 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Furthermore, gene-based analysis revealed AGRN as a novel MG susceptibility gene."

Gene-based association; no functional mediation assay is established by the available abstract.

🗃️

External Assertions

Orphanet adult-onset myasthenia gravis record

Orphanet Structured disease record ORPHA:391490

Orphanet structured record for adult-onset myasthenia gravis, classed as a clinical subtype of myasthenia gravis, with curated cross-references to MONDO, ICD-10, ICD-11, and UMLS.

Show evidence (2 references)

ORPHA:391490 SUPPORT DIRECT BACKGROUND Other

"Adult-onset myasthenia gravis (Clinical subtype, Subtype of disorder)"

Orphanet's own typing of the concept as a clinical subtype is the honest framing for this entry's relationship to the parent myasthenia gravis entry.

ORPHA:391490 SUPPORT DIRECT BACKGROUND Other

"UMLS:C5680024 | Exact"

The Orphanet cross-reference table exactly maps ORPHA:391490 to UMLS C5680024.

💊

Medical Actions

Pyridostigmine

Category: Therapeutic Action: Pharmacotherapy NCIT:C15986

Agent: Pyridostigmine CHEBI:8665

Platform: Small molecule

Acetylcholinesterase inhibition increases acetylcholine availability for symptomatic improvement without suppressing autoantibody production. MuSK-positive patients may respond poorly or tolerate it poorly; treatment is individualized.

Mechanism Target:

MODULATES Impaired Neuromuscular Transmission — Prolongs acetylcholine availability and improves the transmission safety margin.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK559331/ SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Acetylcholinesterase inhibitors increases the level of ACh at the NMJ by preventing its enzymatic degradation."

Direct pharmacological rationale.

Show evidence (2 references)

PMID:38152089 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"For symptomatic therapy of MG, acetylcholinesterase inhibitors (AChE-I), primarily pyridostigmine, should be used."

Symptomatic recommendation.

PMID:38152089 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Patients with MuSK-Ab-positive MG may respond poorly to AChE-I and more often tolerate it poorly."

Important serotype-specific limitation.

Corticosteroids

Category: Therapeutic Action: Pharmacotherapy NCIT:C15986

Agent: prednisone CHEBI:8382

Platform: Small molecule

Glucocorticoids are basic immunotherapy for inadequately controlled ocular or generalized MG. Use the lowest effective exposure with monitoring for infection, metabolic, bone, and other toxicity; early transient worsening and comorbidity influence initiation and bridging care.

Mechanism Target:

MODULATES AChR Autoantibody Production — Broad immune suppression modifies disease activity; the clinical response does not identify a single cellular mediator.

Show evidence (1 reference)

PMID:38152089 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"GKS as monotherapy or in combination with AZA are first-choice agents for immunotherapy."

Supports disease-modifying immunotherapy.

Show evidence (1 reference)

PMID:38152089 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Oral glucocorticosteroids (GKS) should be used to treat mild/moderate to (highly) active gMG/juvenile MG (jMG) and ocular MG (oMG) as basic immunotherapeutics at doses appropriate to disease severity over the shortest possible period of time, taking into account comorbidities, contraindications,..."

Guideline frames benefit against treatment burden.

Azathioprine

Category: Therapeutic Action: Pharmacotherapy NCIT:C15986

Agent: azathioprine CHEBI:2948

Platform: Small molecule

A steroid-sparing immunosuppressant with delayed onset over months. Clinical and laboratory monitoring is necessary. Favorable outcomes in a late-onset observational cohort support applicability to older-onset patients but do not isolate a randomized combination effect.

Mechanism Target:

MODULATES AChR Autoantibody Production — Immunosuppression reduces disease activity through multiple immune processes.

Show evidence (1 reference)

PMID:38152089 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"GKS as monotherapy or in combination with AZA are first-choice agents for immunotherapy."

Disease-modifying use; no claim of selective plasma-cell removal.

Show evidence (2 references)

PMID:38152089 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Due to the slow onset of action, therapeutic success with monotherapy is not to be expected before several months have elapsed."

Delayed azathioprine response in the relevant guideline section.

PMID:31811563 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Use of prednisone + azathioprine had significantly positive effect on outcome."

Association in an observational late-onset cohort.

Cyclosporine

Category: Therapeutic Action: Pharmacotherapy NCIT:C15986

Agent: Cyclosporine NCIT:C406

Platform: Small molecule

Cyclosporine is an alternative when first-choice treatment is unsuitable. A placebo-controlled study supports efficacy, while renal, vascular, and other toxicities and comorbidity constrain use.

Mechanism Target:

MODULATES AChR Autoantibody Production — Alternative broad immunotherapy; a selective antibody-production effect is not measured in the cited clinical synthesis.

Show evidence (1 reference)

PMID:38152089 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Other immunotherapies should be considered as second-choice treatment for MG with increased disease activity and can be used when contraindications, intolerance, or inadequate response to adequate doses of standard therapy apply."

Conditional second-choice use.

Show evidence (1 reference)

PMID:38152089 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"CSA was effective in a placebo-controlled study of class 1 evidence."

Evidence and limits summarized by the guideline.

Mycophenolate Mofetil

Category: Therapeutic Action: Pharmacotherapy NCIT:C15986

Agent: Mycophenolate Mofetil NCIT:C1468

Platform: Small molecule

Mycophenolate is used as an alternative steroid-sparing therapy. Short randomized trials did not demonstrate the intended initial or steroid-sparing advantages; longer observational follow-up suggested benefit. It should not be presented as proven equivalent to azathioprine.

Mechanism Target:

MODULATES AChR Autoantibody Production — Alternative broad immunotherapy; a selective antibody-production effect is not measured in the cited clinical synthesis.

Show evidence (1 reference)

PMID:38152089 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

Conditional second-choice use.

Show evidence (1 reference)

PMID:38152089 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Long-term open-label follow-up data gave evidence of a positive effect of MMF on clinical course as well as a steroid-sparing effect."

Evidence and limits summarized by the guideline.

Tacrolimus

Category: Therapeutic Action: Pharmacotherapy NCIT:C15986

Agent: Tacrolimus NCIT:C1311

Platform: Small molecule

Tacrolimus is an alternative immunosuppressant. Two controlled trials did not confirm their steroid-sparing endpoints; post hoc score improvements provide more limited support.

Mechanism Target:

MODULATES AChR Autoantibody Production — Alternative broad immunotherapy; a selective antibody-production effect is not measured in the cited clinical synthesis.

Show evidence (1 reference)

PMID:38152089 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

Conditional second-choice use.

Show evidence (1 reference)

PMID:38152089 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Two controlled trials could not confirm a steroid-sparing effect of tacrolimus after 6 and 12 months, but a post hoc analysis of the results suggested a benefit in terms of improvement of quantitative myasthenia scores."

Evidence and limits summarized by the guideline.

Methotrexate

Category: Therapeutic Action: Pharmacotherapy NCIT:C15986

Agent: Methotrexate NCIT:C642

Platform: Small molecule

Methotrexate may be considered as a reserve immunosuppressant. Small comparative and placebo-controlled studies gave mixed steroid-sparing results, so evidence is less secure than for first-choice treatment.

Mechanism Target:

MODULATES AChR Autoantibody Production — Alternative broad immunotherapy; a selective antibody-production effect is not measured in the cited clinical synthesis.

Show evidence (1 reference)

PMID:38152089 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

Conditional second-choice use.

Show evidence (1 reference)

PMID:38152089 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"By contrast, a placebo-controlled study over 12 months failed to demonstrate a steroid-sparing effect of 20 mg MTX (p.o.)."

Evidence and limits summarized by the guideline.

Thymectomy for Nonthymomatous AChR-Positive Generalized MG

Category: Therapeutic Action: Thymectomy NCIT:C29894

Platform: Surgery

MGTX randomized 126 adults aged 18–65 with AChR-positive generalized nonthymomatous MG of less than five years duration to extended transsternal thymectomy plus prednisone or prednisone alone. Surgery improved the three-year time-weighted QMG score and reduced steroid requirements. Older adults were included; age-subgroup analyses do not establish benefit exclusively in early-onset disease. Evidence for very old patients, long-standing disease, pure ocular disease, and other surgical approaches is less direct. MuSK-positive MG without a tumor is not an immunological indication.

Mechanism Target:

INHIBITS Ectopic Thymic Germinal Center Formation — Removes the thymic tissue harboring ectopic follicles; persistent peripheral autoreactive cells can sustain disease.

Show evidence (2 references)

PMID:39105625 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"The precise mechanism by which thymus removal imparts clinical benefit is not fully understood."

Clinical benefit does not prove a single mediator.

PMID:39105625 SUPPORT INDIRECT REVIEW SYNTHESIS Human Clinical

"One likely hypothesis is that thymectomy eliminates a considerable source of antigenic stimulation, ultimately reducing the production of AChR antibodies, but autoreactive cells have exited the thymus remain and drive production of pathogenic antibodies"

Supports removal of a thymic antigenic source while qualifying the mediator and persistent peripheral activity.

Show evidence (3 references)

PMID:27509100 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Patients 18 to 65 years of age who had generalized nonthymomatous myasthenia gravis with a disease duration of less than 5 years were included"

Enrollment age is not a proof of exclusively early-onset disease.

PMID:27509100 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Patients who underwent thymectomy had a lower time-weighted average Quantitative Myasthenia Gravis score over a 3-year period than those who received prednisone alone (6.15 vs. 8.99, P<0.001)"

Randomized clinical outcome.

PMID:40022458 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Thymectomy may be a potentially effective treatment for LOMG, particularly in patients who undergo the procedure soon after diagnosis. A randomized controlled study for LOMG patients is needed."

Mostly observational meta-analysis supports continued uncertainty for a dedicated late-onset treatment effect.

Thymoma-Directed Treatment

Category: Therapeutic Action: Thymectomy NCIT:C29894

Platform: Surgery

Assess and manage thymoma according to tumor stage and operability, generally with surgical removal when feasible. This oncological indication applies independently of MG severity or onset-age category; removal does not guarantee resolution of MG.

Mechanism Target:

INHIBITS Thymoma — Resects the tumor when operable.

Show evidence (1 reference)

PMID:38152089 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Every MG patient must be evaluated for the presence of a thymoma. Thymomas must be surgically removed at any age regardless of the severity of myasthenia."

Explicit resection recommendation; the care description preserves operability exceptions.

Show evidence (1 reference)

PMID:38152089 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Every MG patient must be evaluated for the presence of a thymoma. Thymomas must be surgically removed at any age regardless of the severity of myasthenia."

Guideline recommendation, with operability and multimodal exceptions described in its surrounding text.

Rituximab

Category: Therapeutic Action: Pharmacotherapy NCIT:C15986

Agent: Rituximab NCIT:C1702

Platform: Monoclonal antibody

CD20-directed B-cell depletion is particularly supported for MuSK-positive MG. AChR-positive trial results depend on population and endpoint: BeatMG missed its primary steroid-sparing endpoint, whereas RINOMAX supported benefit in new-onset disease. Infusion, infection, and immunoglobulin risks require specialist monitoring; no efficacy ranking against other targeted drugs is inferred.

Mechanism Target:

MODULATES AChR Autoantibody Production — B-cell depletion can reduce replenishment of antibody-producing cells; long-lived plasma cells are not uniformly depleted.

Show evidence (1 reference)

PMID:38152089 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Rituximab is a monoclonal chimeric Ab that specifically binds to the marker CD20 on the membrane of pre-B and mature B lymphocytes and causes transient B-cell depletion"

The direct target is the B-cell compartment, with downstream antibody effects.

Show evidence (3 references)

PMID:38152089 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Rituximab is a monoclonal chimeric Ab that specifically binds to the marker CD20 on the membrane of pre-B and mature B lymphocytes and causes transient B-cell depletion"

Mechanism summarized in the guideline.

PMID:38152089 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Case series suggest that B-cell-depleting treatment with rituximab is effective, particularly in MuSK myasthenia, and should therefore be considered early as a first-choice treatment option as well."

Supports the particular role of rituximab in MuSK-positive MG, based on case-series evidence.

PMID:38152089 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"The recently completed randomized-controlled phase III RINOMAX trial demonstrated that patients with new-onset AChR-Ab-positive gMG on a low-dose rituximab regimen (one infusion of 500 mg) were significantly more likely to meet the primary end point of minimal disease manifestation at 16 weeks..."

New-onset trial context; not all refractory MG populations.

Eculizumab

Category: Therapeutic Action: Pharmacotherapy NCIT:C15986

Agent: Eculizumab NCIT:C48386

Platform: Monoclonal antibody

C5 inhibition for selected AChR-positive generalized MG. REGAIN missed its prespecified worst-rank primary analysis but secondary endpoints favored treatment; later use must be interpreted with its infection risks and patient selection. Meningococcal vaccination and infection precautions remain necessary; these agents do not directly stop autoantibody production.

Mechanism Target:

INHIBITS Complement Activation at the Endplate — Blocks terminal complement activity and membrane attack complex formation.

Show evidence (1 reference)

PMID:38152089 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Eculizumab is a humanized monoclonal IgG-Ab that binds to the protein C5 of the complement system and is designed to prevent the formation of the membrane attack complex induced by C5b"

Class mechanism; individual binding properties differ.

Show evidence (1 reference)

PMID:38152089 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"The primary study end point (improvement in activities of daily living measured by the so-called worst rank ANCOVA analysis) was not met; however, almost all secondary end points"

Guideline trial synthesis.

Ravulizumab

Category: Therapeutic Action: Pharmacotherapy NCIT:C15986

Agent: Ravulizumab NCIT:C124657

Platform: Monoclonal antibody

Longer-acting C5 inhibition for AChR-positive generalized MG. CHAMPION showed an improved MG-ADL primary endpoint; dosing and safety follow the applicable label. Meningococcal vaccination and infection precautions remain necessary; these agents do not directly stop autoantibody production.

Mechanism Target:

INHIBITS Complement Activation at the Endplate — Blocks terminal complement activity and membrane attack complex formation.

Show evidence (1 reference)

PMID:38152089 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"A further development of eculizumab is the complement factor 5 inhibitor ravulizumab, in which the infusion frequency of maintenance therapy is 8 weeks instead of two."

Drug-specific C5 mechanism.

Show evidence (1 reference)

PMID:38152089 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"In the phase III CHAMPION trial, 26 weeks after initiation of therapy, the primary end point (improvement in MG-ADL from baseline) was significantly better in the ravulizumab group than in the placebo group."

Guideline trial synthesis.

Zilucoplan

Category: Therapeutic Action: Pharmacotherapy NCIT:C15986

Agent: Zilucoplan NCIT:C147518

Platform: Peptide

A complement-inhibitory macrocyclic peptide for AChR-positive generalized MG. It binds C5 and also impedes C5b–C6 interaction. Its mechanism does not make it appropriate for the predominant IgG4 MuSK pathway. Meningococcal vaccination and infection precautions remain necessary; these agents do not directly stop autoantibody production.

Mechanism Target:

INHIBITS Complement Activation at the Endplate — Blocks terminal complement activity and membrane attack complex formation.

Show evidence (1 reference)

PMID:39105625 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Zilucoplan is a small macrocyclic peptide that not only binds to C5 to inhibit its cleavage, but also interferes with C5b binding to C6."

Drug-specific terminal-complement mechanism.

Show evidence (1 reference)

PMID:38152089 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Another complement factor 5 inhibitor is zilucoplan, which was successfully tested in a phase III RAISE trial in the indication MG."

Guideline trial synthesis.

Efgartigimod

Category: Therapeutic Action: Pharmacotherapy NCIT:C15986

Agent: Efgartigimod Alfa NCIT:C171817

Platform: Other

Efgartigimod reduces IgG through FcRn blockade and has randomized evidence in AChR-positive generalized MG; seronegative disease is a separate trial question.

Mechanism Target:

MODULATES AChR Autoantibody Binding — Lowers circulating IgG available to bind the junction rather than directly displacing receptor-bound antibody.

Show evidence (1 reference)

PMID:38152089 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Efgartigimod can lower the concentration of auto-Ab directed against AChR and reduce disease activity"

IgG reduction supplies an indirect link to reduced antibody exposure.

Show evidence (1 reference)

PMID:39105625 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Efgartigimod and rozanolixizumab are approved for AChR antibody–positive MG (128, 129), with the latter further approved for MuSK antibody–positive MG."

The 2024 review records the antibody-specific indications.

Rozanolixizumab

Category: Therapeutic Action: Pharmacotherapy NCIT:C15986

Agent: Rozanolixizumab NCIT:C152270

Platform: Monoclonal antibody

Rozanolixizumab is an FcRn-directed treatment for AChR- or MuSK-antibody-positive generalized MG, with phase III evidence. Antibody lowering does not guarantee response in every patient.

Mechanism Target:

MODULATES AChR Autoantibody Binding — Lowers circulating IgG available to bind the junction rather than directly displacing receptor-bound antibody.

Show evidence (1 reference)

PMID:39105625 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"This results in significant reductions in circulating antibodies within days of the initial treatment. Efgartigimod and rozanolixizumab are approved for AChR antibody–positive MG (128, 129), with the latter further approved for MuSK antibody–positive MG."

Review connects FcRn antibody lowering to the named drugs and serotype indications.

MODULATES MuSK Autoantibody Binding — Reduces IgG available to reach and bind MuSK.

Show evidence (1 reference)

PMID:39105625 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

Review connects FcRn antibody lowering to the named drugs and serotype indications.

Show evidence (1 reference)

PMID:39105625 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Efgartigimod and rozanolixizumab are approved for AChR antibody–positive MG (128, 129), with the latter further approved for MuSK antibody–positive MG."

The 2024 review records the antibody-specific indications.

Nipocalimab

Category: Therapeutic Action: Pharmacotherapy NCIT:C15986

Agent: Nipocalimab NCIT:C170891

Platform: Monoclonal antibody

FcRn-directed therapy is labeled for AChR- or MuSK-antibody-positive generalized MG, including adults. In the seropositive primary efficacy population, mean MG-ADL improvement averaged over weeks 22–24 exceeded placebo. This is no longer solely an investigational therapy. Active infection, infusion reactions, vaccination, and immunoglobulin interactions require attention; older-adult comparative data remain limited.

Mechanism Target:

MODULATES AChR Autoantibody Binding — Reduces circulating IgG and pathogenic autoantibody exposure.

Show evidence (1 reference)

url:https://www.jnjlabels.com/package-insert/product-monograph/prescribing-information/IMAAVY-pi.pdf SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Nipocalimab-aahu is a human IgG1 monoclonal antibody that binds to neonatal Fc receptor (FcRn), resulting in the reduction of circulating IgG levels."

Label pharmacology.

MODULATES MuSK Autoantibody Binding — Reduces circulating IgG and pathogenic autoantibody exposure.

Show evidence (1 reference)

url:https://www.jnjlabels.com/package-insert/product-monograph/prescribing-information/IMAAVY-pi.pdf SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Nipocalimab-aahu is a human IgG1 monoclonal antibody that binds to neonatal Fc receptor (FcRn), resulting in the reduction of circulating IgG levels."

Label pharmacology.

Show evidence (1 reference)

url:https://www.jnjlabels.com/package-insert/product-monograph/prescribing-information/IMAAVY-pi.pdf SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"IMAAVY is indicated for the treatment of generalized myasthenia gravis (gMG) in adult and pediatric patients 12 years of age and older who are anti-acetylcholine receptor (AChR) or anti-muscle-specific tyrosine kinase (MuSK) antibody positive."

Current label includes adults and either antibody subgroup.

Inebilizumab

Category: Therapeutic Action: Pharmacotherapy NCIT:C15986

Agent: Inebilizumab NCIT:C88283

Platform: Monoclonal antibody

CD19-directed cytolytic therapy is labeled for adults with AChR- or MuSK-antibody-positive generalized MG. MINT demonstrated overall MG-ADL benefit at week 26. The label describes the therapeutic mechanism as presumed; CD20 counts were used to assess B-cell depletion because the drug interferes with CD19 assays. Screen for HBV, tuberculosis and immunoglobulin deficiency, address vaccination and active infection, and monitor infusion reactions and immunoglobulins.

Mechanism Target:

MODULATES AChR Autoantibody Production — Depletes CD19-expressing B-lineage cells, with downstream effects on humoral autoimmunity.

Show evidence (1 reference)

url:https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/761142s004lbl.pdf SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Following cell surface binding to B lymphocytes, inebilizumab-cdon results in antibody-dependent cellular cytolysis."

Label describes the cellular action; complete clinical mediation is not established.

Show evidence (1 reference)

url:https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/761142s004lbl.pdf SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"UPLIZNA is indicated for the treatment of generalized myasthenia gravis (gMG) in adult patients who are anti-acetylcholine receptor (AChR) or anti-muscle specific tyrosine kinase (MuSK) antibody positive."

FDA label includes both serologic groups as alternatives.

Intravenous Immunoglobulin

Category: Therapeutic Action: Intravenous Immunoglobulin Therapy NCIT:C121331

Platform: Other

Rapid immunomodulation is used for exacerbation or crisis and selected bridging situations. Selection versus plasma exchange depends on comorbidity, access, and clinical circumstances. Maintenance use is individualized and has a different evidence base from crisis treatment.

Mechanism Target:

MODULATES Impaired Neuromuscular Transmission — Improves disease activity through immune effects; it does not mechanically replace ventilation.

Show evidence (1 reference)

PMID:38152089 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"In the treatment of myasthenic exacerbations, PE and IVIG are considered equivalent."

Guideline synthesis of comparative short-term treatment.

Show evidence (1 reference)

PMID:38152089 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"In the event of an impending and manifest myasthenic crisis, rapid admission and treatment must be provided in a monitoring or intensive care unit with experience in neuromuscular disease. IVIG or PE/IA must be used in this situation."

Urgent rescue guideline recommendation.

Plasma Exchange or Immunoadsorption

Category: Therapeutic Action: Plasmapheresis NCIT:C15304

Platform: Other

Rapid removal of circulating humoral factors is used for crisis, severe exacerbation, and selected perioperative stabilization. Benefit is temporary without continuing disease control. MuSK-positive disease may respond particularly well, although comparative serotype-specific trials are limited; vascular, coagulation, and hemodynamic risks matter in older patients.

Mechanism Target:

MODULATES AChR Autoantibody Binding — Reduces circulating pathogenic antibody available to reach the junction.

Show evidence (1 reference)

PMID:38152089 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"In this procedure, either IgG is removed semi-selectively with a tryptophan-polyvinyl gel matrix"

Immunoadsorption removes immunoglobulins; the target link concerns antibody exposure.

MODULATES MuSK Autoantibody Binding — Reduces circulating pathogenic antibody available to reach the junction.

Show evidence (1 reference)

PMID:38152089 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"In this procedure, either IgG is removed semi-selectively with a tryptophan-polyvinyl gel matrix"

Immunoadsorption removes immunoglobulins; the target link concerns antibody exposure.

Show evidence (1 reference)

PMID:38152089 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

Urgent rescue guideline recommendation.

Crisis Monitoring and Respiratory Support

Category: Therapeutic Action: Mechanical Ventilation NCIT:C70909

Platform: Device

Urgent specialist monitored or intensive care includes serial respiratory and bulbar assessment, airway protection or ventilation when necessary, treatment of precipitants, and concurrent rapid immunotherapy.

Mechanism Target:

BYPASSES Myasthenic Crisis — Ventilation supports gas exchange during severe respiratory weakness.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK559331/ SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"myasthenic crisis, an acute respiratory paralysis that requires intensive care"

Respiratory complication requiring intensive care.

Show evidence (1 reference)

PMID:38152089 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

Urgent rescue guideline recommendation.

Ocular Symptom Support

Category: Therapeutic

Platform: Device

Occlusion can relieve diplopia; selected stable small-angle deviations may benefit from prisms. Ptosis aids and, in persistent stable refractory cases, specialist surgical assessment can complement medical treatment.

Mechanism Target:

MODULATES Ptosis — Compensates for the visual consequences without correcting autoimmunity.

Show evidence (1 reference)

PMID:33458590 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Eye patches for diplopia, prisms when eye movement limitation is mild and eyelid crutches for ptosis can be useful."

Specific ocular aids.

MODULATES Diplopia — Compensates for the visual consequences without correcting autoimmunity.

Show evidence (1 reference)

PMID:33458590 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Eye patches for diplopia, prisms when eye movement limitation is mild and eyelid crutches for ptosis can be useful."

Specific ocular aids.

Show evidence (1 reference)

PMID:33458590 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Eye patches for diplopia, prisms when eye movement limitation is mild and eyelid crutches for ptosis can be useful."

Symptomatic ocular support.

Vaccination and Infection-Risk Management

Category: Therapeutic

Review vaccination and infection risks before immunotherapy. Complement inhibition requires meningococcal precautions and, where urgent initiation precludes adequate vaccine protection, antibiotic prophylaxis according to the applicable regimen. Live vaccines are generally avoided during immunotherapy. Protection is not complete after vaccination.

Show evidence (1 reference)

PMID:38152089 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"If the effectiveness of the vaccination cannot be waited for or if a vaccination success cannot be assumed due to the immunotherapy, prophylactic antibiotic therapy should be started in addition to the vaccination."

Guideline complement-inhibitor precaution.

Clinical and Treatment-Toxicity Monitoring

Category: Monitoring

Assess clinical strength, function, MG-ADL or related scales, quality of life, and treatment toxicity over time. Routine antibody titers should not substitute for clinical disease-activity assessment.

Show evidence (1 reference)

PMID:38152089 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Therefore, routine clinical use of autoantibody testing to determine disease activity cannot be recommended."

Correlation is too variable for routine activity monitoring.

Fatigue Management and Rehabilitation

Category: Therapeutic

Assess persistent fatigue separately from muscle weakness, optimize disease control and sleep, and support appropriately paced exercise, nutrition, and psychological care. Fatigue-drug evidence is limited.

Mechanism Target:

MODULATES Fatigue — Addresses contributors to perceived fatigue and function.

Show evidence (1 reference)

PMID:38152089 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Patients should be encouraged to not overprotect themselves or exert themselves beyond the limits set by MG."

Individual pacing rather than unrestricted exercise.

Show evidence (1 reference)

PMID:38152089 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Patients’ self-efficacy should be enhanced via modification of lifestyle factors, such as good sleep hygiene, balanced diet, avoidance of excessive alcohol consumption, and performance of aerobic exercise. If necessary, additional psychological support may be helpful."

Guideline supportive care.

Pregnancy and Reproductive Counseling

Category: Counseling / Informational

Arrange specialist counseling before or during pregnancy, review drug-specific fetal risks and treatment alternatives, and coordinate maternal and neonatal care. Transient neonatal disease from maternal antibody transfer is distinct from inherited congenital myasthenic syndromes.

Show evidence (2 references)

PMID:38152089 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"In case of pregnancy and a desire to have children, a specific consultation should be made in a center specialized in myasthenia."

Specialist counseling recommendation.

PMID:38152089 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Because of the risk of neonatal MG and peripartum deterioration of maternal MG, child delivery should be planned in a maximum care hospital, including those with neonatology and neuropediatric expertise and intensive care monitoring capabilities."

Supports coordinated delivery and neonatal planning.

Medication and Exacerbation Education

Category: Counseling / Informational

Review new medications for possible worsening, discuss infection and intercurrent-illness plans, and teach recognition of bulbar or respiratory deterioration. Medication risk is contextual and should not be replaced by a blanket prohibition of every drug reported to worsen MG.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK559331/ SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"take their medications as directed and to avoid taking new medicines without checking with the medical provider."

Medication review and adherence advice.

🔬

Biochemical Markers

Anti-Acetylcholine Receptor Antibody

Context: AChR antibodies are diagnostically useful in a compatible clinical presentation. Detection rates vary with clinical distribution, assay, and cohort; antibody concentration does not reliably quantify current disease activity.

Show evidence (1 reference)

PMID:22476514 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Anti-AChR antibody titers were elevated in 78 % of patients (65 % with EOMG vs. 85 % with LOMG; p = 0.003)"

Gives the onset-stratified seropositivity rates in a single cohort tested identically.

Anti-Titin Antibody

Context: Titin antibodies are associated with older onset and thymoma in selected cohorts, but are not established causes of neuromuscular transmission failure. A retrospective series found an association with generalized disease within its late-onset subgroup; this is not a validated prediction of progression.

Show evidence (2 references)

PMID:31811563 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"In 95 patients with generalized non-thymomatous LOMG, 60 (63%) were men, 45 (47%) had mild disease, 80 (84%) were anti-AChR, and 56 (61%) were anti-titin positive."

Quantifies anti-titin seropositivity at 61% in generalized non-thymomatous late-onset disease.

PMID:38505076 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Anti-titin positivity was significantly associated with generalized MG in the late-onset group (P=0.005)."

Establishes the late-onset-specific clinical correlate of anti-titin positivity.

Anti-Ryanodine Receptor Antibody

Context: RyR reactivity occurs in MG with striational autoimmunity, but the 2019 cell-based assay also detected substantial reactivity in disease controls and healthy controls. It is neither diagnostic of late-onset MG nor proof of pathogenicity.

Show evidence (2 references)

PMID:30918333 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"MG patients with myositis and/or myocarditis as well as late-onset and thymoma-associated MG had anti-titin, anti-ryanodine receptor, and anti-Kv1.4 antibodies."

Places anti-ryanodine-receptor antibody within the striational panel of late-onset and thymoma-associated disease.

PMID:30918333 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"In contrast, patients with early-onset MG, those with other myopathies and healthy controls did not have anti-titin or anti-Kv1.4 antibodies with some exceptions, but they possessed anti-ryanodine receptor antibodies."

The control reactivity supports the stated specificity limitation.

Anti-MuSK Antibody

Context: MuSK antibodies identify an antibody-mediated subgroup with different effector mechanisms and treatment responses. Negative AChR serology alone does not establish MuSK disease.

Show evidence (1 reference)

PMID:33458590 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Anti-MuSK antibodies are extremely rare in MG with prolonged pure ocular symptoms."

Subtype and clinical-distribution context, not a universal frequency.

🔬

Diagnosis

Clinical assessment with confirmatory testing

Identify fatigable, fluctuating weakness and its ocular, bulbar, respiratory, axial, or limb distribution. Confirm a compatible syndrome with antibody testing and/or neuromuscular electrophysiology; exclude mimics when the pattern or treatment response is atypical.

Show evidence (1 reference)

PMID:38152089 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"The diagnosis of MG is based on the history and physical findings of fatigable and fluctuating muscle weakness. The diagnosis is confirmed by positive findings in auto-Ab diagnostics and/or electrophysiology and/or pharmacological testing."

Guideline diagnostic framework.

Serological subtyping

Test AChR and, where appropriate, MuSK and other antibodies using validated assays. Cell-based AChR testing can identify some conventionally seronegative patients. LRP4 and striational antibody findings require clinical context; they do not independently establish MG.

Show evidence (2 references)

PMID:39105625 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Recently, cell-based assays have been developed with plasma membrane expression of the AChR, allowing the antigen to resemble the native receptor more closely"

Describes improved antigen presentation.

PMID:39105625 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Antibodies against lipoprotein receptor–related protein 4 (LRP-4) may be found associated with the MuSK or AChR antibodies or in isolation, although they are also present in patients with motor neuron disease and patients without evidence of diseases"

LRP4 antibodies also occur in motor neuron disease and in people without disease, which is why LRP4 findings require clinical context.

Repetitive nerve stimulation and single-fiber electromyography

Electrophysiology supports impaired neuromuscular transmission, especially when serology is negative. Sensitivity depends on muscles tested and phenotype. SFEMG is sensitive but nonspecific; abnormal limb jitter in ocular MG does not by itself prove clinical generalization.

Show evidence (2 references)

PMID:33458590 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Repetitive nerve stimulation is not very useful with purely ocular symptoms. Single fiber EMG is very sensitive, but one has to be careful remembering that it is not specific to MG"

Test-specific limitations.

PMID:33458590 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Presence of abnormalities in limb muscles of a patient with OMG does not indicate generalization"

Clinical distribution cannot be inferred solely from abnormal limb jitter.

Thymoma assessment

Evaluate the mediastinum with chest imaging for thymoma. A negative striational-antibody test does not replace imaging.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK559331/ SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Chest computed tomography (CT) or magnetic resonance imaging (MRI) should be performed in patients diagnosed with MG to assess for thymoma."

Explicit imaging recommendation.

Review of seronegative and atypical presentations

Consider congenital myasthenic syndromes, other neuromuscular disorders, and structural ocular or brainstem causes when appropriate. Adult presentation does not exclude a congenital myasthenic syndrome; genetic testing addresses that differential, not routine confirmation of autoimmune MG.

Show evidence (2 references)

PMID:38152089 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"An important, although rare, differential diagnosis of autoimmune myasthenic syndromes – not only in children but also in adults – is the congenital myasthenic syndromes"

Adult differential diagnosis.

PMID:38152089 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"If CMS is suspected, molecular genetic diagnostics must be performed to confirm the diagnosis and plan therapy."

Genetic testing is conditional on a suspected inherited syndrome.

📈

Progression

Adult onset and fluctuating course

Age: Adulthood

Symptoms fluctuate with activity and over time. Early-, late-, and very-late-onset cutoffs vary across studies and do not define obligatory thymic pathology.

Show evidence (1 reference)

PMID:39105625 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"The hallmark of MG is muscle fatigue with a degree of weakness that can fluctuate over minutes and vary in severity over weeks to months."

Describes the variable course.

Ocular disease and possible generalization

Ocular disease may remain restricted or progress to nonocular weakness. Generalization is most often observed within the first two years but can occur later; electrophysiological abnormalities alone do not define clinical generalization.

Show evidence (2 references)

PMID:33458590 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Generalization usually occurs within one year, mostly within 2 years and it is uncommon after 2 years"

Timing is a common pattern, not an absolute two-year cutoff.

PMID:33458590 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Myasthenia generalized after 2 years in another small group of patients."

Primary cohort observations in the review document later progression.

Exacerbation and crisis

Respiratory or severe bulbar weakness can deteriorate rapidly and require monitored or intensive care. Infection, intercurrent illness, medication effects, and withdrawal of effective treatment can precipitate worsening.

Show evidence (2 references)

PMID:38152089 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"In the event of an impending and manifest myasthenic crisis, rapid admission and treatment must be provided in a monitoring or intensive care unit with experience in neuromuscular disease."

Guideline defines the urgent care setting.

PMID:38152089 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Abrupt discontinuation of immunotherapy in an insufficiently stabilized state is risky and should be avoided as it may lead to the recurrence of myasthenic symptoms and can escalate to a myasthenic crisis."

Treatment withdrawal is a potentially preventable precipitant.

🌍

Epidemiology

Increasing late-onset incidence in a Danish population

A population study of nonthymomatous AChR-seropositive MG in Denmark during 1970–1999 found stable early-onset incidence and rising late-onset incidence. These historical, serotype-specific rates are not a contemporary global incidence estimate for all adult-onset MG.

Show evidence (1 reference)

PMID:16186537 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The mean annual incidence rate of early-onset MG was constant at 3.5 x 10(-6). In late-onset MG, the rate increased from 4.7 to 20.8 x 10(-6)."

Historical population observation; not proof of a particular environmental cause.

Contemporary MG prevalence context

A 2025 epidemiology review summarizes approximately 20 incident cases per million person-years and 25 prevalent cases per 100,000 for MG overall. These are not measured adult-onset-only estimates. Population aging, improved ascertainment, and survival contribute to increasing prevalence.

Show evidence (2 references)

PMID:40675734 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Recent high-quality studies have found an annual MG incidence of approximately 20 per million person-years, and a prevalence of approximately 25 per 100,000 population."

All-MG context, deliberately not encoded as a prevalence band for this subtype.

PMID:40675734 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"MG prevalence has increased in recent years because of more elderly people in the general population, improved case finding, and improved MG treatment with reduced mortality."

The review identifies multiple contributors rather than a single biological cause.

📊

Related Datasets

Thymic B lineage cell landscape in Myasthenia gravis geo:GSE233180

Single-cell transcriptome and BCR data from immunotherapy-naive AChR-positive early-onset MG thymi. Twelve patients were recruited; one sample failed quality control, and the final reported atlas comprised 29,688 cells from 11 patients. Repository sample records and recruited patients are not interchangeable denominators.

SINGLE CELL RNA SEQ

PMID:40117520

Accession verified with just verify-datasets; the per-record GEO cache is the verification artifact. Cell trajectories and MIF–CD74 communication are computational inferences, not lineage-tracing or signaling-intervention experiments.

Show evidence (3 references)

GEO:GSE233180 SUPPORT DIRECT BACKGROUND Human Clinical

"Here, we provide a comprehensive and unbiased atlas of hematopoietic cell colonization in thymi derived from 12 immunotherapy-naïve patients with early-onset AChR-Ab+ MG (EOMG) using single-cell RNA sequencing (scRNA‑seq)."

Repository record describes the recruited dataset.

PMID:40117520 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"After enrichment for CD45+ hematopoietic cells, we profiled 29,688 individual cells and annotated 15 distinct populations"

Primary atlas after quality-control exclusions.

PMID:40117520 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"We constructed a single cell-based transcriptional profile of lymphoid cell types in thymi from 11 immunotherapy-naïve patients with EOMG."

States the 11-patient analyzed denominator, distinct from the 12 recruited samples in the repository record.

🔬

Clinical Trials

NCT00294658 PHASE_III COMPLETED

MGTX compared extended transsternal thymectomy plus standardized prednisone with prednisone alone in 126 adults with generalized nonthymomatous AChR-positive MG of less than five years duration. The three-year randomized results support clinical benefit and steroid sparing. Enrollment age 18–65 included older adults; this is not a dedicated, adequately powered very-late-onset trial.

Target Phenotypes: Generalized Muscle Weakness HP:0003324

Show evidence (2 references)

clinicaltrials:NCT00294658 SUPPORT DIRECT BACKGROUND Human Clinical

"The purpose of this trial is to determine if thymectomy combined with prednisone therapy is more beneficial in treating non-thymomatous myasthenia gravis than prednisone therapy alone."

Registry design statement; not clinical outcome evidence.

PMID:27509100 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Patients who underwent thymectomy had a lower time-weighted average Quantitative Myasthenia Gravis score over a 3-year period than those who received prednisone alone (6.15 vs. 8.99, P<0.001)"

Primary randomized clinical outcome.

NCT04524273 PHASE_III ACTIVE_NOT_RECRUITING

MINT tested inebilizumab against placebo with background therapy in 238 adults, including 190 AChR-positive and 48 MuSK-positive participants. The primary pooled week-26 MG-ADL endpoint favored treatment by 1.9 points. The randomized periods differed by serotype, with an extension; an active registry status does not mean the published primary outcome is pending.

Target Phenotypes: Generalized Muscle Weakness HP:0003324

Show evidence (2 references)

clinicaltrials:NCT04524273 SUPPORT DIRECT BACKGROUND Human Clinical

"Randomized, double-blind, placebo-controlled, Phase 3, parallel-group study with optional open-label extension."

Registry design statement; not clinical outcome evidence.

url:https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/761142s004lbl.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"A statistically significant difference favoring UPLIZNA was observed in the mean change from baseline in MG-ADL total score (−4.2 points in the UPLIZNA-treated group compared to −2.2 points for placebo, difference of −1.9, 95% CI: −2.9, −1.0; p-value < 0.0001)."

Label reports the primary pooled trial outcome.

NCT03971422 PHASE_III COMPLETED

MycarinG was the phase III randomized placebo-controlled evaluation of rozanolixizumab in adult generalized MG. The trial and subsequent indication concern antibody-defined generalized disease, not proof of equal efficacy across onset-age strata.

Target Phenotypes: Generalized Muscle Weakness HP:0003324

Show evidence (1 reference)

clinicaltrials:NCT03971422 SUPPORT DIRECT BACKGROUND Human Clinical

"The purpose of the MycarinGstudy is to demonstrate the clinical efficacy and to assess safety and tolerability of rozanolixizumab in patients with generalized myasthenia gravis (MG)."

Registry design statement; not clinical outcome evidence.

NCT04951622 PHASE_III RECRUITING

Vivacity-MG3 randomized 196 adults to nipocalimab or placebo; the primary efficacy population comprised 153 seropositive participants. MG-ADL change averaged over weeks 22–24 favored nipocalimab by 1.5 points. Registry recruitment status includes the continuing study and should not be read as absence of completed primary efficacy results.

Target Phenotypes: Generalized Muscle Weakness HP:0003324

Show evidence (2 references)

clinicaltrials:NCT04951622 SUPPORT DIRECT BACKGROUND Human Clinical

"The purpose of this study is to evaluate the efficacy and safety of nipocalimab compared to placebo in participants with generalized myasthenia gravis (gMG)."

Registry design statement; not clinical outcome evidence.

url:https://www.jnjlabels.com/package-insert/product-monograph/prescribing-information/IMAAVY-pi.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The primary efficacy endpoint was the comparison of the mean change from baseline to Weeks 22, 23, and 24 between treatment groups in the MG-ADL total score."

Defines the averaged primary endpoint.

NCT06298552 PHASE_III ACTIVE_NOT_RECRUITING

Phase III ADAPT SERON tests intravenous efgartigimod against placebo in AChR-binding-antibody-seronegative generalized MG, followed by an open-label period. The registry summary describes design and does not establish efficacy or a regulatory indication in all seronegative patients.

Target Phenotypes: Generalized Muscle Weakness HP:0003324

Show evidence (1 reference)

clinicaltrials:NCT06298552 SUPPORT DIRECT BACKGROUND Human Clinical

"The primary purpose of this study is to measure the efficacy and safety of efgartigimod IV compared to placebo in participants with Acetylcholine Receptor Binding Antibody (AChR-Ab) seronegative Generalized Myasthenia Gravis (gMG). The study consists of a Part A where participants will be..."

Registry design statement; not clinical outcome evidence.

NCT06193889 PHASE_II RECRUITING

KYSA-6 evaluates autologous anti-CD19 CAR T cells against ongoing standard immunosuppressive care in generalized MG. The registry calls this a phase 2/3 open-label randomized study. It remains an investigational cellular strategy; the summary supplies no outcome estimate or proof of superiority.

Target Phenotypes: Generalized Muscle Weakness HP:0003324

Show evidence (1 reference)

clinicaltrials:NCT06193889 SUPPORT DIRECT BACKGROUND Human Clinical

"A Study of the Anti-CD 19 Chimeric Antigen Receptor T Cell Therapy for Patients with Myasthenia Gravis"

Registry design statement; not clinical outcome evidence.

NCT06414954 PHASE_II RECRUITING

Phase IIb dose-ranging evaluation of NMD670 versus placebo over 21 days in adults with AChR- or MuSK-antibody-positive MG. The registry summary supplies trial design, not a demonstrated treatment benefit.

Target Phenotypes: Generalized Muscle Weakness HP:0003324

Show evidence (1 reference)

clinicaltrials:NCT06414954 SUPPORT DIRECT BACKGROUND Human Clinical

"This Phase 2 proof-of-concept, dose range finding study aims to evaluate the safety and efficacy of 3 dose levels of NMD670 vs placebo in adult patients with MG with antibodies against AChR or MuSK, administered twice a day (BID) for 21 days."

Registry design statement; not clinical outcome evidence.

🧫

Experimental Models

AChR-Transfected HEK Antibody-Combination Assays CELL_LINE

Complement deposition and live-cell receptor clustering were measured after exposure to individual antibodies or equal-total-concentration combinations. Epitope combinations showed synergy in the tested panel. The proposed two-dimensional receptor-antibody lattice is a hypothesis; imaging of surface clustering does not itself quantify internalization or prove a universal requirement for multiple epitopes in patients.

Cell source

Transfected HEK cells with recombinant AChR and patient-derived monoclonal antibodies

Publication

PMID:36074148

Pathograph links

Complement Activation at the Endplate partially recapitulates fidelity: moderate observes: cellular Selected antibody combinations increased C3 deposition on receptor-expressing cells.

Limitations: Transfected cells lack a mature neuromuscular endplate and endogenous autoimmunity.

Readouts

Cell-associated C3 fluorescence

Direction: INCREASED

Interpretation: Selected antibody combinations increased C3 deposition on receptor-expressing cells.

Show evidence (1 reference)

PMID:36074148 SUPPORT DIRECT PRIMARY RESULT In Vitro

"The combination of dG101 and eG101, each at half the concentration (i.e., same final concentration as the previously tested single antibodies), and each with negligible ability to activate complement alone, induced strong complement activation"

Direct complement assay.

Show evidence (1 reference)

PMID:36074148 SUPPORT DIRECT PRIMARY RESULT In Vitro

Direct complement assay.

AChR Crosslinking partially recapitulates fidelity: moderate observes: cellular Antibody pairs increased visible receptor clustering.

Limitations: Clustering supports crosslinking but does not resolve molecular lattice structure or internalization.

Readouts

Surface AChR cluster size and number

Direction: INCREASED

Interpretation: Antibody pairs increased visible receptor clustering.

Show evidence (1 reference)

PMID:36074148 SUPPORT DIRECT PRIMARY RESULT In Vitro

"None of the single antibodies had any significant effect on the distribution of the receptor. Combinations of antibodies such as aG112 and bG402, on the other hand, mediated strong clustering"

Direct live-cell localization readout.

Show evidence (1 reference)

PMID:36074148 SUPPORT DIRECT PRIMARY RESULT In Vitro

"None of the single antibodies had any significant effect on the distribution of the receptor. Combinations of antibodies such as aG112 and bG402, on the other hand, mediated strong clustering"

Direct live-cell localization readout.

Human iPSC-Derived Neuromuscular Coculture with MG Sera IPSC_DERIVED_MODEL

Neuronal AMPA stimulation and myotube calcium imaging assessed functional transmission after serum exposure. MG sera inhibited the response after heat inactivation, supporting a complement-independent component. The six cloned antibodies and their tested combinations did not reproduce direct blockade. The assay tests serum effects in an engineered junction, not spontaneous adult-onset autoimmunity or the precise blocking epitope.

Cell source

Adult-fibroblast-derived iPSCs differentiated into MYOD-induced myotubes and NGN2-induced neurons

Publication

PMID:36074148

Pathograph links

AChR Functional Blockade partially recapitulates fidelity: moderate observes: cellular Patient sera reduced the stimulation-evoked myotube response independently of active complement.

Limitations: Calcium activity is an integrated functional readout; individual serum constituents and blocking epitopes remain unresolved.

Readouts

AMPA-evoked myotube calcium response

Direction: DECREASED

Interpretation: Patient sera reduced the stimulation-evoked myotube response independently of active complement.

Show evidence (1 reference)

PMID:36074148 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Direct AChR antagonism by serum constituents was independent of complement, because heat-inactivated sera showed the same results as fresh sera"

Direct serum perturbation in the coculture.

Show evidence (1 reference)

PMID:36074148 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Direct AChR antagonism by serum constituents was independent of complement, because heat-inactivated sera showed the same results as fresh sera"

Direct serum perturbation in the coculture.

Patient MuSK IgG4 in Recombinant Binding and Myotube Assays OTHER

IgG4 fractions from seven patients blocked recombinant LRP4–MuSK binding in a dose-dependent manner, whereas matched IgG1–3 and control antibodies had smaller effects. Patient IgG4 also inhibited agrin-stimulated MuSK phosphorylation in C2 myotubes. The broader cohort included 25 Dutch patients; this does not establish identical epitope or isotype behavior in every population.

Cell source

Purified antibodies from patients; recombinant LRP4/MuSK proteins; cultured C2 myotubes

Publication

PMID:24297891

Pathograph links

Impaired LRP4-MuSK Interaction partially recapitulates fidelity: moderate observes: molecular Patient IgG4 reduced binding in a solid-phase recombinant-protein assay.

Limitations: Purified binding systems isolate this interaction but lack the intact human junction.

Readouts

LRP4–MuSK binding

Direction: DECREASED

Interpretation: Patient IgG4 reduced binding in a solid-phase recombinant-protein assay.

Show evidence (1 reference)

PMID:24297891 SUPPORT DIRECT PRIMARY RESULT In Vitro

"IgG4 autoantibodies from all MuSK MG patients strongly inhibited binding between Lrp4 and MuSK, reducing binding by as much as 80–100%, in a dose-dependent manner"

Binding experiment with IgG4 fractions from seven tested patients.

Show evidence (1 reference)

PMID:24297891 SUPPORT DIRECT PRIMARY RESULT In Vitro

"IgG4 autoantibodies from all MuSK MG patients strongly inhibited binding between Lrp4 and MuSK, reducing binding by as much as 80–100%, in a dose-dependent manner"

Binding experiment with IgG4 fractions from seven tested patients.

Reduced Agrin-Stimulated MuSK Phosphorylation partially recapitulates fidelity: moderate observes: cellular Patient IgG4 suppressed agrin-induced MuSK phosphorylation.

Limitations: C2 myotubes are a cultured mouse-cell system exposed to human antibodies.

Readouts

MuSK tyrosine phosphorylation

Direction: DECREASED

Interpretation: Patient IgG4 suppressed agrin-induced MuSK phosphorylation.

Show evidence (1 reference)

PMID:24297891 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Patient IgG4 antibodies to MuSK blocked MuSK phosphorylation"

Direct phosphorylation assay.

Show evidence (1 reference)

PMID:24297891 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Patient IgG4 antibodies to MuSK blocked MuSK phosphorylation"

Direct phosphorylation assay.

Engineered MuSK Activation in 3T3 Fibroblasts CELL_LINE

MuSK L746M/S747T enabled phosphorylation in the nonmuscle context. Patient IgG4 did not reduce this LRP4-independent activation or MuSK surface expression. These are engineered assay substitutions, not patient pathogenic variants. The phosphorylation result indirectly constrains a direct dimerization-blocking explanation; it is not a direct measurement of MuSK–MuSK binding.

Cell source

3T3 fibroblasts expressing an engineered MuSK activation-loop mutant without LRP4

Publication

PMID:24297891

Pathograph links

Reduced Agrin-Stimulated MuSK Phosphorylation measures fidelity: moderate observes: cellular IgG4 did not suppress LRP4-independent phosphorylation in this engineered context.

Limitations: The system deliberately lacks the agrin–LRP4 step, so its negative result does not refute inhibition in myotubes.

Readouts

LRP4-independent MuSK phosphorylation

Direction: UNCHANGED

Interpretation: IgG4 did not suppress LRP4-independent phosphorylation in this engineered context.

Show evidence (1 reference)

PMID:24297891 SUPPORT DIRECT PRIMARY RESULT In Vitro

"IgG4 antibodies from MuSK MG patients fail to reduce MuSK phosphorylation in 3T3 cells transfected with MuSK but not Lrp4."

Context-specific negative phosphorylation result.

Show evidence (1 reference)

PMID:24297891 SUPPORT DIRECT PRIMARY RESULT In Vitro

"IgG4 antibodies from MuSK MG patients fail to reduce MuSK phosphorylation in 3T3 cells transfected with MuSK but not Lrp4."

Context-specific negative phosphorylation result.

🐁

Animal Models

Patient-Derived AChR Antibody Passive Transfer in Lewis Rats Passive antibody transfer

A single injection of aG101 plus bG402-G1 induced weakness, complement deposition, receptor loss, and junction fragmentation. Total antibody dose was matched to individual-antibody arms; behavior was assessed in 6–7 animals per group pooled from two experiments. A separate early histology cohort assessed complement and morphology. Single antibodies did not produce the overt behavioral phenotype, although aG101 alone increased C3 staining.

Species

Rattus norvegicus

Background

Four-week-old female Lewis rats

Publication

PMID:36074148

Pathograph links

Complement Activation at the Endplate partially recapitulates fidelity: moderate observes: cellular The antibody combination increased junctional C3 staining beyond either control or aG101 alone.

Limitations: Acute passive transfer into four-week-old female Lewis rats bypasses human loss of tolerance and antibody production. bG402 was artificially switched from IgG4 to IgG1. The model does not test aging, late-onset initiation, chronic disease, or MuSK autoimmunity.

Readouts

Junctional C3 immunofluorescence

Direction: INCREASED

Interpretation: The antibody combination increased junctional C3 staining beyond either control or aG101 alone.

Show evidence (1 reference)

PMID:36074148 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Animals given aG101 alone had significantly more C3 labeling than control treated animals but significantly less than animals given the combination of aG101 and bG402-G1"

Measured C3 deposition at the neuromuscular junction.

Show evidence (1 reference)

PMID:36074148 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Animals given aG101 alone had significantly more C3 labeling than control treated animals but significantly less than animals given the combination of aG101 and bG402-G1"

Measured C3 deposition at the neuromuscular junction.

Reduced Surface AChR Availability partially recapitulates fidelity: moderate observes: cellular The combination reduced receptor-associated alpha-bungarotoxin signal at endplates.

Readouts

AChR-to-presynaptic staining ratio

Direction: DECREASED

Interpretation: The combination reduced receptor-associated alpha-bungarotoxin signal at endplates.

Show evidence (1 reference)

PMID:36074148 SUPPORT DIRECT PRIMARY RESULT Model Organism

"This analysis revealed a significant loss of AChR content on the postsynaptic membrane in rats injected with the combination of both antibodies compared to vehicle controls, or to animals given single antibodies"

Measured receptor-associated staining after passive transfer.

Show evidence (1 reference)

PMID:36074148 SUPPORT DIRECT PRIMARY RESULT Model Organism

Measured receptor-associated staining after passive transfer.

Impaired Neuromuscular Transmission partially recapitulates fidelity: moderate observes: organism The combination caused a weakness phenotype, providing an indirect functional readout of junction injury.

Readouts

Rotarod performance

Direction: DECREASED

Interpretation: The combination caused a weakness phenotype, providing an indirect functional readout of junction injury.

Show evidence (1 reference)

PMID:36074148 SUPPORT INDIRECT PRIMARY RESULT Model Organism

"single antibodies had no significant effect on clinical score or rotarod performance, but the combination of the two antibodies was potently pathogenic"

Combination-dependent behavioral phenotype in this tested antibody panel.

Show evidence (1 reference)

PMID:36074148 SUPPORT INDIRECT PRIMARY RESULT Model Organism

"single antibodies had no significant effect on clinical score or rotarod performance, but the combination of the two antibodies was potently pathogenic"

Combination-dependent behavioral phenotype in this tested antibody panel.

Acute passive transfer into four-week-old female Lewis rats bypasses human loss of tolerance and antibody production. bG402 was artificially switched from IgG4 to IgG1. The model does not test aging, late-onset initiation, chronic disease, or MuSK autoimmunity.

Show evidence (1 reference)

PMID:36074148 SUPPORT DIRECT PRIMARY RESULT Model Organism

"single antibodies had no significant effect on clinical score or rotarod performance, but the combination of the two antibodies was potently pathogenic"

Combination-dependent behavioral phenotype in this tested antibody panel.

{ }

Source YAML

click to show

name: Adult-Onset Myasthenia Gravis
creation_date: '2026-08-19T09:00:00Z'
description: Adult-onset myasthenia gravis is acquired autoimmune disease beginning in adulthood, with fluctuating, fatigable skeletal-muscle weakness caused by impaired postsynaptic neuromuscular transmission. Onset-age groups overlap with antibody-defined and thymic subgroups. Early-onset AChR-positive disease often has thymic follicular hyperplasia, whereas late-onset disease more often accompanies an involuted thymus and striational antibodies. These are population patterns, not obligatory features or established distinct initiating mechanisms. AChR antibodies can activate complement, accelerate receptor loss, or interfere with receptor function; predominantly IgG4 MuSK antibodies impair receptor-clustering signals through a different mechanism. Treatment depends on antibody status, clinical activity, thymic pathology, comorbidity, and age.
category: Autoimmune
synonyms:
- adult-onset acquired myasthenia
- adult-onset autoimmune myasthenia gravis
parents:
- Myasthenia Gravis
- Neuromuscular Disease
- Autoimmune Disease
disease_term:
  preferred_term: adult-onset myasthenia gravis
  term:
    id: MONDO:0018324
    label: adult-onset myasthenia gravis
notes: 'This entry covers adult-onset autoimmune MG, complementing the broader Myasthenia Gravis entry. Adult onset is not synonymous with onset after puberty: juvenile cohorts include postpubertal patients below 18 years. Studies use different early/late boundaries, commonly 40–50 years; very-late-onset disease is a subset of late-onset disease, often defined from 65 years. Some cited early-onset cohorts include adolescents, and trials enrolling adults do not necessarily establish adult age at disease onset. Age categories are clinical strata, not causal exposures. Shared antibody mechanisms and care are included where needed to explain the adult presentation and treatment choices.'
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0018324
      label: adult-onset myasthenia gravis
    mapping_predicate: skos:exactMatch
    mapping_source: ORPHA:391490
    mapping_justification: Orphanet lists MONDO:0018324 as an exact cross-reference for ORPHA:391490.
    consistency:
    - reference: ORPHA:391490
      consistent: CONSISTENT
      notes: MONDO:0018324 | Exact
  - term:
      id: MONDO:0009688
      label: myasthenia gravis
    mapping_predicate: skos:broadMatch
    mapping_source: ORPHA:391490
    mapping_justification: Orphanet classes ORPHA:391490 as a clinical subtype of a disorder, and MONDO asserts MONDO:0018324 is_a MONDO:0009688; the general myasthenia gravis concept is therefore broader than this entry. Curated as `skos:broadMatch` so it is not mistaken for a mapping that would retire MONDO:0009688 from the curation queue — that concept is curated separately in `Myasthenia_Gravis.yaml`.
  icd10cm_mappings:
  - term:
      id: ICD10CM:G70.0
      label: Myasthenia gravis
    mapping_predicate: skos:broadMatch
    mapping_source: ORPHA:391490
    mapping_justification: Orphanet records ICD-10 G70.0 as a *narrower* cross-reference direction for ORPHA:391490 — i.e. the ORPHA subtype is narrower than the ICD code — so from this entry's perspective the ICD code is the broader concept.
    consistency:
    - reference: ORPHA:391490
      consistent: CONSISTENT
      notes: ICD-10:G70.0 | Narrower
definitions:
- name: Orphanet disease definition
  definition_type: CASE_DEFINITION
  description: 'Orphanet defines adult-onset myasthenia gravis as a rare autoimmune disorder of the neuromuscular junction with fatigable muscle weakness, frequent ocular signs and/or generalized weakness, and occasional thymoma association.

    '
  evidence:
  - reference: ORPHA:391490
    reference_title: Adult-onset myasthenia gravis
    supports: SUPPORT
    evidence_source: OTHER
    snippet: A rare autoimmune disorder of the neuromuscular junction characterized by fatigable muscle weakness with frequent ocular signs and/or generalized muscle weakness, and occasionally associated with thymoma.
    explanation: Orphanet's definition for the adult-onset subtype anchors the scope of this entry.
    quote_role: BACKGROUND
    directness: DIRECT
external_assertions:
- name: Orphanet adult-onset myasthenia gravis record
  source: Orphanet
  assertion_type: Structured disease record
  external_id: ORPHA:391490
  url: http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=391490
  description: 'Orphanet structured record for adult-onset myasthenia gravis, classed as a clinical subtype of myasthenia gravis, with curated cross-references to MONDO, ICD-10, ICD-11, and UMLS.

    '
  evidence:
  - reference: ORPHA:391490
    reference_title: Adult-onset myasthenia gravis
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Adult-onset myasthenia gravis (Clinical subtype, Subtype of disorder)
    explanation: Orphanet's own typing of the concept as a clinical subtype is the honest framing for this entry's relationship to the parent myasthenia gravis entry.
    quote_role: BACKGROUND
    directness: DIRECT
  - reference: ORPHA:391490
    reference_title: Adult-onset myasthenia gravis
    supports: SUPPORT
    evidence_source: OTHER
    snippet: UMLS:C5680024 | Exact
    explanation: The Orphanet cross-reference table exactly maps ORPHA:391490 to UMLS C5680024.
    quote_role: BACKGROUND
    directness: DIRECT
has_subtypes:
- name: EOMG
  display_name: Early-Onset MG (onset before ~50 years)
  description: Adult-onset disease before the study-specific late-onset boundary, commonly 50 years. Female predominance and follicular thymic hyperplasia are especially associated with AChR-positive early-onset cohorts. Research labeled EOMG may include juvenile cases, so its results are not automatically adult-specific.
  subtype_term:
    preferred_term: early-onset myasthenia gravis
  evidence:
  - reference: PMID:40675735
    reference_title: 'Special populations in myasthenia gravis: Early, late, and very late-onset MG.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: EOMG often presents with distinct immunological and genetic profiles, a predominance of female patients, and a higher incidence of thymic hyperplasia.
    explanation: Defines the early-onset subgroup by its immunogenetic profile, sex skew, and thymic pathology.
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
- name: LOMG
  display_name: Late-Onset MG (onset at or after ~50 years)
  description: Disease beginning at or beyond the study-specific late-onset boundary, commonly 50 years. AChR-positive disease, male predominance, ocular presentation, and anti-titin antibodies are relatively enriched in several cohorts. An atrophic thymus is common but does not prove immunological inactivity or an exclusively extrathymic origin.
  subtype_term:
    preferred_term: late-onset myasthenia gravis
  evidence:
  - reference: PMID:33458590
    reference_title: 'Myasthenia gravis: MuSK MG, late-onset MG and ocular MG.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: LOMG with onset ≥ 50 years of age is more common in men and ocular onset is common. Frequency of anti-AChR and anti-titin antibodies are high.
    explanation: Gives the conventional ≥50-year onset boundary together with the male skew and antibody profile that define the subgroup.
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
  - reference: PMID:40675735
    reference_title: 'Special populations in myasthenia gravis: Early, late, and very late-onset MG.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In contrast, LOMG and VLOMG are characterized by thymic atrophy, differing genetic associations, and milder long-term disease courses with variable treatment responses.
    explanation: Contrasts late-onset thymic and genetic biology with the early-onset subgroup.
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
- name: VLOMG
  display_name: Very Late-Onset MG (onset after ~65 years)
  description: A further age stratum within late-onset disease, often defined as onset at or beyond 65 years. Focal ocular or bulbar presentations can occur; comorbidity, diagnostic alternatives, and treatment tolerability warrant particular attention. The threshold varies between reports.
  subtype_term:
    preferred_term: very late-onset myasthenia gravis
  evidence:
  - reference: PMID:23893883
    reference_title: 'Late-onset myasthenia gravis: a review when incidence in older adults keeps increasing.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We define late-onset myasthenia gravis (LOMG) when symptoms appear at ≥65 years of age. There has been a continuous increase in the incidence of LOMG with a clear male predominance.
    explanation: Documents the ≥65-year boundary used for the very-late-onset tier — and, by differing from the ≥50-year boundary used elsewhere, shows that the cut-point itself is a convention rather than a measured discontinuity.
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
  - reference: PMID:23893883
    reference_title: 'Late-onset myasthenia gravis: a review when incidence in older adults keeps increasing.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Commonly, patients present with focal (ocular or bulbar) weakness. A high index of suspicion required to achieve early diagnosis and to improve prognosis.
    explanation: Supports focal presentation and diagnostic delay as characteristic of the oldest-onset group.
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
progression:
- phase: Adult onset and fluctuating course
  age_range: Adulthood
  notes: Symptoms fluctuate with activity and over time. Early-, late-, and very-late-onset cutoffs vary across studies and do not define obligatory thymic pathology.
  evidence:
  - reference: PMID:39105625
    reference_title: 'Myasthenia gravis: the future is here.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: The hallmark of MG is muscle fatigue with a degree of weakness that can fluctuate over minutes and vary in severity over weeks to months.
    explanation: Describes the variable course.
- phase: Ocular disease and possible generalization
  notes: Ocular disease may remain restricted or progress to nonocular weakness. Generalization is most often observed within the first two years but can occur later; electrophysiological abnormalities alone do not define clinical generalization.
  evidence:
  - reference: PMID:33458590
    reference_title: 'Myasthenia gravis: MuSK MG, late-onset MG and ocular MG.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Generalization usually occurs within one year, mostly within 2 years and it is uncommon after 2 years
    explanation: Timing is a common pattern, not an absolute two-year cutoff.
  - reference: PMID:33458590
    reference_title: 'Myasthenia gravis: MuSK MG, late-onset MG and ocular MG.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Myasthenia generalized after 2 years in another small group of patients.
    explanation: Primary cohort observations in the review document later progression.
- phase: Exacerbation and crisis
  notes: Respiratory or severe bulbar weakness can deteriorate rapidly and require monitored or intensive care. Infection, intercurrent illness, medication effects, and withdrawal of effective treatment can precipitate worsening.
  evidence:
  - reference: PMID:38152089
    reference_title: Guideline for the management of myasthenic syndromes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: In the event of an impending and manifest myasthenic crisis, rapid admission and treatment must be provided in a monitoring or intensive care unit with experience in neuromuscular disease.
    explanation: Guideline defines the urgent care setting.
  - reference: PMID:38152089
    reference_title: Guideline for the management of myasthenic syndromes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Abrupt discontinuation of immunotherapy in an insufficiently stabilized state is risky and should be avoided as it may lead to the recurrence of myasthenic symptoms and can escalate to a myasthenic crisis.
    explanation: Treatment withdrawal is a potentially preventable precipitant.
pathophysiology:
- name: Thymic Chemokine Overexpression
  description: CXCL13 and CCL21 overexpression in hyperplastic AChR-positive MG thymus is associated with recruitment of peripheral lymphocytes. This is an early-onset-enriched pathway; its initiating stimulus is unresolved.
  biological_scale: MOLECULAR
  evidence:
  - reference: PMID:39105625
    reference_title: 'Myasthenia gravis: the future is here.'
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: B cell infiltration and germinal center formation is associated with overexpression of CXCL13, CCL21, and B cell–activating factor (BAFF) in thymic epithelial cells
    explanation: Review synthesis of thymic chemokine findings.
  downstream:
  - target: Thymic Lymphocyte Recruitment
    description: Chemokines favor peripheral lymphocyte recruitment into the inflammatory thymus.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:29125185
      reference_title: Thymus involvement in early-onset myasthenia gravis.
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      directness: INDIRECT
      snippet: 'The hyperplastic MG thymus displays all the characteristics of tertiary lymphoid organs (TLOs): neoangiogenic processes with high endothelial venule and lymphatic vessel development, chemokine overexpression favoring peripheral cell recruitment, and ectopic germinal center development.'
      explanation: Review-supported recruitment mechanism; complete initiating sequence remains unresolved.
  subtypes:
  - EOMG
  locations:
  - preferred_term: thymus
    term:
      id: UBERON:0002370
      label: thymus
- name: Thymic Lymphocyte Recruitment
  description: Peripheral B cells and helper T cells accumulate in the hyperplastic thymus, with vascular changes that support cellular entry.
  biological_scale: CELLULAR
  evidence:
  - reference: PMID:29125185
    reference_title: Thymus involvement in early-onset myasthenia gravis.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: 'The hyperplastic MG thymus displays all the characteristics of tertiary lymphoid organs (TLOs): neoangiogenic processes with high endothelial venule and lymphatic vessel development, chemokine overexpression favoring peripheral cell recruitment, and ectopic germinal center development.'
    explanation: Thymic cellular recruitment described in a mechanistic review.
  downstream:
  - target: Ectopic Thymic Germinal Center Formation
    description: Recruited lymphocytes support ectopic germinal-center organization.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:29125185
      reference_title: Thymus involvement in early-onset myasthenia gravis.
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      directness: INDIRECT
      snippet: 'The hyperplastic MG thymus displays all the characteristics of tertiary lymphoid organs (TLOs): neoangiogenic processes with high endothelial venule and lymphatic vessel development, chemokine overexpression favoring peripheral cell recruitment, and ectopic germinal center development.'
      explanation: Review supports the linked tissue process without establishing a single direct molecular step.
  subtypes:
  - EOMG
  locations:
  - preferred_term: thymus
    term:
      id: UBERON:0002370
      label: thymus
  cell_types:
  - preferred_term: B cell
    term:
      id: CL:0000236
      label: B cell
- name: Ectopic Thymic Germinal Center Formation
  description: Ectopic thymic follicles provide a niche for B-cell clonal expansion and maturation, particularly in AChR-positive early-onset disease. A 2025 single-cell study analyzed 11 immunotherapy-naive thymi after one of 12 recruited samples failed quality control; inferred trajectories are not lineage tracing.
  biological_scale: TISSUE
  evidence:
  - reference: PMID:40117520
    reference_title: Single-Cell Transcriptomics Identifies a Prominent Role for the MIF-CD74 Axis in Myasthenia Gravis Thymus.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Clonally expanded sequences were most enriched in the GC and cycling B-cell subsets
    explanation: Primary BCR sequencing supports local clonal expansion, not antigen specificity of every expanded clone.
  - reference: PMID:38886398
    reference_title: Comparison of juvenile and adult myasthenia gravis in a French cohort with focus on thymic histology.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    directness: DIRECT
    snippet: EOMG is often characterized by B cells infiltrating the thymus, leading to ectopic germinal center (GC) development (lymphofollicular hyperplasia) for AChR+ MG
    explanation: The introduction of this thymic-histology cohort study restates the established association of AChR-positive early-onset MG with B-cell thymic infiltration and ectopic germinal-center formation.
  biological_processes:
  - preferred_term: germinal center formation
    term:
      id: GO:0002467
      label: germinal center formation
  downstream:
  - target: AChR Autoantibody Production
    description: The thymic germinal-center environment can sustain AChR-reactive B-lineage cells; circulating antibody-producing cells also maintain disease after thymectomy.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:39105625
      reference_title: 'Myasthenia gravis: the future is here.'
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      directness: INDIRECT
      snippet: Thymocytes produce AChR antibodies, as do circulating plasma cells
      explanation: Established antibody production summarized in the review; germinal-center counts alone do not prove initiation.
  - target: Thymic Follicular Hyperplasia
    description: Ectopic follicles contribute to the histological hyperplasia.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:38886398
      reference_title: Comparison of juvenile and adult myasthenia gravis in a French cohort with focus on thymic histology.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: BACKGROUND
      directness: DIRECT
      snippet: EOMG is often characterized by B cells infiltrating the thymus, leading to ectopic germinal center (GC) development (lymphofollicular hyperplasia) for AChR+ MG
      explanation: Equates ectopic germinal-center development with lymphofollicular hyperplasia, the histological pattern this edge links to.
  subtypes:
  - EOMG
  locations:
  - preferred_term: thymus
    term:
      id: UBERON:0002370
      label: thymus
  cell_types:
  - preferred_term: B cell
    term:
      id: CL:0000236
      label: B cell
- name: Thymoma-Associated Loss of Immune Tolerance
  description: In thymoma-associated disease, abnormal T-cell selection and export of autoreactive T cells can support AChR autoimmunity. Tumor histology and immune changes vary; no single molecular lesion is asserted for every thymoma.
  biological_scale: CELLULAR
  evidence:
  - reference: PMID:39105625
    reference_title: 'Myasthenia gravis: the future is here.'
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Development of MG requires the generation of autoreactive T cells within the tumor and subsequent exit of these T cells to the periphery and is further associated with a reduction of Tregs
    explanation: Review synthesis of the thymoma-associated mechanism.
  downstream:
  - target: AChR Autoantibody Production
    description: Autoreactive T-cell help can support antibody-producing B cells outside the tumor, permitting persistent or delayed disease after resection.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:39105625
      reference_title: 'Myasthenia gravis: the future is here.'
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      directness: INDIRECT
      snippet: With egress of autoreactive T cells, MG would be maintained by mechanisms independent of the tumor.
      explanation: Mechanistic interpretation summarized in a review.
  locations:
  - preferred_term: thymus
    term:
      id: UBERON:0002370
      label: thymus
- name: AChR Autoantibody Production
  description: Autoreactive B-lineage cells produce AChR-directed antibodies in the thymus and peripheral compartments. Antibody titer alone does not determine pathogenic activity or clinical severity.
  biological_scale: CELLULAR
  evidence:
  - reference: PMID:39105625
    reference_title: 'Myasthenia gravis: the future is here.'
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Thymocytes produce AChR antibodies, as do circulating plasma cells
    explanation: Review identifies intrathymic and circulating sources.
  biological_processes:
  - preferred_term: immunoglobulin production
    term:
      id: GO:0002377
      label: immunoglobulin production
  downstream:
  - target: AChR Autoantibody Binding
    description: Circulating antibodies with accessible extracellular epitopes bind the muscle receptor; not every detected antibody is pathogenic.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:39105625
      reference_title: 'Myasthenia gravis: the future is here.'
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      directness: INDIRECT
      snippet: Individuals with MG produce autoantibodies that mediate disruption of the NMJ leading to compromised neuromuscular transmission.
      explanation: Review establishes antibody-mediated disease; production-to-junction binding requires circulation and tissue access.
  cell_types:
  - preferred_term: plasma cell
    term:
      id: CL:0000786
      label: plasma cell
- name: AChR Autoantibody Binding
  description: AChR-reactive antibodies bind the postsynaptic receptor. Isotype, epitope, combinations of antibodies, and tissue access affect their ability to cause injury.
  biological_scale: MOLECULAR
  evidence:
  - reference: PMID:36074148
    reference_title: Receptor clustering and pathogenic complement activation in myasthenia gravis depend on synergy between antibodies with multiple subunit specificities.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: All AChR-specific antibodies were hypermutated, including isotypes IgG1, IgG3, and IgG4, and recognized different subunits of the AChR.
    explanation: Patient-derived monoclonal antibodies characterize binding specificity in experimental assays.
  downstream:
  - target: Complement Activation at the Endplate
    description: Complement-fixing antibody combinations recruit the complement cascade.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:39105625
      reference_title: 'Myasthenia gravis: the future is here.'
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      directness: DIRECT
      snippet: Upon binding of AChR antibody, the membrane attack complex is formed on the postsynaptic surface and leads to the shedding of AChR-rich membrane resulting in the loss of synaptic folding as well as Na+ channels
      explanation: Review supports complement activation after receptor binding.
  - target: AChR Crosslinking
    description: Bivalent antibodies and complementary epitope specificities can crosslink receptors.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:39105625
      reference_title: 'Myasthenia gravis: the future is here.'
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      directness: DIRECT
      snippet: This refers to the capacity of an antibody against link two antigen molecules, instigating a cellular signal that expedites the process of endocytosis and subsequent degradation of the complex
      explanation: Review describes antigenic modulation.
  - target: AChR Functional Blockade
    description: Some antibodies interfere with receptor activation independently of complement-mediated injury.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:39105625
      reference_title: 'Myasthenia gravis: the future is here.'
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      directness: DIRECT
      snippet: This occurs when antibodies bind to the ACh binding site
      explanation: Review describes receptor blockade; this is not a property of every AChR antibody.
  cellular_components:
  - preferred_term: neuromuscular junction
    term:
      id: GO:0031594
      label: neuromuscular junction
  locations:
  - preferred_term: skeletal muscle tissue
    term:
      id: UBERON:0001134
      label: skeletal muscle tissue
- name: Complement Activation at the Endplate
  description: Complement-fixing AChR antibodies promote terminal complement activation and membrane attack complex formation at the postsynaptic membrane. This is distinct from the predominant IgG4 MuSK mechanism.
  biological_scale: MOLECULAR
  evidence:
  - reference: PMID:39105625
    reference_title: 'Myasthenia gravis: the future is here.'
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Upon binding of AChR antibody, the membrane attack complex is formed on the postsynaptic surface and leads to the shedding of AChR-rich membrane resulting in the loss of synaptic folding as well as Na+ channels
    explanation: Established complement mechanism, with variable contribution between patients.
  biological_processes:
  - preferred_term: complement activation
    term:
      id: GO:0006956
      label: complement activation
  downstream:
  - target: Postsynaptic Membrane Injury
    description: Membrane attack complex formation injures receptor-rich membrane and synaptic folds.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:39105625
      reference_title: 'Myasthenia gravis: the future is here.'
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      directness: DIRECT
      snippet: Upon binding of AChR antibody, the membrane attack complex is formed on the postsynaptic surface and leads to the shedding of AChR-rich membrane resulting in the loss of synaptic folding as well as Na+ channels
      explanation: Review-supported direct membrane injury.
  cellular_components:
  - preferred_term: neuromuscular junction
    term:
      id: GO:0031594
      label: neuromuscular junction
  locations:
  - preferred_term: skeletal muscle tissue
    term:
      id: UBERON:0001134
      label: skeletal muscle tissue
- name: Postsynaptic Membrane Injury
  description: Complement-associated injury removes receptor-rich postsynaptic membrane and simplifies junctional architecture. Loss of sodium channels also reduces the transmission safety factor.
  biological_scale: CELLULAR
  evidence:
  - reference: PMID:39105625
    reference_title: 'Myasthenia gravis: the future is here.'
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Upon binding of AChR antibody, the membrane attack complex is formed on the postsynaptic surface and leads to the shedding of AChR-rich membrane resulting in the loss of synaptic folding as well as Na+ channels
    explanation: Review describes receptor-rich membrane shedding and channel loss.
  downstream:
  - target: Reduced Surface AChR Availability
    description: Loss of receptor-bearing membrane reduces available postsynaptic AChRs.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:39105625
      reference_title: 'Myasthenia gravis: the future is here.'
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      directness: DIRECT
      snippet: Upon binding of AChR antibody, the membrane attack complex is formed on the postsynaptic surface and leads to the shedding of AChR-rich membrane resulting in the loss of synaptic folding as well as Na+ channels
      explanation: Structural receptor loss follows membrane injury.
  - target: Reduced Endplate Potential Safety Margin
    description: Postsynaptic structural and sodium-channel loss make generation of a muscle action potential less reliable.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:39105625
      reference_title: 'Myasthenia gravis: the future is here.'
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      directness: INDIRECT
      snippet: Upon binding of AChR antibody, the membrane attack complex is formed on the postsynaptic surface and leads to the shedding of AChR-rich membrane resulting in the loss of synaptic folding as well as Na+ channels
      explanation: Biophysical consequence of structural injury; the complete intermediary sequence is not measured by this review.
  cellular_components:
  - preferred_term: neuromuscular junction
    term:
      id: GO:0031594
      label: neuromuscular junction
  locations:
  - preferred_term: skeletal muscle tissue
    term:
      id: UBERON:0001134
      label: skeletal muscle tissue
- name: AChR Crosslinking
  description: Antibodies can crosslink AChR molecules into abnormal surface assemblies, distinct from physiological receptor clustering. Patient-derived antibody combinations showed greater clustering than individual antibodies in transfected cells.
  biological_scale: MOLECULAR
  evidence:
  - reference: PMID:36074148
    reference_title: Receptor clustering and pathogenic complement activation in myasthenia gravis depend on synergy between antibodies with multiple subunit specificities.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: None of the single antibodies had any significant effect on the distribution of the receptor. Combinations of antibodies such as aG112 and bG402, on the other hand, mediated strong clustering
    explanation: Live-cell experiments support antibody-combination-dependent clustering in the tested panel.
  downstream:
  - target: Accelerated AChR Internalization
    description: Crosslinking can accelerate receptor endocytosis and degradation, the antigenic-modulation pathway.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:39105625
      reference_title: 'Myasthenia gravis: the future is here.'
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      directness: DIRECT
      snippet: This refers to the capacity of an antibody against link two antigen molecules, instigating a cellular signal that expedites the process of endocytosis and subsequent degradation of the complex
      explanation: Established mechanism from prior work; the 2022 live-cell clustering experiment itself did not quantify internalization.
  cellular_components:
  - preferred_term: neuromuscular junction
    term:
      id: GO:0031594
      label: neuromuscular junction
  locations:
  - preferred_term: skeletal muscle tissue
    term:
      id: UBERON:0001134
      label: skeletal muscle tissue
- name: Accelerated AChR Internalization
  description: Antigenic modulation accelerates endocytosis and degradation of antibody-crosslinked receptors.
  biological_scale: CELLULAR
  evidence:
  - reference: PMID:39105625
    reference_title: 'Myasthenia gravis: the future is here.'
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: This refers to the capacity of an antibody against link two antigen molecules, instigating a cellular signal that expedites the process of endocytosis and subsequent degradation of the complex
    explanation: Mechanistic review summarizes receptor internalization and degradation.
  biological_processes:
  - preferred_term: endocytosis
    term:
      id: GO:0006897
      label: endocytosis
  downstream:
  - target: Reduced Surface AChR Availability
    description: Accelerated removal lowers the available surface receptor pool.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:39105625
      reference_title: 'Myasthenia gravis: the future is here.'
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      directness: DIRECT
      snippet: This refers to the capacity of an antibody against link two antigen molecules, instigating a cellular signal that expedites the process of endocytosis and subsequent degradation of the complex
      explanation: Receptor depletion follows endocytosis and degradation.
  cellular_components:
  - preferred_term: neuromuscular junction
    term:
      id: GO:0031594
      label: neuromuscular junction
  locations:
  - preferred_term: skeletal muscle tissue
    term:
      id: UBERON:0001134
      label: skeletal muscle tissue
- name: Reduced Surface AChR Availability
  description: Loss of receptor-bearing membrane, enhanced internalization, and impaired clustering reduce receptor availability at functional postsynaptic sites.
  biological_scale: MOLECULAR
  evidence:
  - reference: PMID:39105625
    reference_title: 'Myasthenia gravis: the future is here.'
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Neuromuscular transmission failure occurs owing to a reduction in the number or activity of AChR molecules at the NMJ, leading to a decrease in the end-plate potential (EPP).
    explanation: Review connects receptor number/activity to reduced endplate potential.
  downstream:
  - target: Reduced Endplate Potential Safety Margin
    description: Fewer functional receptors reduce the evoked endplate depolarization.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:39105625
      reference_title: 'Myasthenia gravis: the future is here.'
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      directness: DIRECT
      snippet: Neuromuscular transmission failure occurs owing to a reduction in the number or activity of AChR molecules at the NMJ, leading to a decrease in the end-plate potential (EPP).
      explanation: Biophysical consequence described in the review.
  cellular_components:
  - preferred_term: neuromuscular junction
    term:
      id: GO:0031594
      label: neuromuscular junction
  locations:
  - preferred_term: skeletal muscle tissue
    term:
      id: UBERON:0001134
      label: skeletal muscle tissue
- name: AChR Functional Blockade
  description: Some AChR antibodies inhibit receptor activation without requiring complement. Patient sera inhibited neurotransmission in an iPSC-derived system after heat inactivation, but the six cloned antibodies in that study did not reproduce blockade, either individually or in tested combinations.
  biological_scale: MOLECULAR
  evidence:
  - reference: PMID:39105625
    reference_title: 'Myasthenia gravis: the future is here.'
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: This occurs when antibodies bind to the ACh binding site
    explanation: Review summarizes the established blockade mechanism.
  - reference: PMID:36074148
    reference_title: Receptor clustering and pathogenic complement activation in myasthenia gravis depend on synergy between antibodies with multiple subunit specificities.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Direct AChR antagonism by serum constituents was independent of complement, because heat-inactivated sera showed the same results as fresh sera
    explanation: Serum perturbation supports a complement-independent effect; it does not map every serum effect to a particular epitope.
  downstream:
  - target: Reduced Endplate Potential Safety Margin
    description: Receptor blockade reduces effective cholinergic activation.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:39105625
      reference_title: 'Myasthenia gravis: the future is here.'
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      directness: DIRECT
      snippet: Neuromuscular transmission failure occurs owing to a reduction in the number or activity of AChR molecules at the NMJ, leading to a decrease in the end-plate potential (EPP).
      explanation: Review connects receptor activity to endplate potential.
  cellular_components:
  - preferred_term: neuromuscular junction
    term:
      id: GO:0031594
      label: neuromuscular junction
  locations:
  - preferred_term: skeletal muscle tissue
    term:
      id: UBERON:0001134
      label: skeletal muscle tissue
- name: MuSK Autoantibody Binding
  description: Predominantly IgG4 MuSK antibodies bind extracellular MuSK epitopes. This serologic branch is not confined to one adult age group and does not require complement activation as its principal mechanism.
  biological_scale: MOLECULAR
  evidence:
  - reference: PMID:24297891
    reference_title: MuSK IgG4 autoantibodies cause myasthenia gravis by inhibiting binding between MuSK and Lrp4.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Here we show that pathogenic IgG4 antibodies to MuSK bind to a structural epitope in the first Ig-like domain of MuSK, prevent binding between MuSK and Lrp4, and inhibit Agrin-stimulated MuSK phosphorylation.
    explanation: Purified human patient antibodies were tested with recombinant proteins and cultured cells.
  downstream:
  - target: Impaired LRP4-MuSK Interaction
    description: Patient IgG4 antibodies block association between LRP4 and MuSK.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:24297891
      reference_title: MuSK IgG4 autoantibodies cause myasthenia gravis by inhibiting binding between MuSK and Lrp4.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: Here we show that pathogenic IgG4 antibodies to MuSK bind to a structural epitope in the first Ig-like domain of MuSK, prevent binding between MuSK and Lrp4, and inhibit Agrin-stimulated MuSK phosphorylation.
      explanation: Direct binding experiments support this molecular inhibition.
  cellular_components:
  - preferred_term: neuromuscular junction
    term:
      id: GO:0031594
      label: neuromuscular junction
  locations:
  - preferred_term: skeletal muscle tissue
    term:
      id: UBERON:0001134
      label: skeletal muscle tissue
- name: Impaired LRP4-MuSK Interaction
  description: MuSK IgG4 binding impedes the agrin-dependent interaction between LRP4 and MuSK. The 2013 experiments did not show a direct effect on MuSK homodimerization or surface abundance in the engineered fibroblast context.
  biological_scale: MOLECULAR
  evidence:
  - reference: PMID:24297891
    reference_title: MuSK IgG4 autoantibodies cause myasthenia gravis by inhibiting binding between MuSK and Lrp4.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Here we show that pathogenic IgG4 antibodies to MuSK bind to a structural epitope in the first Ig-like domain of MuSK, prevent binding between MuSK and Lrp4, and inhibit Agrin-stimulated MuSK phosphorylation.
    explanation: Direct recombinant-protein binding assay.
  downstream:
  - target: Reduced Agrin-Stimulated MuSK Phosphorylation
    description: Loss of LRP4 engagement impairs agrin-induced activation of MuSK.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:24297891
      reference_title: MuSK IgG4 autoantibodies cause myasthenia gravis by inhibiting binding between MuSK and Lrp4.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: Patient IgG4 antibodies to MuSK blocked MuSK phosphorylation
      explanation: Primary phosphorylation assay in C2 myotubes.
  cellular_components:
  - preferred_term: neuromuscular junction
    term:
      id: GO:0031594
      label: neuromuscular junction
  locations:
  - preferred_term: skeletal muscle tissue
    term:
      id: UBERON:0001134
      label: skeletal muscle tissue
- name: Reduced Agrin-Stimulated MuSK Phosphorylation
  description: MuSK-directed IgG4 reduces agrin-stimulated MuSK phosphorylation in cultured myotubes, impairing the signaling that organizes the postsynaptic receptor apparatus.
  biological_scale: MOLECULAR
  evidence:
  - reference: PMID:24297891
    reference_title: MuSK IgG4 autoantibodies cause myasthenia gravis by inhibiting binding between MuSK and Lrp4.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Patient IgG4 antibodies to MuSK blocked MuSK phosphorylation
    explanation: Measured signaling response in C2 myotubes.
  downstream:
  - target: Impaired Postsynaptic AChR Clustering
    description: Reduced MuSK signaling compromises receptor clustering through downstream postsynaptic signaling and scaffolding.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:39105625
      reference_title: 'Myasthenia gravis: the future is here.'
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      directness: INDIRECT
      snippet: MuSK antibodies interfere with clustering of AChR on the postsynaptic muscle surface directly opposed to the nerve terminal.
      explanation: Review-supported downstream effect; the 2013 phosphorylation study does not itself resolve every signaling intermediate.
  cellular_components:
  - preferred_term: neuromuscular junction
    term:
      id: GO:0031594
      label: neuromuscular junction
  locations:
  - preferred_term: skeletal muscle tissue
    term:
      id: UBERON:0001134
      label: skeletal muscle tissue
- name: Impaired Postsynaptic AChR Clustering
  description: MuSK-pathway disruption reduces proper accumulation of AChRs at the postsynaptic muscle membrane. This differs from antibody-induced crosslinking of receptors in AChR-positive disease.
  biological_scale: CELLULAR
  evidence:
  - reference: PMID:39105625
    reference_title: 'Myasthenia gravis: the future is here.'
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: MuSK antibodies interfere with clustering of AChR on the postsynaptic muscle surface directly opposed to the nerve terminal.
    explanation: Review-supported MuSK pathway effect.
  downstream:
  - target: Reduced Surface AChR Availability
    description: Failure of physiological synaptic clustering reduces the receptor pool available at the junction.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:39105625
      reference_title: 'Myasthenia gravis: the future is here.'
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      directness: INDIRECT
      snippet: MuSK antibodies interfere with clustering of AChR on the postsynaptic muscle surface directly opposed to the nerve terminal.
      explanation: Localization defect contributes to reduced junctional availability.
  cellular_components:
  - preferred_term: neuromuscular junction
    term:
      id: GO:0031594
      label: neuromuscular junction
  locations:
  - preferred_term: skeletal muscle tissue
    term:
      id: UBERON:0001134
      label: skeletal muscle tissue
- name: Reduced Endplate Potential Safety Margin
  description: The margin between endplate depolarization and the threshold for a muscle action potential is reduced. Repetitive activation can then make transmission fail in individual fibers.
  biological_scale: CELLULAR
  evidence:
  - reference: PMID:39105625
    reference_title: 'Myasthenia gravis: the future is here.'
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Neuromuscular transmission failure occurs owing to a reduction in the number or activity of AChR molecules at the NMJ, leading to a decrease in the end-plate potential (EPP).
    explanation: Review connects reduced receptor number/activity to endplate potential.
  downstream:
  - target: Impaired Neuromuscular Transmission
    description: During repetitive activity, endplate depolarization can fall below the action-potential threshold.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:39105625
      reference_title: 'Myasthenia gravis: the future is here.'
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      directness: DIRECT
      snippet: At rest, this EPP reduction may still adequately support neuromuscular transmission; however, during repetitive activity, when the quantal release of acetylcholine (ACh) is reduced, the EPP may fall below the threshold required to trigger an action potential.
      explanation: Direct physiological explanation of use-dependent transmission failure.
  cellular_components:
  - preferred_term: neuromuscular junction
    term:
      id: GO:0031594
      label: neuromuscular junction
  locations:
  - preferred_term: skeletal muscle tissue
    term:
      id: UBERON:0001134
      label: skeletal muscle tissue
- name: Impaired Neuromuscular Transmission
  description: Motor-nerve activation increasingly fails to elicit muscle-fiber action potentials and contraction, producing fatigable weakness in variably affected skeletal-muscle groups.
  biological_scale: TISSUE
  evidence:
  - reference: PMID:39105625
    reference_title: 'Myasthenia gravis: the future is here.'
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Neuromuscular fatigue, characterized by a progressive loss of force generation, occurs as increasing numbers of muscle fibers become incapable of contracting.
    explanation: Shared downstream physiology of antibody-mediated MG.
  biological_processes:
  - preferred_term: neuromuscular synaptic transmission
    term:
      id: GO:0007274
      label: neuromuscular synaptic transmission
  downstream:
  - target: Fatigable Muscle Weakness
    description: Failure of transmission in the affected muscle group produces this clinical manifestation.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK559331/
      reference_title: Myasthenia Gravis - StatPearls - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      directness: INDIRECT
      snippet: The distinguishing clinical feature of MG is the fluctuating muscle weakness that varies in severity, worsens with physical activity, and improves with rest.
      explanation: Defines clinical fatigability.
  - target: Ptosis
    description: Failure of transmission in the affected muscle group produces this clinical manifestation.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:33458590
      reference_title: 'Myasthenia gravis: MuSK MG, late-onset MG and ocular MG.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      directness: INDIRECT
      snippet: Ocular MG (OMG) refers to patients whose symptoms are confined to ocular muscles (levator palpebrae superioris and extraocular muscles), resulting in ptosis and diplopia; orbicularis oculi muscles are variably weak.
      explanation: Names the ocular findings explicitly.
  - target: Diplopia
    description: Failure of transmission in the affected muscle group produces this clinical manifestation.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:33458590
      reference_title: 'Myasthenia gravis: MuSK MG, late-onset MG and ocular MG.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      directness: INDIRECT
      snippet: Ocular MG (OMG) refers to patients whose symptoms are confined to ocular muscles (levator palpebrae superioris and extraocular muscles), resulting in ptosis and diplopia; orbicularis oculi muscles are variably weak.
      explanation: Names the ocular findings explicitly.
  - target: Dysphagia
    description: Failure of transmission in the affected muscle group produces this clinical manifestation.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK559331/
      reference_title: Myasthenia Gravis - StatPearls - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      directness: INDIRECT
      snippet: causes symptoms like difficulty chewing or frequent choking, dysphagia, hoarseness, and dysarthria.
      explanation: General clinical MG synthesis supports the specific bulbar symptom, without an adult-specific frequency.
  - target: Dysarthria
    description: Failure of transmission in the affected muscle group produces this clinical manifestation.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK559331/
      reference_title: Myasthenia Gravis - StatPearls - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      directness: INDIRECT
      snippet: causes symptoms like difficulty chewing or frequent choking, dysphagia, hoarseness, and dysarthria.
      explanation: General clinical MG synthesis supports the specific bulbar symptom, without an adult-specific frequency.
  - target: Generalized Muscle Weakness
    description: Failure of transmission in the affected muscle group produces this clinical manifestation.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:39105625
      reference_title: 'Myasthenia gravis: the future is here.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      directness: INDIRECT
      snippet: generalized MG, which involves weakness of any voluntary muscle. Generalized weakness can range from highly isolated manifestations, particularly bulbar muscles, to widespread muscle weakness
      explanation: Clarifies the clinical category.
  - target: Neck Muscle Weakness
    description: Failure of transmission in the affected muscle group produces this clinical manifestation.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:33458590
      reference_title: 'Myasthenia gravis: MuSK MG, late-onset MG and ocular MG.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      directness: INDIRECT
      snippet: Bulbar, neck and respiratory muscles are involved with fast progression of the disease to life-threatening symptoms
      explanation: Review describes the MuSK-associated distribution.
  - target: Myasthenic Crisis
    description: Failure of transmission in the affected muscle group produces this clinical manifestation.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:39105625
      reference_title: 'Myasthenia gravis: the future is here.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      directness: INDIRECT
      snippet: Generalized weakness can range from highly isolated manifestations, particularly bulbar muscles, to widespread muscle weakness, including respiratory insufficiency producing respiratory failure
      explanation: Places respiratory failure at the severe end of generalized myasthenic weakness, linking transmission failure in respiratory muscles to crisis.
  cellular_components:
  - preferred_term: neuromuscular junction
    term:
      id: GO:0031594
      label: neuromuscular junction
  locations:
  - preferred_term: skeletal muscle tissue
    term:
      id: UBERON:0001134
      label: skeletal muscle tissue
phenotypes:
- name: Fatigable Muscle Weakness
  category: Neuromuscular
  description: Fluctuating weakness increases with sustained activity and improves with rest.
  phenotype_term:
    preferred_term: Fatigable weakness
    term:
      id: HP:0003473
      label: Fatigable weakness
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK559331/
    reference_title: Myasthenia Gravis - StatPearls - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: The distinguishing clinical feature of MG is the fluctuating muscle weakness that varies in severity, worsens with physical activity, and improves with rest.
    explanation: Defines clinical fatigability.
- name: Ptosis
  category: Ocular
  description: Fluctuating eyelid droop can be unilateral, alternating, or bilateral.
  phenotype_term:
    preferred_term: Ptosis
    term:
      id: HP:0000508
      label: Ptosis
  evidence:
  - reference: PMID:33458590
    reference_title: 'Myasthenia gravis: MuSK MG, late-onset MG and ocular MG.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Ocular MG (OMG) refers to patients whose symptoms are confined to ocular muscles (levator palpebrae superioris and extraocular muscles), resulting in ptosis and diplopia; orbicularis oculi muscles are variably weak.
    explanation: Names the ocular findings explicitly.
- name: Diplopia
  category: Ocular
  description: Double vision reflects variable extraocular muscle weakness.
  phenotype_term:
    preferred_term: Diplopia
    term:
      id: HP:0000651
      label: Diplopia
  evidence:
  - reference: PMID:33458590
    reference_title: 'Myasthenia gravis: MuSK MG, late-onset MG and ocular MG.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Ocular MG (OMG) refers to patients whose symptoms are confined to ocular muscles (levator palpebrae superioris and extraocular muscles), resulting in ptosis and diplopia; orbicularis oculi muscles are variably weak.
    explanation: Names the ocular findings explicitly.
- category: Ocular
  name: Ocular-Restricted Disease
  subtype: LOMG
  description: Weakness may remain confined to eyelid and extraocular muscles. A single cohort reported ocular MG in 40% of late-onset versus 18% of early-onset cases; this is not a universal frequency.
  phenotype_term:
    preferred_term: Ocular-restricted disease distribution
  notes: This is a disease-distribution category, not the sign of ophthalmoplegia. It remains unbound pending a suitable distribution term.
  evidence:
  - reference: PMID:22476514
    reference_title: Characteristics of late-onset myasthenia gravis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Ocular MG was more common in LOMG compared to EOMG (40 vs. 18 %, p = 0.021).
    explanation: Quantifies the excess of ocular-restricted disease in the late-onset subgroup.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
- name: Dysphagia
  category: Bulbar
  description: Fatigable swallowing difficulty may accompany choking and aspiration risk.
  phenotype_term:
    preferred_term: Dysphagia
    term:
      id: HP:0002015
      label: Dysphagia
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK559331/
    reference_title: Myasthenia Gravis - StatPearls - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: causes symptoms like difficulty chewing or frequent choking, dysphagia, hoarseness, and dysarthria.
    explanation: General clinical MG synthesis supports the specific bulbar symptom, without an adult-specific frequency.
- name: Dysarthria
  category: Bulbar
  description: Bulbar weakness can produce slurred or altered speech.
  phenotype_term:
    preferred_term: Dysarthria
    term:
      id: HP:0001260
      label: Dysarthria
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK559331/
    reference_title: Myasthenia Gravis - StatPearls - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: causes symptoms like difficulty chewing or frequent choking, dysphagia, hoarseness, and dysarthria.
    explanation: General clinical MG synthesis supports the specific bulbar symptom, without an adult-specific frequency.
- name: Generalized Muscle Weakness
  category: Neuromuscular
  description: In MG classification, generalized disease means clinical weakness beyond the ocular muscles; it need not involve every limb or muscle group.
  phenotype_term:
    preferred_term: Generalized muscle weakness
    term:
      id: HP:0003324
      label: Generalized muscle weakness
  evidence:
  - reference: PMID:39105625
    reference_title: 'Myasthenia gravis: the future is here.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: generalized MG, which involves weakness of any voluntary muscle. Generalized weakness can range from highly isolated manifestations, particularly bulbar muscles, to widespread muscle weakness
    explanation: Clarifies the clinical category.
- name: Neck Muscle Weakness
  category: Neuromuscular
  description: Neck weakness, sometimes producing head drop, is particularly important in MuSK-positive presentations.
  phenotype_term:
    preferred_term: Neck muscle weakness
    term:
      id: HP:0000467
      label: Neck muscle weakness
  evidence:
  - reference: PMID:33458590
    reference_title: 'Myasthenia gravis: MuSK MG, late-onset MG and ocular MG.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Bulbar, neck and respiratory muscles are involved with fast progression of the disease to life-threatening symptoms
    explanation: Review describes the MuSK-associated distribution.
- name: Myasthenic Crisis
  category: Respiratory
  description: Severe respiratory-muscle or bulbar weakness can cause respiratory failure requiring ventilatory support. A historical cohort observed crises in 13% of both generalized early- and late-onset groups; that cohort does not establish equal risk in all populations.
  phenotype_term:
    preferred_term: Respiratory failure
    term:
      id: HP:0002878
      label: Respiratory failure
  evidence:
  - reference: PMID:22476514
    reference_title: Characteristics of late-onset myasthenia gravis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Myasthenic crisis was equally common in generalized EOMG and LOMG (13 %).
    explanation: Source-specific observation; no general population frequency is assigned.
  - reference: PMID:39105625
    reference_title: 'Myasthenia gravis: the future is here.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Generalized weakness can range from highly isolated manifestations, particularly bulbar muscles, to widespread muscle weakness, including respiratory insufficiency producing respiratory failure
    explanation: Supports the respiratory-failure manifestation; the cohort quote separately supports only its source-specific crisis frequency.
- name: Fatigue
  category: Constitutional
  description: Patient-reported fatigue may persist despite control of demonstrable muscle weakness. Sleep disturbance, psychological factors, and disease activity may contribute; this is distinct from use-dependent neuromuscular fatigability.
  phenotype_term:
    preferred_term: Fatigue
    term:
      id: HP:0012378
      label: Fatigue
  evidence:
  - reference: PMID:39105625
    reference_title: 'Myasthenia gravis: the future is here.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Despite resolution of manifest weakness with treatment, many patients complain of general fatigue
    explanation: Review distinguishes fatigue from manifest weakness.
- name: Thymic Follicular Hyperplasia
  category: Thymic
  description: Follicular hyperplasia with germinal centers is enriched in early-onset AChR-positive MG, especially women. Surgical series do not establish its population prevalence.
  phenotype_term:
    preferred_term: Thymus hyperplasia
    term:
      id: HP:0010516
      label: Thymus hyperplasia
  evidence:
  - reference: PMID:27273086
    reference_title: 'Thymic Germinal Centers and Corticosteroids in Myasthenia Gravis: an Immunopathological Study in 1035 Cases and a Critical Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: We show that among patients presenting a thymic hyperplasia with germinal centers (GC), 80 % are females
    explanation: Primary histological result; the denominator is those with hyperplasia, not all women with MG.
  subtype: EOMG
- name: Thymoma
  category: Thymic
  description: A thymic epithelial tumor occurs in a minority and changes oncological management independently of the onset-age category.
  phenotype_term:
    preferred_term: Thymoma
    term:
      id: HP:0100522
      label: Thymoma
  evidence:
  - reference: ORPHA:391490
    reference_title: Adult-onset myasthenia gravis
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: BACKGROUND
    directness: DIRECT
    snippet: generalized muscle weakness, and occasionally associated with thymoma.
    explanation: Structured adult-onset disease record.
biochemical:
- name: Anti-Acetylcholine Receptor Antibody
  context: AChR antibodies are diagnostically useful in a compatible clinical presentation. Detection rates vary with clinical distribution, assay, and cohort; antibody concentration does not reliably quantify current disease activity.
  biomarker_term:
    preferred_term: Anti-acetylcholine receptor antibody positivity
    term:
      id: HP:6001064
      label: Anti-acetylcholine receptor antibody positivity
  evidence:
  - reference: PMID:22476514
    reference_title: Characteristics of late-onset myasthenia gravis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Anti-AChR antibody titers were elevated in 78 % of patients (65 % with EOMG vs. 85 % with LOMG; p = 0.003)
    explanation: Gives the onset-stratified seropositivity rates in a single cohort tested identically.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
- name: Anti-Titin Antibody
  subtype: LOMG
  context: Titin antibodies are associated with older onset and thymoma in selected cohorts, but are not established causes of neuromuscular transmission failure. A retrospective series found an association with generalized disease within its late-onset subgroup; this is not a validated prediction of progression.
  biomarker_term:
    preferred_term: Anti-titin antibody positivity
    term:
      id: HP:5000038
      label: Anti-titin antibody positivity
  evidence:
  - reference: PMID:31811563
    reference_title: 'Late-onset generalized myasthenia gravis: clinical features, treatment, and outcome.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In 95 patients with generalized non-thymomatous LOMG, 60 (63%) were men, 45 (47%) had mild disease, 80 (84%) were anti-AChR, and 56 (61%) were anti-titin positive.
    explanation: Quantifies anti-titin seropositivity at 61% in generalized non-thymomatous late-onset disease.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - reference: PMID:38505076
    reference_title: Anti-titin antibodies in a cohort of myasthenia gravis patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Anti-titin positivity was significantly associated with generalized MG in the late-onset group (P=0.005).
    explanation: Establishes the late-onset-specific clinical correlate of anti-titin positivity.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  notes: The 2019 cohort abstract reports 56 positive and 61% within 95 participants without specifying the tested denominator in the excerpt. No pooled frequency is inferred. In the 2024 cohort, 130 of 230 clinic patients were tested; 32 were positive, and testing often occurred long after thymectomy.
- name: Anti-Ryanodine Receptor Antibody
  subtype: LOMG
  context: RyR reactivity occurs in MG with striational autoimmunity, but the 2019 cell-based assay also detected substantial reactivity in disease controls and healthy controls. It is neither diagnostic of late-onset MG nor proof of pathogenicity.
  biomarker_term:
    preferred_term: Anti-ryanodine receptor antibody
    term:
      id: HP:5000047
      label: Anti-ryanodine receptor antibody
  notes: 'No onset-stratified frequency is asserted here: the late-onset cohorts cited in this entry quantified anti-titin but not anti-ryanodine-receptor seropositivity, so a frequency would be unsupported.'
  evidence:
  - reference: PMID:30918333
    reference_title: Cytometric cell-based assays for anti-striational antibodies in myasthenia gravis with myositis and/or myocarditis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: MG patients with myositis and/or myocarditis as well as late-onset and thymoma-associated MG had anti-titin, anti-ryanodine receptor, and anti-Kv1.4 antibodies.
    explanation: Places anti-ryanodine-receptor antibody within the striational panel of late-onset and thymoma-associated disease.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - reference: PMID:30918333
    reference_title: Cytometric cell-based assays for anti-striational antibodies in myasthenia gravis with myositis and/or myocarditis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In contrast, patients with early-onset MG, those with other myopathies and healthy controls did not have anti-titin or anti-Kv1.4 antibodies with some exceptions, but they possessed anti-ryanodine receptor antibodies.
    explanation: The control reactivity supports the stated specificity limitation.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
- name: Anti-MuSK Antibody
  context: MuSK antibodies identify an antibody-mediated subgroup with different effector mechanisms and treatment responses. Negative AChR serology alone does not establish MuSK disease.
  biomarker_term:
    preferred_term: Anti-muscle-specific tyrosine kinase antibody
    term:
      id: HP:0030210
      label: Anti-muscle-specific tyrosine kinase antibody
  evidence:
  - reference: PMID:33458590
    reference_title: 'Myasthenia gravis: MuSK MG, late-onset MG and ocular MG.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Anti-MuSK antibodies are extremely rare in MG with prolonged pure ocular symptoms.
    explanation: Subtype and clinical-distribution context, not a universal frequency.
genetic:
- name: HLA-B*08
  subtype: EOMG
  relationship_type: SUSCEPTIBILITY
  gene_term:
    preferred_term: HLA-B
    term:
      id: hgnc:4932
      label: HLA-B
  features: A major association in North European AChR-positive, nonthymomatous early-onset MG. The 2012 study analyzed 649 cases and 2,596 controls; eligibility allowed onset above 10 years, so it was not exclusively adult-onset. Conditioning on HLA-B*08 removed the marginal DRB1*03:01 signal, but linkage disequilibrium prevents a simple inference of a unique causal allele or demonstrated CD8-cell mechanism.
  evidence:
  - reference: PMID:23055271
    reference_title: Risk for myasthenia gravis maps to a (151) Pro→Ala change in TNIP1 and to human leukocyte antigen-B*08.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We observed the strongest association in the HLA class I region at rs7750641
    explanation: Locates the strongest early-onset genome-wide signal in the HLA class I region.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - reference: PMID:23055271
    reference_title: Risk for myasthenia gravis maps to a (151) Pro→Ala change in TNIP1 and to human leukocyte antigen-B*08.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: By imputation and conditional analyses, HLA-B*08 proves to be the major associated allele (p = 2.87 × 10(-113) ; OR, 6.41).
    explanation: Imputation and conditional analysis support the association, without a functional antigen-presentation assay.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - reference: PMID:23055271
    reference_title: Risk for myasthenia gravis maps to a (151) Pro→Ala change in TNIP1 and to human leukocyte antigen-B*08.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: 'All EOMG cases included in these studies were North European and met the following criteria: 1) clinical diagnostic criteria for MG; 2) anti-AChR antibody positive; 3) no evidence of thymoma; 4) onset-age >10 years and either <40 years or <45 years with hyperplastic thymic histology.'
    explanation: Defines the ancestry, serotype, thymoma exclusion, and juvenile inclusion.
- name: HLA-DRB1
  relationship_type: SUSCEPTIBILITY
  gene_term:
    preferred_term: HLA-DRB1
    term:
      id: hgnc:4948
      label: HLA-DRB1
  features: Onset-associated HLA class II signals differ between cohorts. The 2017 study reports enrichment of DRB1*03 in early-onset and DRB1*01 in late-onset cases. These marginal associations do not prove independence from linked HLA loci. The 2024 GWAS also observed opposite directions for several HLA alleles across onset groups, potentially reflecting modulation of onset timing.
  evidence:
  - reference: PMID:28495048
    reference_title: HLA and age of onset in myasthenia gravis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: HLA-DRB1*03 allele was overrepresented in the global MG. When the early-onset subgroup was considered, this association became even stronger.
    explanation: Shows the class II risk allele concentrating in the early-onset subgroup.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - reference: PMID:28495048
    reference_title: HLA and age of onset in myasthenia gravis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Regarding the late-onset subgroup, the frequency of HLA-DRB1*01 allele was higher than in the CP.
    explanation: Shows a different class II allele associating with the late-onset subgroup in the same cohort.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
- name: HLA-DQA1
  relationship_type: SUSCEPTIBILITY
  gene_term:
    preferred_term: HLA-DQA1
    term:
      id: hgnc:4942
      label: HLA-DQA1
  features: In a European AChR-positive, nonthymomatous case-control study, DQA1*05:01 was associated with lower odds of late-onset disease but higher odds in the previously studied early-onset cohort. Conditional analyses favored DQA1 among class II candidates, without proving that it is the unique causal gene. The 532 late-onset cases and their 449-person onset-at-least-60 subset are one cohort, not independent replication.
  evidence:
  - reference: PMID:26562150
    reference_title: 'Genome-Wide Association Study of Late-Onset Myasthenia Gravis: Confirmation of TNFRSF11A and Identification of ZBTB10 and Three Distinct HLA Associations.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Moreover, the strongest associations were in opposite directions from EOMG, including an OR of 0.54 for DQA1*05:01 in LOMG (P = 5.9 × 10-12) versus 2.82 in EOMG (P = 3.86 × 10-45).
    explanation: 'States the onset-direction reversal directly, with both effect sizes: DQA1*05:01 is protective in late-onset and predisposing in early-onset disease.'
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - reference: PMID:26562150
    reference_title: 'Genome-Wide Association Study of Late-Onset Myasthenia Gravis: Confirmation of TNFRSF11A and Identification of ZBTB10 and Three Distinct HLA Associations.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Association and conditioning studies for the MHC region showed three distinct and largely independent association peaks for LOMG corresponding to (a) MHC class II (highest attenuation when conditioning on DQA1), (b) HLA-A and (c) MHC class III SNPs.
    explanation: Three conditional association peaks were observed. Attenuation with DQA1 conditioning does not uniquely identify the causal allele or mechanism.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - reference: PMID:26562150
    reference_title: 'Genome-Wide Association Study of Late-Onset Myasthenia Gravis: Confirmation of TNFRSF11A and Identification of ZBTB10 and Three Distinct HLA Associations.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: we conducted a genome-wide association study imputation of>6 million single nucleotide polymorphisms (SNPs) in 532 LOMG cases (anti-acetylcholine receptor ... antibody positive; onset age≥50 years) and 2,128 controls matched for sex and population substructure.
    explanation: Defines the primary study population, AChR-antibody-positive late-onset cases with onset at age 50 or later.
- name: TNIP1
  subtype: EOMG
  relationship_type: SUSCEPTIBILITY
  gene_term:
    preferred_term: TNIP1
    term:
      id: hgnc:16903
      label: TNIP1
  features: The p.Pro151Ala variant was associated with early-onset MG in 2012, but its functional effect was not measured. Ubiquitin/NF-kB signaling was a proposed interpretation rather than an established variant mechanism. Failure to detect a signal in the modest 2015 late-onset cohort does not establish universal early-onset specificity; the 2024 meta-analysis also implicated this region in overall MG, while its early-onset replication was unsuccessful.
  evidence:
  - reference: PMID:23055271
    reference_title: Risk for myasthenia gravis maps to a (151) Pro→Ala change in TNIP1 and to human leukocyte antigen-B*08.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: INDIRECT
    snippet: These data thus implicate the TNIP1 151Ala replacement itself in EOMG pathogenesis, although without direct functional data, this remains a hypothesis to be proven.
    explanation: The authors explicitly distinguish association from untested function.
  - reference: PMID:26562150
    reference_title: 'Genome-Wide Association Study of Late-Onset Myasthenia Gravis: Confirmation of TNFRSF11A and Identification of ZBTB10 and Three Distinct HLA Associations.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In contrast, EOMG-associated SNPs in TNIP1 showed no association in LOMG, nor did other loci suggested for EOMG.
    explanation: Absence of a detected association in this cohort is not evidence of absence in every late-onset population.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
- name: PTPN22
  relationship_type: SUSCEPTIBILITY
  gene_term:
    preferred_term: PTPN22
    term:
      id: hgnc:9652
      label: PTPN22
  features: The R620W autoimmunity variant is associated with early-onset MG and showed suggestive, rather than conventional genome-wide, significance in the 2015 late-onset study. It is a susceptibility factor, not a Mendelian cause of autoimmune MG.
  evidence:
  - reference: PMID:26562150
    reference_title: 'Genome-Wide Association Study of Late-Onset Myasthenia Gravis: Confirmation of TNFRSF11A and Identification of ZBTB10 and Three Distinct HLA Associations.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Several other SNPs showed suggestive significance including rs2476601 (P = 6.5 × 10-6, OR 1.62) encoding the PTPN22 R620W variant noted in early-onset myasthenia gravis (EOMG) and other autoimmune diseases.
    explanation: The late-onset association was suggestive in this study.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
- name: TNFRSF11A
  subtype: LOMG
  relationship_type: SUSCEPTIBILITY
  gene_term:
    preferred_term: TNFRSF11A
    term:
      id: hgnc:11908
      label: TNFRSF11A
  features: A susceptibility region supported by prior and later GWAS. The 2015 late-onset association at rs4574025 was suggestive by the conventional genome-wide threshold; the 2022 meta-analysis reported genome-wide association at rs4369774. Association does not itself establish a RANK-mediated cellular defect in patients.
  evidence:
  - reference: PMID:26562150
    reference_title: 'Genome-Wide Association Study of Late-Onset Myasthenia Gravis: Confirmation of TNFRSF11A and Identification of ZBTB10 and Three Distinct HLA Associations.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The data confirm reported TNFRSF11A associations (rs4574025, P = 3.9 × 10-7, odds ratio [OR] 1.42)
    explanation: Supports the reported association at P=3.9×10^-7, short of the conventional 5×10^-8 threshold in this study.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - reference: PMID:34400559
    reference_title: Myasthenia gravis genome-wide association study implicates AGRN as a risk locus.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: We confirmed the previously reported MG association with TNFRSF11A (rs4369774; p=1.09×10-13, OR=1.4).
    explanation: The later meta-analysis supports the locus while not constituting an independent replication of every earlier cohort.
- name: ZBTB10
  subtype: LOMG
  relationship_type: SUSCEPTIBILITY
  gene_term:
    preferred_term: ZBTB10
    term:
      id: hgnc:30953
      label: ZBTB10
  features: The 2015 late-onset study identified rs6998967, approximately 34 kb upstream of ZBTB10, with a protective-associated minor allele (odds ratio 0.53). ZBTB10 was nominated as a candidate gene, not functionally established as causal. The study lacked an independent replication cohort.
  evidence:
  - reference: PMID:26562150
    reference_title: 'Genome-Wide Association Study of Late-Onset Myasthenia Gravis: Confirmation of TNFRSF11A and Identification of ZBTB10 and Three Distinct HLA Associations.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: identify a novel candidate gene, ZBTB10, achieving genome-wide significance (rs6998967, P = 8.9 × 10-10, OR 0.53)
    explanation: Genome-wide association nominates the nearby gene; the odds ratio denotes lower odds for the tested allele.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
- name: CHRNA1
  relationship_type: SUSCEPTIBILITY
  gene_term:
    preferred_term: CHRNA1
    term:
      id: hgnc:1955
      label: CHRNA1
  features: The 2024 European-ancestry MG GWAS nominated this gene through positional, eQTL, and chromatin-interaction mapping. This is computational prioritization of an associated locus, not a patient-variant perturbation assay or a Mendelian explanation for adult autoimmune MG.
  evidence:
  - reference: PMID:39537604
    reference_title: Genome-wide meta-analysis of myasthenia gravis uncovers new loci and provides insights into polygenic prediction.
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: To link loci implicated by the GWAS to protein-coding genes, we applied positional mapping, expression quantitative trait loci (eQTL), and chromatin interaction gene mapping.
    explanation: Describes the gene-nomination method.
  - reference: PMID:39537604
    reference_title: Genome-wide meta-analysis of myasthenia gravis uncovers new loci and provides insights into polygenic prediction.
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Four of these loci (rs6433501, rs231779, rs6861227, rs215918) only contained a single protein-coding gene (CHRNA1,CTLA4,TNIP1, TBX18).
    explanation: Names the nominated single-gene loci.
- name: CTLA4
  relationship_type: SUSCEPTIBILITY
  gene_term:
    preferred_term: CTLA4
    term:
      id: hgnc:2505
      label: CTLA4
  features: The 2024 European-ancestry MG GWAS nominated this gene through positional, eQTL, and chromatin-interaction mapping. This is computational prioritization of an associated locus, not a patient-variant perturbation assay or a Mendelian explanation for adult autoimmune MG.
  evidence:
  - reference: PMID:39537604
    reference_title: Genome-wide meta-analysis of myasthenia gravis uncovers new loci and provides insights into polygenic prediction.
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: To link loci implicated by the GWAS to protein-coding genes, we applied positional mapping, expression quantitative trait loci (eQTL), and chromatin interaction gene mapping.
    explanation: Describes the gene-nomination method.
  - reference: PMID:39537604
    reference_title: Genome-wide meta-analysis of myasthenia gravis uncovers new loci and provides insights into polygenic prediction.
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Four of these loci (rs6433501, rs231779, rs6861227, rs215918) only contained a single protein-coding gene (CHRNA1,CTLA4,TNIP1, TBX18).
    explanation: Names the nominated single-gene loci.
- name: TBX18
  relationship_type: SUSCEPTIBILITY
  gene_term:
    preferred_term: TBX18
    term:
      id: hgnc:11595
      label: TBX18
  features: The 2024 European-ancestry MG GWAS nominated this gene through positional, eQTL, and chromatin-interaction mapping. This is computational prioritization of an associated locus, not a patient-variant perturbation assay or a Mendelian explanation for adult autoimmune MG.
  evidence:
  - reference: PMID:39537604
    reference_title: Genome-wide meta-analysis of myasthenia gravis uncovers new loci and provides insights into polygenic prediction.
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: To link loci implicated by the GWAS to protein-coding genes, we applied positional mapping, expression quantitative trait loci (eQTL), and chromatin interaction gene mapping.
    explanation: Describes the gene-nomination method.
  - reference: PMID:39537604
    reference_title: Genome-wide meta-analysis of myasthenia gravis uncovers new loci and provides insights into polygenic prediction.
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Four of these loci (rs6433501, rs231779, rs6861227, rs215918) only contained a single protein-coding gene (CHRNA1,CTLA4,TNIP1, TBX18).
    explanation: Names the nominated single-gene loci.
- name: AGRN
  relationship_type: SUSCEPTIBILITY
  gene_term:
    preferred_term: AGRN
    term:
      id: hgnc:329
      label: AGRN
  features: A 2022 meta-analysis of 1,401 cases and 3,508 controls nominated AGRN through gene-based association. This is susceptibility evidence for autoimmune MG, not proof of altered agrin activity in these patients or of the recessive congenital myasthenic mechanism.
  evidence:
  - reference: PMID:34400559
    reference_title: Myasthenia gravis genome-wide association study implicates AGRN as a risk locus.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Furthermore, gene-based analysis revealed AGRN as a novel MG susceptibility gene.
    explanation: Gene-based association; no functional mediation assay is established by the available abstract.
treatments:
- name: Pyridostigmine
  description: Acetylcholinesterase inhibition increases acetylcholine availability for symptomatic improvement without suppressing autoantibody production. MuSK-positive patients may respond poorly or tolerate it poorly; treatment is individualized.
  action_category: THERAPEUTIC
  evidence:
  - reference: PMID:38152089
    reference_title: Guideline for the management of myasthenic syndromes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: For symptomatic therapy of MG, acetylcholinesterase inhibitors (AChE-I), primarily pyridostigmine, should be used.
    explanation: Symptomatic recommendation.
  - reference: PMID:38152089
    reference_title: Guideline for the management of myasthenic syndromes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Patients with MuSK-Ab-positive MG may respond poorly to AChE-I and more often tolerate it poorly.
    explanation: Important serotype-specific limitation.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: Pyridostigmine
      term:
        id: CHEBI:8665
        label: Pyridostigmine
  target_mechanisms:
  - target: Impaired Neuromuscular Transmission
    treatment_effect: MODULATES
    description: Prolongs acetylcholine availability and improves the transmission safety margin.
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK559331/
      reference_title: Myasthenia Gravis - StatPearls - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      directness: DIRECT
      snippet: Acetylcholinesterase inhibitors increases the level of ACh at the NMJ by preventing its enzymatic degradation.
      explanation: Direct pharmacological rationale.
- name: Corticosteroids
  description: Glucocorticoids are basic immunotherapy for inadequately controlled ocular or generalized MG. Use the lowest effective exposure with monitoring for infection, metabolic, bone, and other toxicity; early transient worsening and comorbidity influence initiation and bridging care.
  action_category: THERAPEUTIC
  evidence:
  - reference: PMID:38152089
    reference_title: Guideline for the management of myasthenic syndromes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Oral glucocorticosteroids (GKS) should be used to treat mild/moderate to (highly) active gMG/juvenile MG (jMG) and ocular MG (oMG) as basic immunotherapeutics at doses appropriate to disease severity over the shortest possible period of time, taking into account comorbidities, contraindications, and side effects.
    explanation: Guideline frames benefit against treatment burden.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: prednisone
      term:
        id: CHEBI:8382
        label: prednisone
  target_mechanisms:
  - target: AChR Autoantibody Production
    treatment_effect: MODULATES
    description: Broad immune suppression modifies disease activity; the clinical response does not identify a single cellular mediator.
    evidence:
    - reference: PMID:38152089
      reference_title: Guideline for the management of myasthenic syndromes.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      directness: DIRECT
      snippet: GKS as monotherapy or in combination with AZA are first-choice agents for immunotherapy.
      explanation: Supports disease-modifying immunotherapy.
- name: Azathioprine
  description: A steroid-sparing immunosuppressant with delayed onset over months. Clinical and laboratory monitoring is necessary. Favorable outcomes in a late-onset observational cohort support applicability to older-onset patients but do not isolate a randomized combination effect.
  action_category: THERAPEUTIC
  evidence:
  - reference: PMID:38152089
    reference_title: Guideline for the management of myasthenic syndromes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Due to the slow onset of action, therapeutic success with monotherapy is not to be expected before several months have elapsed.
    explanation: Delayed azathioprine response in the relevant guideline section.
  - reference: PMID:31811563
    reference_title: 'Late-onset generalized myasthenia gravis: clinical features, treatment, and outcome.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Use of prednisone + azathioprine had significantly positive effect on outcome.
    explanation: Association in an observational late-onset cohort.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: azathioprine
      term:
        id: CHEBI:2948
        label: azathioprine
  target_mechanisms:
  - target: AChR Autoantibody Production
    treatment_effect: MODULATES
    description: Immunosuppression reduces disease activity through multiple immune processes.
    evidence:
    - reference: PMID:38152089
      reference_title: Guideline for the management of myasthenic syndromes.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      directness: DIRECT
      snippet: GKS as monotherapy or in combination with AZA are first-choice agents for immunotherapy.
      explanation: Disease-modifying use; no claim of selective plasma-cell removal.
- name: Cyclosporine
  description: Cyclosporine is an alternative when first-choice treatment is unsuitable. A placebo-controlled study supports efficacy, while renal, vascular, and other toxicities and comorbidity constrain use.
  action_category: THERAPEUTIC
  evidence:
  - reference: PMID:38152089
    reference_title: Guideline for the management of myasthenic syndromes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: CSA was effective in a placebo-controlled study of class 1 evidence.
    explanation: Evidence and limits summarized by the guideline.
  therapeutic_modality: SMALL_MOLECULE
  target_mechanisms:
  - target: AChR Autoantibody Production
    treatment_effect: MODULATES
    description: Alternative broad immunotherapy; a selective antibody-production effect is not measured in the cited clinical synthesis.
    evidence:
    - reference: PMID:38152089
      reference_title: Guideline for the management of myasthenic syndromes.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      directness: DIRECT
      snippet: Other immunotherapies should be considered as second-choice treatment for MG with increased disease activity and can be used when contraindications, intolerance, or inadequate response to adequate doses of standard therapy apply.
      explanation: Conditional second-choice use.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: Cyclosporine
      term:
        id: NCIT:C406
        label: Cyclosporine
- name: Mycophenolate Mofetil
  description: Mycophenolate is used as an alternative steroid-sparing therapy. Short randomized trials did not demonstrate the intended initial or steroid-sparing advantages; longer observational follow-up suggested benefit. It should not be presented as proven equivalent to azathioprine.
  action_category: THERAPEUTIC
  evidence:
  - reference: PMID:38152089
    reference_title: Guideline for the management of myasthenic syndromes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Long-term open-label follow-up data gave evidence of a positive effect of MMF on clinical course as well as a steroid-sparing effect.
    explanation: Evidence and limits summarized by the guideline.
  therapeutic_modality: SMALL_MOLECULE
  target_mechanisms:
  - target: AChR Autoantibody Production
    treatment_effect: MODULATES
    description: Alternative broad immunotherapy; a selective antibody-production effect is not measured in the cited clinical synthesis.
    evidence:
    - reference: PMID:38152089
      reference_title: Guideline for the management of myasthenic syndromes.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      directness: DIRECT
      snippet: Other immunotherapies should be considered as second-choice treatment for MG with increased disease activity and can be used when contraindications, intolerance, or inadequate response to adequate doses of standard therapy apply.
      explanation: Conditional second-choice use.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: Mycophenolate Mofetil
      term:
        id: NCIT:C1468
        label: Mycophenolate Mofetil
- name: Tacrolimus
  description: Tacrolimus is an alternative immunosuppressant. Two controlled trials did not confirm their steroid-sparing endpoints; post hoc score improvements provide more limited support.
  action_category: THERAPEUTIC
  evidence:
  - reference: PMID:38152089
    reference_title: Guideline for the management of myasthenic syndromes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Two controlled trials could not confirm a steroid-sparing effect of tacrolimus after 6 and 12 months, but a post hoc analysis of the results suggested a benefit in terms of improvement of quantitative myasthenia scores.
    explanation: Evidence and limits summarized by the guideline.
  therapeutic_modality: SMALL_MOLECULE
  target_mechanisms:
  - target: AChR Autoantibody Production
    treatment_effect: MODULATES
    description: Alternative broad immunotherapy; a selective antibody-production effect is not measured in the cited clinical synthesis.
    evidence:
    - reference: PMID:38152089
      reference_title: Guideline for the management of myasthenic syndromes.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      directness: DIRECT
      snippet: Other immunotherapies should be considered as second-choice treatment for MG with increased disease activity and can be used when contraindications, intolerance, or inadequate response to adequate doses of standard therapy apply.
      explanation: Conditional second-choice use.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: Tacrolimus
      term:
        id: NCIT:C1311
        label: Tacrolimus
- name: Methotrexate
  description: Methotrexate may be considered as a reserve immunosuppressant. Small comparative and placebo-controlled studies gave mixed steroid-sparing results, so evidence is less secure than for first-choice treatment.
  action_category: THERAPEUTIC
  evidence:
  - reference: PMID:38152089
    reference_title: Guideline for the management of myasthenic syndromes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: By contrast, a placebo-controlled study over 12 months failed to demonstrate a steroid-sparing effect of 20 mg MTX (p.o.).
    explanation: Evidence and limits summarized by the guideline.
  therapeutic_modality: SMALL_MOLECULE
  target_mechanisms:
  - target: AChR Autoantibody Production
    treatment_effect: MODULATES
    description: Alternative broad immunotherapy; a selective antibody-production effect is not measured in the cited clinical synthesis.
    evidence:
    - reference: PMID:38152089
      reference_title: Guideline for the management of myasthenic syndromes.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      directness: DIRECT
      snippet: Other immunotherapies should be considered as second-choice treatment for MG with increased disease activity and can be used when contraindications, intolerance, or inadequate response to adequate doses of standard therapy apply.
      explanation: Conditional second-choice use.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: Methotrexate
      term:
        id: NCIT:C642
        label: Methotrexate
- name: Thymectomy for Nonthymomatous AChR-Positive Generalized MG
  description: MGTX randomized 126 adults aged 18–65 with AChR-positive generalized nonthymomatous MG of less than five years duration to extended transsternal thymectomy plus prednisone or prednisone alone. Surgery improved the three-year time-weighted QMG score and reduced steroid requirements. Older adults were included; age-subgroup analyses do not establish benefit exclusively in early-onset disease. Evidence for very old patients, long-standing disease, pure ocular disease, and other surgical approaches is less direct. MuSK-positive MG without a tumor is not an immunological indication.
  action_category: THERAPEUTIC
  evidence:
  - reference: PMID:27509100
    reference_title: Randomized Trial of Thymectomy in Myasthenia Gravis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Patients 18 to 65 years of age who had generalized nonthymomatous myasthenia gravis with a disease duration of less than 5 years were included
    explanation: Enrollment age is not a proof of exclusively early-onset disease.
  - reference: PMID:27509100
    reference_title: Randomized Trial of Thymectomy in Myasthenia Gravis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Patients who underwent thymectomy had a lower time-weighted average Quantitative Myasthenia Gravis score over a 3-year period than those who received prednisone alone (6.15 vs. 8.99, P<0.001)
    explanation: Randomized clinical outcome.
  - reference: PMID:40022458
    reference_title: Can Non-Thymomatous Late-Onset Myasthenia Gravis Benefit From Thymectomy? A Systematic Review and Meta-Analysis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Thymectomy may be a potentially effective treatment for LOMG, particularly in patients who undergo the procedure soon after diagnosis. A randomized controlled study for LOMG patients is needed.
    explanation: Mostly observational meta-analysis supports continued uncertainty for a dedicated late-onset treatment effect.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: Thymectomy
    term:
      id: NCIT:C29894
      label: Thymectomy
  target_mechanisms:
  - target: Ectopic Thymic Germinal Center Formation
    treatment_effect: INHIBITS
    description: Removes the thymic tissue harboring ectopic follicles; persistent peripheral autoreactive cells can sustain disease.
    evidence:
    - reference: PMID:39105625
      reference_title: 'Myasthenia gravis: the future is here.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      directness: DIRECT
      snippet: The precise mechanism by which thymus removal imparts clinical benefit is not fully understood.
      explanation: Clinical benefit does not prove a single mediator.
    - reference: PMID:39105625
      reference_title: 'Myasthenia gravis: the future is here.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      directness: INDIRECT
      snippet: One likely hypothesis is that thymectomy eliminates a considerable source of antigenic stimulation, ultimately reducing the production of AChR antibodies, but autoreactive cells have exited the thymus remain and drive production of pathogenic antibodies
      explanation: Supports removal of a thymic antigenic source while qualifying the mediator and persistent peripheral activity.
- name: Thymoma-Directed Treatment
  description: Assess and manage thymoma according to tumor stage and operability, generally with surgical removal when feasible. This oncological indication applies independently of MG severity or onset-age category; removal does not guarantee resolution of MG.
  action_category: THERAPEUTIC
  evidence:
  - reference: PMID:38152089
    reference_title: Guideline for the management of myasthenic syndromes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Every MG patient must be evaluated for the presence of a thymoma. Thymomas must be surgically removed at any age regardless of the severity of myasthenia.
    explanation: Guideline recommendation, with operability and multimodal exceptions described in its surrounding text.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: Thymectomy
    term:
      id: NCIT:C29894
      label: Thymectomy
  target_mechanisms:
  - target: Thymoma
    treatment_effect: INHIBITS
    description: Resects the tumor when operable.
    evidence:
    - reference: PMID:38152089
      reference_title: Guideline for the management of myasthenic syndromes.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      directness: DIRECT
      snippet: Every MG patient must be evaluated for the presence of a thymoma. Thymomas must be surgically removed at any age regardless of the severity of myasthenia.
      explanation: Explicit resection recommendation; the care description preserves operability exceptions.
- name: Rituximab
  description: 'CD20-directed B-cell depletion is particularly supported for MuSK-positive MG. AChR-positive trial results depend on population and endpoint: BeatMG missed its primary steroid-sparing endpoint, whereas RINOMAX supported benefit in new-onset disease. Infusion, infection, and immunoglobulin risks require specialist monitoring; no efficacy ranking against other targeted drugs is inferred.'
  action_category: THERAPEUTIC
  evidence:
  - reference: PMID:38152089
    reference_title: Guideline for the management of myasthenic syndromes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Rituximab is a monoclonal chimeric Ab that specifically binds to the marker CD20 on the membrane of pre-B and mature B lymphocytes and causes transient B-cell depletion
    explanation: Mechanism summarized in the guideline.
  - reference: PMID:38152089
    reference_title: Guideline for the management of myasthenic syndromes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Case series suggest that B-cell-depleting treatment with rituximab is effective, particularly in MuSK myasthenia, and should therefore be considered early as a first-choice treatment option as well.
    explanation: Supports the particular role of rituximab in MuSK-positive MG, based on case-series evidence.
  - reference: PMID:38152089
    reference_title: Guideline for the management of myasthenic syndromes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: The recently completed randomized-controlled phase III RINOMAX trial demonstrated that patients with new-onset AChR-Ab-positive gMG on a low-dose rituximab regimen (one infusion of 500 mg) were significantly more likely to meet the primary end point of minimal disease manifestation at 16 weeks than placebo-treated patients.
    explanation: New-onset trial context; not all refractory MG populations.
  therapeutic_modality: MONOCLONAL_ANTIBODY
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: Rituximab
      term:
        id: NCIT:C1702
        label: Rituximab
  target_mechanisms:
  - target: AChR Autoantibody Production
    treatment_effect: MODULATES
    description: B-cell depletion can reduce replenishment of antibody-producing cells; long-lived plasma cells are not uniformly depleted.
    evidence:
    - reference: PMID:38152089
      reference_title: Guideline for the management of myasthenic syndromes.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      directness: DIRECT
      snippet: Rituximab is a monoclonal chimeric Ab that specifically binds to the marker CD20 on the membrane of pre-B and mature B lymphocytes and causes transient B-cell depletion
      explanation: The direct target is the B-cell compartment, with downstream antibody effects.
- name: Eculizumab
  description: C5 inhibition for selected AChR-positive generalized MG. REGAIN missed its prespecified worst-rank primary analysis but secondary endpoints favored treatment; later use must be interpreted with its infection risks and patient selection. Meningococcal vaccination and infection precautions remain necessary; these agents do not directly stop autoantibody production.
  action_category: THERAPEUTIC
  evidence:
  - reference: PMID:38152089
    reference_title: Guideline for the management of myasthenic syndromes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: The primary study end point (improvement in activities of daily living measured by the so-called worst rank ANCOVA analysis) was not met; however, almost all secondary end points
    explanation: Guideline trial synthesis.
  therapeutic_modality: MONOCLONAL_ANTIBODY
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: Eculizumab
      term:
        id: NCIT:C48386
        label: Eculizumab
  target_mechanisms:
  - target: Complement Activation at the Endplate
    treatment_effect: INHIBITS
    description: Blocks terminal complement activity and membrane attack complex formation.
    evidence:
    - reference: PMID:38152089
      reference_title: Guideline for the management of myasthenic syndromes.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      directness: DIRECT
      snippet: Eculizumab is a humanized monoclonal IgG-Ab that binds to the protein C5 of the complement system and is designed to prevent the formation of the membrane attack complex induced by C5b
      explanation: Class mechanism; individual binding properties differ.
- name: Ravulizumab
  description: Longer-acting C5 inhibition for AChR-positive generalized MG. CHAMPION showed an improved MG-ADL primary endpoint; dosing and safety follow the applicable label. Meningococcal vaccination and infection precautions remain necessary; these agents do not directly stop autoantibody production.
  action_category: THERAPEUTIC
  evidence:
  - reference: PMID:38152089
    reference_title: Guideline for the management of myasthenic syndromes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: In the phase III CHAMPION trial, 26 weeks after initiation of therapy, the primary end point (improvement in MG-ADL from baseline) was significantly better in the ravulizumab group than in the placebo group.
    explanation: Guideline trial synthesis.
  therapeutic_modality: MONOCLONAL_ANTIBODY
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: Ravulizumab
      term:
        id: NCIT:C124657
        label: Ravulizumab
  target_mechanisms:
  - target: Complement Activation at the Endplate
    treatment_effect: INHIBITS
    description: Blocks terminal complement activity and membrane attack complex formation.
    evidence:
    - reference: PMID:38152089
      reference_title: Guideline for the management of myasthenic syndromes.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      directness: DIRECT
      snippet: A further development of eculizumab is the complement factor 5 inhibitor ravulizumab, in which the infusion frequency of maintenance therapy is 8 weeks instead of two.
      explanation: Drug-specific C5 mechanism.
- name: Zilucoplan
  description: A complement-inhibitory macrocyclic peptide for AChR-positive generalized MG. It binds C5 and also impedes C5b–C6 interaction. Its mechanism does not make it appropriate for the predominant IgG4 MuSK pathway. Meningococcal vaccination and infection precautions remain necessary; these agents do not directly stop autoantibody production.
  action_category: THERAPEUTIC
  evidence:
  - reference: PMID:38152089
    reference_title: Guideline for the management of myasthenic syndromes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Another complement factor 5 inhibitor is zilucoplan, which was successfully tested in a phase III RAISE trial in the indication MG.
    explanation: Guideline trial synthesis.
  therapeutic_modality: PEPTIDE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: Zilucoplan
      term:
        id: NCIT:C147518
        label: Zilucoplan
  target_mechanisms:
  - target: Complement Activation at the Endplate
    treatment_effect: INHIBITS
    description: Blocks terminal complement activity and membrane attack complex formation.
    evidence:
    - reference: PMID:39105625
      reference_title: 'Myasthenia gravis: the future is here.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      directness: DIRECT
      snippet: Zilucoplan is a small macrocyclic peptide that not only binds to C5 to inhibit its cleavage, but also interferes with C5b binding to C6.
      explanation: Drug-specific terminal-complement mechanism.
- name: Efgartigimod
  description: Efgartigimod reduces IgG through FcRn blockade and has randomized evidence in AChR-positive generalized MG; seronegative disease is a separate trial question.
  action_category: THERAPEUTIC
  evidence:
  - reference: PMID:39105625
    reference_title: 'Myasthenia gravis: the future is here.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Efgartigimod and rozanolixizumab are approved for AChR antibody–positive MG (128, 129), with the latter further approved for MuSK antibody–positive MG.
    explanation: The 2024 review records the antibody-specific indications.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: Efgartigimod Alfa
      term:
        id: NCIT:C171817
        label: Efgartigimod Alfa
  target_mechanisms:
  - target: AChR Autoantibody Binding
    treatment_effect: MODULATES
    description: Lowers circulating IgG available to bind the junction rather than directly displacing receptor-bound antibody.
    evidence:
    - reference: PMID:38152089
      reference_title: Guideline for the management of myasthenic syndromes.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      directness: DIRECT
      snippet: Efgartigimod can lower the concentration of auto-Ab directed against AChR and reduce disease activity
      explanation: IgG reduction supplies an indirect link to reduced antibody exposure.
- name: Rozanolixizumab
  description: Rozanolixizumab is an FcRn-directed treatment for AChR- or MuSK-antibody-positive generalized MG, with phase III evidence. Antibody lowering does not guarantee response in every patient.
  action_category: THERAPEUTIC
  evidence:
  - reference: PMID:39105625
    reference_title: 'Myasthenia gravis: the future is here.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Efgartigimod and rozanolixizumab are approved for AChR antibody–positive MG (128, 129), with the latter further approved for MuSK antibody–positive MG.
    explanation: The 2024 review records the antibody-specific indications.
  therapeutic_modality: MONOCLONAL_ANTIBODY
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: Rozanolixizumab
      term:
        id: NCIT:C152270
        label: Rozanolixizumab
  target_mechanisms:
  - target: AChR Autoantibody Binding
    treatment_effect: MODULATES
    description: Lowers circulating IgG available to bind the junction rather than directly displacing receptor-bound antibody.
    evidence:
    - reference: PMID:39105625
      reference_title: 'Myasthenia gravis: the future is here.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      directness: DIRECT
      snippet: This results in significant reductions in circulating antibodies within days of the initial treatment. Efgartigimod and rozanolixizumab are approved for AChR antibody–positive MG (128, 129), with the latter further approved for MuSK antibody–positive MG.
      explanation: Review connects FcRn antibody lowering to the named drugs and serotype indications.
  - target: MuSK Autoantibody Binding
    treatment_effect: MODULATES
    description: Reduces IgG available to reach and bind MuSK.
    evidence:
    - reference: PMID:39105625
      reference_title: 'Myasthenia gravis: the future is here.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      directness: DIRECT
      snippet: This results in significant reductions in circulating antibodies within days of the initial treatment. Efgartigimod and rozanolixizumab are approved for AChR antibody–positive MG (128, 129), with the latter further approved for MuSK antibody–positive MG.
      explanation: Review connects FcRn antibody lowering to the named drugs and serotype indications.
- name: Nipocalimab
  description: FcRn-directed therapy is labeled for AChR- or MuSK-antibody-positive generalized MG, including adults. In the seropositive primary efficacy population, mean MG-ADL improvement averaged over weeks 22–24 exceeded placebo. This is no longer solely an investigational therapy. Active infection, infusion reactions, vaccination, and immunoglobulin interactions require attention; older-adult comparative data remain limited.
  action_category: THERAPEUTIC
  evidence:
  - reference: url:https://www.jnjlabels.com/package-insert/product-monograph/prescribing-information/IMAAVY-pi.pdf
    reference_title: https://www.jnjlabels.com/package-insert/product-monograph/prescribing-information/IMAAVY-pi.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: IMAAVY is indicated for the treatment of generalized myasthenia gravis (gMG) in adult and pediatric patients 12 years of age and older who are anti-acetylcholine receptor (AChR) or anti-muscle-specific tyrosine kinase (MuSK) antibody positive.
    explanation: Current label includes adults and either antibody subgroup.
  therapeutic_modality: MONOCLONAL_ANTIBODY
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: Nipocalimab
      term:
        id: NCIT:C170891
        label: Nipocalimab
  target_mechanisms:
  - target: AChR Autoantibody Binding
    treatment_effect: MODULATES
    description: Reduces circulating IgG and pathogenic autoantibody exposure.
    evidence:
    - reference: url:https://www.jnjlabels.com/package-insert/product-monograph/prescribing-information/IMAAVY-pi.pdf
      reference_title: https://www.jnjlabels.com/package-insert/product-monograph/prescribing-information/IMAAVY-pi.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      directness: DIRECT
      snippet: Nipocalimab-aahu is a human IgG1 monoclonal antibody that binds to neonatal Fc receptor (FcRn), resulting in the reduction of circulating IgG levels.
      explanation: Label pharmacology.
  - target: MuSK Autoantibody Binding
    treatment_effect: MODULATES
    description: Reduces circulating IgG and pathogenic autoantibody exposure.
    evidence:
    - reference: url:https://www.jnjlabels.com/package-insert/product-monograph/prescribing-information/IMAAVY-pi.pdf
      reference_title: https://www.jnjlabels.com/package-insert/product-monograph/prescribing-information/IMAAVY-pi.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      directness: DIRECT
      snippet: Nipocalimab-aahu is a human IgG1 monoclonal antibody that binds to neonatal Fc receptor (FcRn), resulting in the reduction of circulating IgG levels.
      explanation: Label pharmacology.
- name: Inebilizumab
  description: CD19-directed cytolytic therapy is labeled for adults with AChR- or MuSK-antibody-positive generalized MG. MINT demonstrated overall MG-ADL benefit at week 26. The label describes the therapeutic mechanism as presumed; CD20 counts were used to assess B-cell depletion because the drug interferes with CD19 assays. Screen for HBV, tuberculosis and immunoglobulin deficiency, address vaccination and active infection, and monitor infusion reactions and immunoglobulins.
  action_category: THERAPEUTIC
  evidence:
  - reference: url:https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/761142s004lbl.pdf
    reference_title: https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/761142s004lbl.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: UPLIZNA is indicated for the treatment of generalized myasthenia gravis (gMG) in adult patients who are anti-acetylcholine receptor (AChR) or anti-muscle specific tyrosine kinase (MuSK) antibody positive.
    explanation: FDA label includes both serologic groups as alternatives.
  therapeutic_modality: MONOCLONAL_ANTIBODY
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: Inebilizumab
      term:
        id: NCIT:C88283
        label: Inebilizumab
  target_mechanisms:
  - target: AChR Autoantibody Production
    treatment_effect: MODULATES
    description: Depletes CD19-expressing B-lineage cells, with downstream effects on humoral autoimmunity.
    evidence:
    - reference: url:https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/761142s004lbl.pdf
      reference_title: https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/761142s004lbl.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      directness: DIRECT
      snippet: Following cell surface binding to B lymphocytes, inebilizumab-cdon results in antibody-dependent cellular cytolysis.
      explanation: Label describes the cellular action; complete clinical mediation is not established.
- name: Intravenous Immunoglobulin
  description: Rapid immunomodulation is used for exacerbation or crisis and selected bridging situations. Selection versus plasma exchange depends on comorbidity, access, and clinical circumstances. Maintenance use is individualized and has a different evidence base from crisis treatment.
  action_category: THERAPEUTIC
  evidence:
  - &id001
    reference: PMID:38152089
    reference_title: Guideline for the management of myasthenic syndromes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: In the event of an impending and manifest myasthenic crisis, rapid admission and treatment must be provided in a monitoring or intensive care unit with experience in neuromuscular disease. IVIG or PE/IA must be used in this situation.
    explanation: Urgent rescue guideline recommendation.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Intravenous Immunoglobulin Therapy
    term:
      id: NCIT:C121331
      label: Intravenous Immunoglobulin Therapy
  target_mechanisms:
  - target: Impaired Neuromuscular Transmission
    treatment_effect: MODULATES
    description: Improves disease activity through immune effects; it does not mechanically replace ventilation.
    evidence:
    - reference: PMID:38152089
      reference_title: Guideline for the management of myasthenic syndromes.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      directness: DIRECT
      snippet: In the treatment of myasthenic exacerbations, PE and IVIG are considered equivalent.
      explanation: Guideline synthesis of comparative short-term treatment.
- name: Plasma Exchange or Immunoadsorption
  description: Rapid removal of circulating humoral factors is used for crisis, severe exacerbation, and selected perioperative stabilization. Benefit is temporary without continuing disease control. MuSK-positive disease may respond particularly well, although comparative serotype-specific trials are limited; vascular, coagulation, and hemodynamic risks matter in older patients.
  action_category: THERAPEUTIC
  evidence:
  - *id001
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Plasmapheresis
    term:
      id: NCIT:C15304
      label: Plasmapheresis
  target_mechanisms:
  - target: AChR Autoantibody Binding
    treatment_effect: MODULATES
    description: Reduces circulating pathogenic antibody available to reach the junction.
    evidence:
    - reference: PMID:38152089
      reference_title: Guideline for the management of myasthenic syndromes.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      directness: DIRECT
      snippet: In this procedure, either IgG is removed semi-selectively with a tryptophan-polyvinyl gel matrix
      explanation: Immunoadsorption removes immunoglobulins; the target link concerns antibody exposure.
  - target: MuSK Autoantibody Binding
    treatment_effect: MODULATES
    description: Reduces circulating pathogenic antibody available to reach the junction.
    evidence:
    - reference: PMID:38152089
      reference_title: Guideline for the management of myasthenic syndromes.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      directness: DIRECT
      snippet: In this procedure, either IgG is removed semi-selectively with a tryptophan-polyvinyl gel matrix
      explanation: Immunoadsorption removes immunoglobulins; the target link concerns antibody exposure.
- name: Crisis Monitoring and Respiratory Support
  description: Urgent specialist monitored or intensive care includes serial respiratory and bulbar assessment, airway protection or ventilation when necessary, treatment of precipitants, and concurrent rapid immunotherapy.
  action_category: THERAPEUTIC
  evidence:
  - *id001
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: Mechanical Ventilation
    term:
      id: NCIT:C70909
      label: Mechanical Ventilation
  target_mechanisms:
  - target: Myasthenic Crisis
    treatment_effect: BYPASSES
    description: Ventilation supports gas exchange during severe respiratory weakness.
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK559331/
      reference_title: Myasthenia Gravis - StatPearls - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      directness: DIRECT
      snippet: myasthenic crisis, an acute respiratory paralysis that requires intensive care
      explanation: Respiratory complication requiring intensive care.
- name: Ocular Symptom Support
  description: Occlusion can relieve diplopia; selected stable small-angle deviations may benefit from prisms. Ptosis aids and, in persistent stable refractory cases, specialist surgical assessment can complement medical treatment.
  action_category: THERAPEUTIC
  evidence:
  - reference: PMID:33458590
    reference_title: 'Myasthenia gravis: MuSK MG, late-onset MG and ocular MG.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Eye patches for diplopia, prisms when eye movement limitation is mild and eyelid crutches for ptosis can be useful.
    explanation: Symptomatic ocular support.
  therapeutic_modality: DEVICE
  target_mechanisms:
  - target: Ptosis
    treatment_effect: MODULATES
    description: Compensates for the visual consequences without correcting autoimmunity.
    evidence:
    - reference: PMID:33458590
      reference_title: 'Myasthenia gravis: MuSK MG, late-onset MG and ocular MG.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      directness: DIRECT
      snippet: Eye patches for diplopia, prisms when eye movement limitation is mild and eyelid crutches for ptosis can be useful.
      explanation: Specific ocular aids.
  - target: Diplopia
    treatment_effect: MODULATES
    description: Compensates for the visual consequences without correcting autoimmunity.
    evidence:
    - reference: PMID:33458590
      reference_title: 'Myasthenia gravis: MuSK MG, late-onset MG and ocular MG.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      directness: DIRECT
      snippet: Eye patches for diplopia, prisms when eye movement limitation is mild and eyelid crutches for ptosis can be useful.
      explanation: Specific ocular aids.
- name: Vaccination and Infection-Risk Management
  description: Review vaccination and infection risks before immunotherapy. Complement inhibition requires meningococcal precautions and, where urgent initiation precludes adequate vaccine protection, antibiotic prophylaxis according to the applicable regimen. Live vaccines are generally avoided during immunotherapy. Protection is not complete after vaccination.
  action_category: THERAPEUTIC
  evidence:
  - reference: PMID:38152089
    reference_title: Guideline for the management of myasthenic syndromes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: If the effectiveness of the vaccination cannot be waited for or if a vaccination success cannot be assumed due to the immunotherapy, prophylactic antibiotic therapy should be started in addition to the vaccination.
    explanation: Guideline complement-inhibitor precaution.
- name: Clinical and Treatment-Toxicity Monitoring
  description: Assess clinical strength, function, MG-ADL or related scales, quality of life, and treatment toxicity over time. Routine antibody titers should not substitute for clinical disease-activity assessment.
  action_category: MONITORING
  evidence:
  - reference: PMID:38152089
    reference_title: Guideline for the management of myasthenic syndromes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Therefore, routine clinical use of autoantibody testing to determine disease activity cannot be recommended.
    explanation: Correlation is too variable for routine activity monitoring.
- name: Fatigue Management and Rehabilitation
  description: Assess persistent fatigue separately from muscle weakness, optimize disease control and sleep, and support appropriately paced exercise, nutrition, and psychological care. Fatigue-drug evidence is limited.
  action_category: THERAPEUTIC
  evidence:
  - reference: PMID:38152089
    reference_title: Guideline for the management of myasthenic syndromes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Patients’ self-efficacy should be enhanced via modification of lifestyle factors, such as good sleep hygiene, balanced diet, avoidance of excessive alcohol consumption, and performance of aerobic exercise. If necessary, additional psychological support may be helpful.
    explanation: Guideline supportive care.
  target_mechanisms:
  - target: Fatigue
    treatment_effect: MODULATES
    description: Addresses contributors to perceived fatigue and function.
    evidence:
    - reference: PMID:38152089
      reference_title: Guideline for the management of myasthenic syndromes.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      directness: DIRECT
      snippet: Patients should be encouraged to not overprotect themselves or exert themselves beyond the limits set by MG.
      explanation: Individual pacing rather than unrestricted exercise.
- name: Pregnancy and Reproductive Counseling
  description: Arrange specialist counseling before or during pregnancy, review drug-specific fetal risks and treatment alternatives, and coordinate maternal and neonatal care. Transient neonatal disease from maternal antibody transfer is distinct from inherited congenital myasthenic syndromes.
  action_category: COUNSELING_INFORMATIONAL
  evidence:
  - reference: PMID:38152089
    reference_title: Guideline for the management of myasthenic syndromes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: In case of pregnancy and a desire to have children, a specific consultation should be made in a center specialized in myasthenia.
    explanation: Specialist counseling recommendation.
  - reference: PMID:38152089
    reference_title: Guideline for the management of myasthenic syndromes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Because of the risk of neonatal MG and peripartum deterioration of maternal MG, child delivery should be planned in a maximum care hospital, including those with neonatology and neuropediatric expertise and intensive care monitoring capabilities.
    explanation: Supports coordinated delivery and neonatal planning.
- name: Medication and Exacerbation Education
  description: Review new medications for possible worsening, discuss infection and intercurrent-illness plans, and teach recognition of bulbar or respiratory deterioration. Medication risk is contextual and should not be replaced by a blanket prohibition of every drug reported to worsen MG.
  action_category: COUNSELING_INFORMATIONAL
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK559331/
    reference_title: Myasthenia Gravis - StatPearls - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: take their medications as directed and to avoid taking new medicines without checking with the medical provider.
    explanation: Medication review and adherence advice.
references:
- reference: GEO:GSE233180
  title: Thymic B lineage cell landscape in Myasthenia gravis
- reference: ORPHA:391490
  title: Adult-onset myasthenia gravis
- reference: PMID:16186537
  title: Increasing incidence of late-onset anti-AChR antibody-seropositive myasthenia gravis.
- reference: PMID:22476514
  title: Characteristics of late-onset myasthenia gravis.
- reference: PMID:23055271
  title: Risk for myasthenia gravis maps to a (151) Pro→Ala change in TNIP1 and to human leukocyte antigen-B*08.
- reference: PMID:23893883
  title: 'Late-onset myasthenia gravis: a review when incidence in older adults keeps increasing.'
- reference: PMID:24297891
  title: MuSK IgG4 autoantibodies cause myasthenia gravis by inhibiting binding between MuSK and Lrp4.
- reference: PMID:26562150
  title: 'Genome-Wide Association Study of Late-Onset Myasthenia Gravis: Confirmation of TNFRSF11A and Identification of ZBTB10 and Three Distinct HLA Associations.'
- reference: PMID:27273086
  title: 'Thymic Germinal Centers and Corticosteroids in Myasthenia Gravis: an Immunopathological Study in 1035 Cases and a Critical Review.'
- reference: PMID:27509100
  title: Randomized Trial of Thymectomy in Myasthenia Gravis.
- reference: PMID:28495048
  title: HLA and age of onset in myasthenia gravis.
- reference: PMID:29125185
  title: Thymus involvement in early-onset myasthenia gravis.
- reference: PMID:30918333
  title: Cytometric cell-based assays for anti-striational antibodies in myasthenia gravis with myositis and/or myocarditis.
- reference: PMID:31811563
  title: 'Late-onset generalized myasthenia gravis: clinical features, treatment, and outcome.'
- reference: PMID:33458590
  title: 'Myasthenia gravis: MuSK MG, late-onset MG and ocular MG.'
- reference: PMID:34400559
  title: Myasthenia gravis genome-wide association study implicates AGRN as a risk locus.
- reference: PMID:36074148
  title: Receptor clustering and pathogenic complement activation in myasthenia gravis depend on synergy between antibodies with multiple subunit specificities.
- reference: PMID:38152089
  title: Guideline for the management of myasthenic syndromes.
- reference: PMID:38505076
  title: Anti-titin antibodies in a cohort of myasthenia gravis patients.
- reference: PMID:38886398
  title: Comparison of juvenile and adult myasthenia gravis in a French cohort with focus on thymic histology.
- reference: PMID:39105625
  title: 'Myasthenia gravis: the future is here.'
- reference: PMID:39537604
  title: Genome-wide meta-analysis of myasthenia gravis uncovers new loci and provides insights into polygenic prediction.
- reference: PMID:40022458
  title: Can Non-Thymomatous Late-Onset Myasthenia Gravis Benefit From Thymectomy? A Systematic Review and Meta-Analysis.
- reference: PMID:40117520
  title: Single-Cell Transcriptomics Identifies a Prominent Role for the MIF-CD74 Axis in Myasthenia Gravis Thymus.
- reference: PMID:40675734
  title: Epidemiology of myasthenia gravis.
- reference: PMID:40675735
  title: 'Special populations in myasthenia gravis: Early, late, and very late-onset MG.'
- reference: clinicaltrials:NCT00294658
  title: A Multi-Center, Single-Blind, Randomized Study Comparing Thymectomy to No Thymectomy in Non-Thymomatous Myasthenia Gravis (MG) Patients Receiving Prednisone
- reference: clinicaltrials:NCT03971422
  title: A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study Evaluating Efficacy and Safety of Rozanolixizumab in Adult Patients With Generalized Myasthenia Gravis
- reference: clinicaltrials:NCT04524273
  title: A Randomized, Double-blind, Multicenter, Placebo-controlled Phase 3 Study With Open-label Period to Evaluate the Efficacy and Safety of Inebilizumab in Adults With Myasthenia Gravis
- reference: clinicaltrials:NCT04951622
  title: Phase 3, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy, Safety, Pharmacokinetics, and Pharmacodynamics of Nipocalimab Administered to Adults With Generalized Myasthenia Gravis
- reference: clinicaltrials:NCT06193889
  title: 'KYSA-6: A Phase 2/3, Open-Label, Randomized, Controlled, Multicenter Study of KYV-101, an Autologous Fully Human Anti-CD19 Chimeric Antigen Receptor T-cell (CD19 CAR T) Therapy, Versus Ongoing Standard-Of-Care Immunosuppressive Therapy in Patients With Generalized Myasthenia Gravis'
- reference: clinicaltrials:NCT06298552
  title: A Randomized, Double-Blinded, Placebo-Controlled, Phase 3, Parallel-Group Design Study Evaluating the Efficacy and Safety of Efgartigimod IV in Adult Participants With Acetylcholine Receptor Binding Antibody Seronegative Generalized Myasthenia Gravis
- reference: clinicaltrials:NCT06414954
  title: A Phase 2b, Randomised, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy, Safety, and Tolerability of 3 Dose Levels of NMD670 Over 21 Days in Adult Patients With AChR/MuSK-Ab+ Myasthenia Gravis
- reference: url:https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/761142s004lbl.pdf
  title: https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/761142s004lbl.pdf
- reference: url:https://www.jnjlabels.com/package-insert/product-monograph/prescribing-information/IMAAVY-pi.pdf
  title: https://www.jnjlabels.com/package-insert/product-monograph/prescribing-information/IMAAVY-pi.pdf
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK559331/
  title: Myasthenia Gravis - StatPearls - NCBI Bookshelf
  tags:
  - StatPearls
epidemiology:
- name: Increasing late-onset incidence in a Danish population
  description: A population study of nonthymomatous AChR-seropositive MG in Denmark during 1970–1999 found stable early-onset incidence and rising late-onset incidence. These historical, serotype-specific rates are not a contemporary global incidence estimate for all adult-onset MG.
  evidence:
  - reference: PMID:16186537
    reference_title: Increasing incidence of late-onset anti-AChR antibody-seropositive myasthenia gravis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: The mean annual incidence rate of early-onset MG was constant at 3.5 x 10(-6). In late-onset MG, the rate increased from 4.7 to 20.8 x 10(-6).
    explanation: Historical population observation; not proof of a particular environmental cause.
- name: Contemporary MG prevalence context
  description: A 2025 epidemiology review summarizes approximately 20 incident cases per million person-years and 25 prevalent cases per 100,000 for MG overall. These are not measured adult-onset-only estimates. Population aging, improved ascertainment, and survival contribute to increasing prevalence.
  evidence:
  - reference: PMID:40675734
    reference_title: Epidemiology of myasthenia gravis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Recent high-quality studies have found an annual MG incidence of approximately 20 per million person-years, and a prevalence of approximately 25 per 100,000 population.
    explanation: All-MG context, deliberately not encoded as a prevalence band for this subtype.
  - reference: PMID:40675734
    reference_title: Epidemiology of myasthenia gravis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: MG prevalence has increased in recent years because of more elderly people in the general population, improved case finding, and improved MG treatment with reduced mortality.
    explanation: The review identifies multiple contributors rather than a single biological cause.
diagnosis:
- name: Clinical assessment with confirmatory testing
  description: Identify fatigable, fluctuating weakness and its ocular, bulbar, respiratory, axial, or limb distribution. Confirm a compatible syndrome with antibody testing and/or neuromuscular electrophysiology; exclude mimics when the pattern or treatment response is atypical.
  evidence:
  - reference: PMID:38152089
    reference_title: Guideline for the management of myasthenic syndromes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: The diagnosis of MG is based on the history and physical findings of fatigable and fluctuating muscle weakness. The diagnosis is confirmed by positive findings in auto-Ab diagnostics and/or electrophysiology and/or pharmacological testing.
    explanation: Guideline diagnostic framework.
- name: Serological subtyping
  description: Test AChR and, where appropriate, MuSK and other antibodies using validated assays. Cell-based AChR testing can identify some conventionally seronegative patients. LRP4 and striational antibody findings require clinical context; they do not independently establish MG.
  evidence:
  - reference: PMID:39105625
    reference_title: 'Myasthenia gravis: the future is here.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Recently, cell-based assays have been developed with plasma membrane expression of the AChR, allowing the antigen to resemble the native receptor more closely
    explanation: Describes improved antigen presentation.
  - reference: PMID:39105625
    reference_title: 'Myasthenia gravis: the future is here.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Antibodies against lipoprotein receptor–related protein 4 (LRP-4) may be found associated with the MuSK or AChR antibodies or in isolation, although they are also present in patients with motor neuron disease and patients without evidence of diseases
    explanation: LRP4 antibodies also occur in motor neuron disease and in people without disease, which is why LRP4 findings require clinical context.
- name: Repetitive nerve stimulation and single-fiber electromyography
  description: Electrophysiology supports impaired neuromuscular transmission, especially when serology is negative. Sensitivity depends on muscles tested and phenotype. SFEMG is sensitive but nonspecific; abnormal limb jitter in ocular MG does not by itself prove clinical generalization.
  evidence:
  - reference: PMID:33458590
    reference_title: 'Myasthenia gravis: MuSK MG, late-onset MG and ocular MG.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Repetitive nerve stimulation is not very useful with purely ocular symptoms. Single fiber EMG is very sensitive, but one has to be careful remembering that it is not specific to MG
    explanation: Test-specific limitations.
  - reference: PMID:33458590
    reference_title: 'Myasthenia gravis: MuSK MG, late-onset MG and ocular MG.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Presence of abnormalities in limb muscles of a patient with OMG does not indicate generalization
    explanation: Clinical distribution cannot be inferred solely from abnormal limb jitter.
- name: Thymoma assessment
  description: Evaluate the mediastinum with chest imaging for thymoma. A negative striational-antibody test does not replace imaging.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK559331/
    reference_title: Myasthenia Gravis - StatPearls - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Chest computed tomography (CT) or magnetic resonance imaging (MRI) should be performed in patients diagnosed with MG to assess for thymoma.
    explanation: Explicit imaging recommendation.
- name: Review of seronegative and atypical presentations
  description: Consider congenital myasthenic syndromes, other neuromuscular disorders, and structural ocular or brainstem causes when appropriate. Adult presentation does not exclude a congenital myasthenic syndrome; genetic testing addresses that differential, not routine confirmation of autoimmune MG.
  evidence:
  - reference: PMID:38152089
    reference_title: Guideline for the management of myasthenic syndromes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: An important, although rare, differential diagnosis of autoimmune myasthenic syndromes – not only in children but also in adults – is the congenital myasthenic syndromes
    explanation: Adult differential diagnosis.
  - reference: PMID:38152089
    reference_title: Guideline for the management of myasthenic syndromes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: If CMS is suspected, molecular genetic diagnostics must be performed to confirm the diagnosis and plan therapy.
    explanation: Genetic testing is conditional on a suspected inherited syndrome.
discussions:
- evidence:
  - reference: PMID:39537604
    reference_title: Genome-wide meta-analysis of myasthenia gravis uncovers new loci and provides insights into polygenic prediction.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: We defined EOMG cases as those under 50 years old at participation.
    explanation: The replication proxy differs from measured onset age.
  - reference: PMID:39537604
    reference_title: Genome-wide meta-analysis of myasthenia gravis uncovers new loci and provides insights into polygenic prediction.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: As no age of onset information was available, we replicated the LOMG discovery GWAS loci using the full 23andMe MG dataset.
    explanation: The late-onset replication was not restricted to verified late-onset cases.
  - reference: PMID:34400559
    reference_title: Myasthenia gravis genome-wide association study implicates AGRN as a risk locus.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: MG onset-specific analysis reveals differences in the genetic architecture of early-onset MG (EOMG) versus late-onset MG (LOMG).
    explanation: The abstract supports differences, not complete genetic separation.
  discussion_id: adult-mg-interpretation-1
  prompt: Onset-associated genetic architecture and ascertainment
  rationale: Onset-age strata show differing HLA and non-HLA associations, with shared susceptibility and substantial ascertainment limits. Older studies were enriched for European AChR-positive, nonthymomatous disease and early-onset cohorts could include adolescents. The 2024 discovery analysis included 5,708 cases and 432,028 controls and reused prior European cohorts; replication used 3,989 self-reported cases and 226,643 controls. Its early-onset replication used age below 50 at participation, while late-onset replication used all cases because onset age was unavailable. These results do not prove that the age strata are distinct diseases or establish clinical diagnostic use of polygenic scores.
  kind: INTERPRETATION
  status: OPEN
- evidence:
  - reference: PMID:30918333
    reference_title: Cytometric cell-based assays for anti-striational antibodies in myasthenia gravis with myositis and/or myocarditis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: MG patients with myositis and/or myocarditis as well as late-onset and thymoma-associated MG had anti-titin, anti-ryanodine receptor, and anti-Kv1.4 antibodies.
    explanation: Primary selected-sample assay findings; no general frequency or pathogenic function is inferred.
  discussion_id: adult-mg-interpretation-2
  prompt: Striational antibodies and associated muscle or cardiac inflammation
  rationale: Myositis and myocarditis can accompany MG, particularly in selected thymoma-associated or late-onset series. A 2019 study analyzed stored sera from 30 patients selected for MG with myositis and/or myocarditis; it was not a population-incidence study. Titin and Kv1.4 antibodies were common in that selected group, while RyR reactivity lacked specificity. These assays do not establish that the antibodies caused muscle or cardiac injury, and myocarditis mortality must not be presented as the mortality of myasthenic crisis.
  kind: INTERPRETATION
  status: OPEN
- evidence:
  - reference: PMID:40117520
    reference_title: Single-Cell Transcriptomics Identifies a Prominent Role for the MIF-CD74 Axis in Myasthenia Gravis Thymus.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Clonally expanded sequences were most enriched in the GC and cycling B-cell subsets
    explanation: Measured clonal enrichment in the primary dataset; antigen specificity and proposed communication require further validation.
  - reference: PMID:40117520
    reference_title: Single-Cell Transcriptomics Identifies a Prominent Role for the MIF-CD74 Axis in Myasthenia Gravis Thymus.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Cell-cell interactome predictions identified strong interactions between T cells and GC-associated and memory B cells, dominated by B-cell prosurvival signaling through the MIF-CD74 axis.
    explanation: The MIF-CD74 communication is a computational interactome prediction, which is why the discussion treats it as an emerging hypothesis rather than a demonstrated signaling requirement.
  discussion_id: adult-mg-interpretation-3
  prompt: Emerging thymic cell-interaction hypotheses
  rationale: Single-cell and BCR profiling of untreated early-onset MG thymi identified clonal expansion and inferred cell-state trajectories and MIF–CD74 communication. Spatial proximity and protein staining support the tissue context but do not demonstrate signaling necessity, lineage ancestry, or response to MIF blockade. Serum MIF associations are exploratory and are not a validated diagnostic or disease-activity test.
  kind: EMERGING_HYPOTHESIS
  status: OPEN
animal_models:
- name: Patient-Derived AChR Antibody Passive Transfer in Lewis Rats
  species: Rattus norvegicus
  background: Four-week-old female Lewis rats
  category: Passive antibody transfer
  description: A single injection of aG101 plus bG402-G1 induced weakness, complement deposition, receptor loss, and junction fragmentation. Total antibody dose was matched to individual-antibody arms; behavior was assessed in 6–7 animals per group pooled from two experiments. A separate early histology cohort assessed complement and morphology. Single antibodies did not produce the overt behavioral phenotype, although aG101 alone increased C3 staining.
  publication: PMID:36074148
  notes: Acute passive transfer into four-week-old female Lewis rats bypasses human loss of tolerance and antibody production. bG402 was artificially switched from IgG4 to IgG1. The model does not test aging, late-onset initiation, chronic disease, or MuSK autoimmunity.
  modeled_mechanisms:
  - target: Complement Activation at the Endplate
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: The antibody combination increased junctional C3 staining beyond either control or aG101 alone.
    limitations: Acute passive transfer into four-week-old female Lewis rats bypasses human loss of tolerance and antibody production. bG402 was artificially switched from IgG4 to IgG1. The model does not test aging, late-onset initiation, chronic disease, or MuSK autoimmunity.
    evidence:
    - reference: PMID:36074148
      reference_title: Receptor clustering and pathogenic complement activation in myasthenia gravis depend on synergy between antibodies with multiple subunit specificities.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: Animals given aG101 alone had significantly more C3 labeling than control treated animals but significantly less than animals given the combination of aG101 and bG402-G1
      explanation: Measured C3 deposition at the neuromuscular junction.
    readouts:
    - name: Junctional C3 immunofluorescence
      target: Complement Activation at the Endplate
      direction: INCREASED
      interpretation: The antibody combination increased junctional C3 staining beyond either control or aG101 alone.
      evidence:
      - reference: PMID:36074148
        reference_title: Receptor clustering and pathogenic complement activation in myasthenia gravis depend on synergy between antibodies with multiple subunit specificities.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        quote_role: PRIMARY_RESULT
        directness: DIRECT
        snippet: Animals given aG101 alone had significantly more C3 labeling than control treated animals but significantly less than animals given the combination of aG101 and bG402-G1
        explanation: Measured C3 deposition at the neuromuscular junction.
  - target: Reduced Surface AChR Availability
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: The combination reduced receptor-associated alpha-bungarotoxin signal at endplates.
    limitations: Acute passive transfer into four-week-old female Lewis rats bypasses human loss of tolerance and antibody production. bG402 was artificially switched from IgG4 to IgG1. The model does not test aging, late-onset initiation, chronic disease, or MuSK autoimmunity.
    evidence:
    - reference: PMID:36074148
      reference_title: Receptor clustering and pathogenic complement activation in myasthenia gravis depend on synergy between antibodies with multiple subunit specificities.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: This analysis revealed a significant loss of AChR content on the postsynaptic membrane in rats injected with the combination of both antibodies compared to vehicle controls, or to animals given single antibodies
      explanation: Measured receptor-associated staining after passive transfer.
    readouts:
    - name: AChR-to-presynaptic staining ratio
      target: Reduced Surface AChR Availability
      direction: DECREASED
      interpretation: The combination reduced receptor-associated alpha-bungarotoxin signal at endplates.
      evidence:
      - reference: PMID:36074148
        reference_title: Receptor clustering and pathogenic complement activation in myasthenia gravis depend on synergy between antibodies with multiple subunit specificities.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        quote_role: PRIMARY_RESULT
        directness: DIRECT
        snippet: This analysis revealed a significant loss of AChR content on the postsynaptic membrane in rats injected with the combination of both antibodies compared to vehicle controls, or to animals given single antibodies
        explanation: Measured receptor-associated staining after passive transfer.
  - target: Impaired Neuromuscular Transmission
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: The combination caused a weakness phenotype, providing an indirect functional readout of junction injury.
    limitations: Acute passive transfer into four-week-old female Lewis rats bypasses human loss of tolerance and antibody production. bG402 was artificially switched from IgG4 to IgG1. The model does not test aging, late-onset initiation, chronic disease, or MuSK autoimmunity. Rotarod and clinical score do not directly measure endplate potentials.
    evidence:
    - reference: PMID:36074148
      reference_title: Receptor clustering and pathogenic complement activation in myasthenia gravis depend on synergy between antibodies with multiple subunit specificities.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: single antibodies had no significant effect on clinical score or rotarod performance, but the combination of the two antibodies was potently pathogenic
      explanation: Combination-dependent behavioral phenotype in this tested antibody panel.
    readouts:
    - name: Rotarod performance
      target: Impaired Neuromuscular Transmission
      direction: DECREASED
      interpretation: The combination caused a weakness phenotype, providing an indirect functional readout of junction injury.
      evidence:
      - reference: PMID:36074148
        reference_title: Receptor clustering and pathogenic complement activation in myasthenia gravis depend on synergy between antibodies with multiple subunit specificities.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        quote_role: PRIMARY_RESULT
        directness: INDIRECT
        snippet: single antibodies had no significant effect on clinical score or rotarod performance, but the combination of the two antibodies was potently pathogenic
        explanation: Combination-dependent behavioral phenotype in this tested antibody panel.
  evidence:
  - reference: PMID:36074148
    reference_title: Receptor clustering and pathogenic complement activation in myasthenia gravis depend on synergy between antibodies with multiple subunit specificities.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: single antibodies had no significant effect on clinical score or rotarod performance, but the combination of the two antibodies was potently pathogenic
    explanation: Combination-dependent behavioral phenotype in this tested antibody panel.
experimental_models:
- name: AChR-Transfected HEK Antibody-Combination Assays
  experimental_model_type: CELL_LINE
  cell_source: Transfected HEK cells with recombinant AChR and patient-derived monoclonal antibodies
  description: Complement deposition and live-cell receptor clustering were measured after exposure to individual antibodies or equal-total-concentration combinations. Epitope combinations showed synergy in the tested panel. The proposed two-dimensional receptor-antibody lattice is a hypothesis; imaging of surface clustering does not itself quantify internalization or prove a universal requirement for multiple epitopes in patients.
  publication: PMID:36074148
  modeled_mechanisms:
  - target: Complement Activation at the Endplate
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: Selected antibody combinations increased C3 deposition on receptor-expressing cells.
    limitations: Transfected cells lack a mature neuromuscular endplate and endogenous autoimmunity.
    evidence:
    - reference: PMID:36074148
      reference_title: Receptor clustering and pathogenic complement activation in myasthenia gravis depend on synergy between antibodies with multiple subunit specificities.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: The combination of dG101 and eG101, each at half the concentration (i.e., same final concentration as the previously tested single antibodies), and each with negligible ability to activate complement alone, induced strong complement activation
      explanation: Direct complement assay.
    readouts:
    - name: Cell-associated C3 fluorescence
      target: Complement Activation at the Endplate
      direction: INCREASED
      interpretation: Selected antibody combinations increased C3 deposition on receptor-expressing cells.
      evidence:
      - reference: PMID:36074148
        reference_title: Receptor clustering and pathogenic complement activation in myasthenia gravis depend on synergy between antibodies with multiple subunit specificities.
        supports: SUPPORT
        evidence_source: IN_VITRO
        quote_role: PRIMARY_RESULT
        directness: DIRECT
        snippet: The combination of dG101 and eG101, each at half the concentration (i.e., same final concentration as the previously tested single antibodies), and each with negligible ability to activate complement alone, induced strong complement activation
        explanation: Direct complement assay.
  - target: AChR Crosslinking
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: Antibody pairs increased visible receptor clustering.
    limitations: Clustering supports crosslinking but does not resolve molecular lattice structure or internalization.
    evidence:
    - reference: PMID:36074148
      reference_title: Receptor clustering and pathogenic complement activation in myasthenia gravis depend on synergy between antibodies with multiple subunit specificities.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: None of the single antibodies had any significant effect on the distribution of the receptor. Combinations of antibodies such as aG112 and bG402, on the other hand, mediated strong clustering
      explanation: Direct live-cell localization readout.
    readouts:
    - name: Surface AChR cluster size and number
      target: AChR Crosslinking
      direction: INCREASED
      interpretation: Antibody pairs increased visible receptor clustering.
      evidence:
      - reference: PMID:36074148
        reference_title: Receptor clustering and pathogenic complement activation in myasthenia gravis depend on synergy between antibodies with multiple subunit specificities.
        supports: SUPPORT
        evidence_source: IN_VITRO
        quote_role: PRIMARY_RESULT
        directness: DIRECT
        snippet: None of the single antibodies had any significant effect on the distribution of the receptor. Combinations of antibodies such as aG112 and bG402, on the other hand, mediated strong clustering
        explanation: Direct live-cell localization readout.
- name: Human iPSC-Derived Neuromuscular Coculture with MG Sera
  experimental_model_type: IPSC_DERIVED_MODEL
  cell_source: Adult-fibroblast-derived iPSCs differentiated into MYOD-induced myotubes and NGN2-induced neurons
  description: Neuronal AMPA stimulation and myotube calcium imaging assessed functional transmission after serum exposure. MG sera inhibited the response after heat inactivation, supporting a complement-independent component. The six cloned antibodies and their tested combinations did not reproduce direct blockade. The assay tests serum effects in an engineered junction, not spontaneous adult-onset autoimmunity or the precise blocking epitope.
  publication: PMID:36074148
  modeled_mechanisms:
  - target: AChR Functional Blockade
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: Patient sera reduced the stimulation-evoked myotube response independently of active complement.
    limitations: Calcium activity is an integrated functional readout; individual serum constituents and blocking epitopes remain unresolved.
    evidence:
    - reference: PMID:36074148
      reference_title: Receptor clustering and pathogenic complement activation in myasthenia gravis depend on synergy between antibodies with multiple subunit specificities.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: Direct AChR antagonism by serum constituents was independent of complement, because heat-inactivated sera showed the same results as fresh sera
      explanation: Direct serum perturbation in the coculture.
    readouts:
    - name: AMPA-evoked myotube calcium response
      target: AChR Functional Blockade
      direction: DECREASED
      interpretation: Patient sera reduced the stimulation-evoked myotube response independently of active complement.
      evidence:
      - reference: PMID:36074148
        reference_title: Receptor clustering and pathogenic complement activation in myasthenia gravis depend on synergy between antibodies with multiple subunit specificities.
        supports: SUPPORT
        evidence_source: IN_VITRO
        quote_role: PRIMARY_RESULT
        directness: DIRECT
        snippet: Direct AChR antagonism by serum constituents was independent of complement, because heat-inactivated sera showed the same results as fresh sera
        explanation: Direct serum perturbation in the coculture.
- name: Patient MuSK IgG4 in Recombinant Binding and Myotube Assays
  experimental_model_type: OTHER
  cell_source: Purified antibodies from patients; recombinant LRP4/MuSK proteins; cultured C2 myotubes
  description: IgG4 fractions from seven patients blocked recombinant LRP4–MuSK binding in a dose-dependent manner, whereas matched IgG1–3 and control antibodies had smaller effects. Patient IgG4 also inhibited agrin-stimulated MuSK phosphorylation in C2 myotubes. The broader cohort included 25 Dutch patients; this does not establish identical epitope or isotype behavior in every population.
  publication: PMID:24297891
  modeled_mechanisms:
  - target: Impaired LRP4-MuSK Interaction
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: MOLECULAR
    description: Patient IgG4 reduced binding in a solid-phase recombinant-protein assay.
    limitations: Purified binding systems isolate this interaction but lack the intact human junction.
    evidence:
    - reference: PMID:24297891
      reference_title: MuSK IgG4 autoantibodies cause myasthenia gravis by inhibiting binding between MuSK and Lrp4.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: IgG4 autoantibodies from all MuSK MG patients strongly inhibited binding between Lrp4 and MuSK, reducing binding by as much as 80–100%, in a dose-dependent manner
      explanation: Binding experiment with IgG4 fractions from seven tested patients.
    readouts:
    - name: LRP4–MuSK binding
      target: Impaired LRP4-MuSK Interaction
      direction: DECREASED
      interpretation: Patient IgG4 reduced binding in a solid-phase recombinant-protein assay.
      evidence:
      - reference: PMID:24297891
        reference_title: MuSK IgG4 autoantibodies cause myasthenia gravis by inhibiting binding between MuSK and Lrp4.
        supports: SUPPORT
        evidence_source: IN_VITRO
        quote_role: PRIMARY_RESULT
        directness: DIRECT
        snippet: IgG4 autoantibodies from all MuSK MG patients strongly inhibited binding between Lrp4 and MuSK, reducing binding by as much as 80–100%, in a dose-dependent manner
        explanation: Binding experiment with IgG4 fractions from seven tested patients.
  - target: Reduced Agrin-Stimulated MuSK Phosphorylation
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: Patient IgG4 suppressed agrin-induced MuSK phosphorylation.
    limitations: C2 myotubes are a cultured mouse-cell system exposed to human antibodies.
    evidence:
    - reference: PMID:24297891
      reference_title: MuSK IgG4 autoantibodies cause myasthenia gravis by inhibiting binding between MuSK and Lrp4.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: Patient IgG4 antibodies to MuSK blocked MuSK phosphorylation
      explanation: Direct phosphorylation assay.
    readouts:
    - name: MuSK tyrosine phosphorylation
      target: Reduced Agrin-Stimulated MuSK Phosphorylation
      direction: DECREASED
      interpretation: Patient IgG4 suppressed agrin-induced MuSK phosphorylation.
      evidence:
      - reference: PMID:24297891
        reference_title: MuSK IgG4 autoantibodies cause myasthenia gravis by inhibiting binding between MuSK and Lrp4.
        supports: SUPPORT
        evidence_source: IN_VITRO
        quote_role: PRIMARY_RESULT
        directness: DIRECT
        snippet: Patient IgG4 antibodies to MuSK blocked MuSK phosphorylation
        explanation: Direct phosphorylation assay.
- name: Engineered MuSK Activation in 3T3 Fibroblasts
  experimental_model_type: CELL_LINE
  cell_source: 3T3 fibroblasts expressing an engineered MuSK activation-loop mutant without LRP4
  description: MuSK L746M/S747T enabled phosphorylation in the nonmuscle context. Patient IgG4 did not reduce this LRP4-independent activation or MuSK surface expression. These are engineered assay substitutions, not patient pathogenic variants. The phosphorylation result indirectly constrains a direct dimerization-blocking explanation; it is not a direct measurement of MuSK–MuSK binding.
  publication: PMID:24297891
  modeled_mechanisms:
  - target: Reduced Agrin-Stimulated MuSK Phosphorylation
    relationship: MEASURES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: IgG4 did not suppress LRP4-independent phosphorylation in this engineered context.
    limitations: The system deliberately lacks the agrin–LRP4 step, so its negative result does not refute inhibition in myotubes.
    evidence:
    - reference: PMID:24297891
      reference_title: MuSK IgG4 autoantibodies cause myasthenia gravis by inhibiting binding between MuSK and Lrp4.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: IgG4 antibodies from MuSK MG patients fail to reduce MuSK phosphorylation in 3T3 cells transfected with MuSK but not Lrp4.
      explanation: Context-specific negative phosphorylation result.
    readouts:
    - name: LRP4-independent MuSK phosphorylation
      target: Reduced Agrin-Stimulated MuSK Phosphorylation
      direction: UNCHANGED
      interpretation: IgG4 did not suppress LRP4-independent phosphorylation in this engineered context.
      evidence:
      - reference: PMID:24297891
        reference_title: MuSK IgG4 autoantibodies cause myasthenia gravis by inhibiting binding between MuSK and Lrp4.
        supports: SUPPORT
        evidence_source: IN_VITRO
        quote_role: PRIMARY_RESULT
        directness: DIRECT
        snippet: IgG4 antibodies from MuSK MG patients fail to reduce MuSK phosphorylation in 3T3 cells transfected with MuSK but not Lrp4.
        explanation: Context-specific negative phosphorylation result.
clinical_trials:
- name: NCT00294658
  phase: PHASE_III
  status: COMPLETED
  description: MGTX compared extended transsternal thymectomy plus standardized prednisone with prednisone alone in 126 adults with generalized nonthymomatous AChR-positive MG of less than five years duration. The three-year randomized results support clinical benefit and steroid sparing. Enrollment age 18–65 included older adults; this is not a dedicated, adequately powered very-late-onset trial.
  notes: Registry status checked against ClinicalTrials.gov API on 2026-09-21. The generated cache contains a brief summary, so status and complete design were separately checked in the live record.
  evidence:
  - reference: clinicaltrials:NCT00294658
    reference_title: A Multi-Center, Single-Blind, Randomized Study Comparing Thymectomy to No Thymectomy in Non-Thymomatous Myasthenia Gravis (MG) Patients Receiving Prednisone
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    directness: DIRECT
    snippet: The purpose of this trial is to determine if thymectomy combined with prednisone therapy is more beneficial in treating non-thymomatous myasthenia gravis than prednisone therapy alone.
    explanation: Registry design statement; not clinical outcome evidence.
  - reference: PMID:27509100
    reference_title: Randomized Trial of Thymectomy in Myasthenia Gravis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Patients who underwent thymectomy had a lower time-weighted average Quantitative Myasthenia Gravis score over a 3-year period than those who received prednisone alone (6.15 vs. 8.99, P<0.001)
    explanation: Primary randomized clinical outcome.
  target_phenotypes:
  - preferred_term: Generalized Muscle Weakness
    term:
      id: HP:0003324
      label: Generalized muscle weakness
- name: NCT04524273
  phase: PHASE_III
  status: ACTIVE_NOT_RECRUITING
  description: MINT tested inebilizumab against placebo with background therapy in 238 adults, including 190 AChR-positive and 48 MuSK-positive participants. The primary pooled week-26 MG-ADL endpoint favored treatment by 1.9 points. The randomized periods differed by serotype, with an extension; an active registry status does not mean the published primary outcome is pending.
  notes: Registry status checked against ClinicalTrials.gov API on 2026-09-21. The generated cache contains a brief summary, so status and complete design were separately checked in the live record.
  evidence:
  - reference: clinicaltrials:NCT04524273
    reference_title: A Randomized, Double-blind, Multicenter, Placebo-controlled Phase 3 Study With Open-label Period to Evaluate the Efficacy and Safety of Inebilizumab in Adults With Myasthenia Gravis
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    directness: DIRECT
    snippet: Randomized, double-blind, placebo-controlled, Phase 3, parallel-group study with optional open-label extension.
    explanation: Registry design statement; not clinical outcome evidence.
  - reference: url:https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/761142s004lbl.pdf
    reference_title: https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/761142s004lbl.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: 'A statistically significant difference favoring UPLIZNA was observed in the mean change from baseline in MG-ADL total score (−4.2 points in the UPLIZNA-treated group compared to −2.2 points for placebo, difference of −1.9, 95% CI: −2.9, −1.0; p-value < 0.0001).'
    explanation: Label reports the primary pooled trial outcome.
  target_phenotypes:
  - preferred_term: Generalized Muscle Weakness
    term:
      id: HP:0003324
      label: Generalized muscle weakness
- name: NCT03971422
  phase: PHASE_III
  status: COMPLETED
  description: MycarinG was the phase III randomized placebo-controlled evaluation of rozanolixizumab in adult generalized MG. The trial and subsequent indication concern antibody-defined generalized disease, not proof of equal efficacy across onset-age strata.
  notes: Registry status checked against ClinicalTrials.gov API on 2026-09-21. The generated cache contains a brief summary, so status and complete design were separately checked in the live record.
  evidence:
  - reference: clinicaltrials:NCT03971422
    reference_title: A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study Evaluating Efficacy and Safety of Rozanolixizumab in Adult Patients With Generalized Myasthenia Gravis
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    directness: DIRECT
    snippet: The purpose of the MycarinGstudy is to demonstrate the clinical efficacy and to assess safety and tolerability of rozanolixizumab in patients with generalized myasthenia gravis (MG).
    explanation: Registry design statement; not clinical outcome evidence.
  target_phenotypes:
  - preferred_term: Generalized Muscle Weakness
    term:
      id: HP:0003324
      label: Generalized muscle weakness
- name: NCT04951622
  phase: PHASE_III
  status: RECRUITING
  description: Vivacity-MG3 randomized 196 adults to nipocalimab or placebo; the primary efficacy population comprised 153 seropositive participants. MG-ADL change averaged over weeks 22–24 favored nipocalimab by 1.5 points. Registry recruitment status includes the continuing study and should not be read as absence of completed primary efficacy results.
  notes: Registry status checked against ClinicalTrials.gov API on 2026-09-21. The generated cache contains a brief summary, so status and complete design were separately checked in the live record.
  evidence:
  - reference: clinicaltrials:NCT04951622
    reference_title: Phase 3, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy, Safety, Pharmacokinetics, and Pharmacodynamics of Nipocalimab Administered to Adults With Generalized Myasthenia Gravis
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    directness: DIRECT
    snippet: The purpose of this study is to evaluate the efficacy and safety of nipocalimab compared to placebo in participants with generalized myasthenia gravis (gMG).
    explanation: Registry design statement; not clinical outcome evidence.
  - reference: url:https://www.jnjlabels.com/package-insert/product-monograph/prescribing-information/IMAAVY-pi.pdf
    reference_title: https://www.jnjlabels.com/package-insert/product-monograph/prescribing-information/IMAAVY-pi.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: The primary efficacy endpoint was the comparison of the mean change from baseline to Weeks 22, 23, and 24 between treatment groups in the MG-ADL total score.
    explanation: Defines the averaged primary endpoint.
  target_phenotypes:
  - preferred_term: Generalized Muscle Weakness
    term:
      id: HP:0003324
      label: Generalized muscle weakness
- name: NCT06298552
  phase: PHASE_III
  status: ACTIVE_NOT_RECRUITING
  description: Phase III ADAPT SERON tests intravenous efgartigimod against placebo in AChR-binding-antibody-seronegative generalized MG, followed by an open-label period. The registry summary describes design and does not establish efficacy or a regulatory indication in all seronegative patients.
  notes: Registry status checked against ClinicalTrials.gov API on 2026-09-21. The generated cache contains a brief summary, so status and complete design were separately checked in the live record.
  evidence:
  - reference: clinicaltrials:NCT06298552
    reference_title: A Randomized, Double-Blinded, Placebo-Controlled, Phase 3, Parallel-Group Design Study Evaluating the Efficacy and Safety of Efgartigimod IV in Adult Participants With Acetylcholine Receptor Binding Antibody Seronegative Generalized Myasthenia Gravis
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    directness: DIRECT
    snippet: The primary purpose of this study is to measure the efficacy and safety of efgartigimod IV compared to placebo in participants with Acetylcholine Receptor Binding Antibody (AChR-Ab) seronegative Generalized Myasthenia Gravis (gMG). The study consists of a Part A where participants will be randomized to receive either efgartigimod IV or placebo IV and a Part B where participants completing part A will receive open-label efgartigimod IV. Participants will be in the study for up to (approximately) 3.5 years.
    explanation: Registry design statement; not clinical outcome evidence.
  target_phenotypes:
  - preferred_term: Generalized Muscle Weakness
    term:
      id: HP:0003324
      label: Generalized muscle weakness
- name: NCT06193889
  phase: PHASE_II
  status: RECRUITING
  description: KYSA-6 evaluates autologous anti-CD19 CAR T cells against ongoing standard immunosuppressive care in generalized MG. The registry calls this a phase 2/3 open-label randomized study. It remains an investigational cellular strategy; the summary supplies no outcome estimate or proof of superiority.
  notes: Registry status checked against ClinicalTrials.gov API on 2026-09-21. The generated cache contains a brief summary, so status and complete design were separately checked in the live record. The phase enum records phase II; the registry includes both phases II and III.
  evidence:
  - reference: clinicaltrials:NCT06193889
    reference_title: 'KYSA-6: A Phase 2/3, Open-Label, Randomized, Controlled, Multicenter Study of KYV-101, an Autologous Fully Human Anti-CD19 Chimeric Antigen Receptor T-cell (CD19 CAR T) Therapy, Versus Ongoing Standard-Of-Care Immunosuppressive Therapy in Patients With Generalized Myasthenia Gravis'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    directness: DIRECT
    snippet: A Study of the Anti-CD 19 Chimeric Antigen Receptor T Cell Therapy for Patients with Myasthenia Gravis
    explanation: Registry design statement; not clinical outcome evidence.
  target_phenotypes:
  - preferred_term: Generalized Muscle Weakness
    term:
      id: HP:0003324
      label: Generalized muscle weakness
- name: NCT06414954
  phase: PHASE_II
  status: RECRUITING
  description: Phase IIb dose-ranging evaluation of NMD670 versus placebo over 21 days in adults with AChR- or MuSK-antibody-positive MG. The registry summary supplies trial design, not a demonstrated treatment benefit.
  notes: Registry status checked against ClinicalTrials.gov API on 2026-09-21. The generated cache contains a brief summary, so status and complete design were separately checked in the live record.
  evidence:
  - reference: clinicaltrials:NCT06414954
    reference_title: A Phase 2b, Randomised, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy, Safety, and Tolerability of 3 Dose Levels of NMD670 Over 21 Days in Adult Patients With AChR/MuSK-Ab+ Myasthenia Gravis
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    directness: DIRECT
    snippet: This Phase 2 proof-of-concept, dose range finding study aims to evaluate the safety and efficacy of 3 dose levels of NMD670 vs placebo in adult patients with MG with antibodies against AChR or MuSK, administered twice a day (BID) for 21 days.
    explanation: Registry design statement; not clinical outcome evidence.
  target_phenotypes:
  - preferred_term: Generalized Muscle Weakness
    term:
      id: HP:0003324
      label: Generalized muscle weakness
datasets:
- accession: geo:GSE233180
  title: Thymic B lineage cell landscape in Myasthenia gravis
  description: Single-cell transcriptome and BCR data from immunotherapy-naive AChR-positive early-onset MG thymi. Twelve patients were recruited; one sample failed quality control, and the final reported atlas comprised 29,688 cells from 11 patients. Repository sample records and recruited patients are not interchangeable denominators.
  data_type: SINGLE_CELL_RNA_SEQ
  publication: PMID:40117520
  notes: Accession verified with just verify-datasets; the per-record GEO cache is the verification artifact. Cell trajectories and MIF–CD74 communication are computational inferences, not lineage-tracing or signaling-intervention experiments.
  evidence:
  - reference: GEO:GSE233180
    reference_title: Thymic B lineage cell landscape in Myasthenia gravis
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    directness: DIRECT
    snippet: Here, we provide a comprehensive and unbiased atlas of hematopoietic cell colonization in thymi derived from 12 immunotherapy-naïve patients with early-onset AChR-Ab+ MG (EOMG) using single-cell RNA sequencing (scRNA‑seq).
    explanation: Repository record describes the recruited dataset.
  - reference: PMID:40117520
    reference_title: Single-Cell Transcriptomics Identifies a Prominent Role for the MIF-CD74 Axis in Myasthenia Gravis Thymus.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: After enrichment for CD45+ hematopoietic cells, we profiled 29,688 individual cells and annotated 15 distinct populations
    explanation: Primary atlas after quality-control exclusions.
  - reference: PMID:40117520
    reference_title: Single-Cell Transcriptomics Identifies a Prominent Role for the MIF-CD74 Axis in Myasthenia Gravis Thymus.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: We constructed a single cell-based transcriptional profile of lymphoid cell types in thymi from 11 immunotherapy-naïve patients with EOMG.
    explanation: States the 11-patient analyzed denominator, distinct from the 12 recruited samples in the repository record.
review_notes: Comprehensive review read the original entry, matching falcon research report, citation sidecar and extracted entity table; every original cited abstract; and actual cached full scientific bodies rather than trusting content-type metadata. Original full sources consumed were PMID27509100, 26562150, 30918333, 33458590, 38505076, 38886398 and 40022458; PMID23055271 was regenerated to full XML and independently audited. Added full sources PMID38152089, 39105625, 40117520, 24297891 and 36074148, plus the existing full 2024 GWAS PMID39537604 (independent complete Methods/Results/Discussion audit). The 2025 epidemiology/special-population papers and unrecovered older sources remain abstract-supported. The general MG StatPearls chapter was read in full for clinical presentation and diagnosis; its older treatment and simplified molecular claims were not imported over the newer guideline and primary evidence. No adult-onset-specific GeneReviews chapter was found by the repository baseline check. The 2023 guideline was consumed across diagnosis, immune therapy, crisis, ocular disease, fatigue, vaccination, pregnancy and specialist care; its 2024 erratum corrects authorship and ravulizumab
  day-15 dosing, so no uncorrected dosing schedule is reproduced. The MGTX erratum record was identified but its correction text was unavailable; no alternate-day dose schedule is transcribed. Current FDA/manufacturer labels supply the newer inebilizumab and nipocalimab indications and trial outcomes; regulatory labels describe trial results but do not constitute head-to-head efficacy comparisons. Seven registry summaries were generated and their full live records checked for current status. Research clinical, genetic, mechanistic, diagnostic and treatment themes are represented; predictive metabolomics and causal viral initiation remain exploratory, while immune-checkpoint-inhibitor-induced MG is a related acquired subgroup rather than a proved driver of ordinary early/late-onset disease. All specific numeric frequencies retain their source denominators and ascertainment limits. Independent reviews assessed old and new GWAS interpretation, mechanism graph and clinical care. No reference cache was hand-edited.

📚

References & Deep Research

References

GEO:GSE233180

Thymic B lineage cell landscape in Myasthenia gravis

No top-level findings curated for this source.

ORPHA:391490

Adult-onset myasthenia gravis

No top-level findings curated for this source.

PMID:16186537

Increasing incidence of late-onset anti-AChR antibody-seropositive myasthenia gravis.

No top-level findings curated for this source.

PMID:22476514

Characteristics of late-onset myasthenia gravis.

No top-level findings curated for this source.

PMID:23055271

Risk for myasthenia gravis maps to a (151) Pro→Ala change in TNIP1 and to human leukocyte antigen-B*08.

No top-level findings curated for this source.

PMID:23893883

Late-onset myasthenia gravis: a review when incidence in older adults keeps increasing.

No top-level findings curated for this source.

PMID:24297891

MuSK IgG4 autoantibodies cause myasthenia gravis by inhibiting binding between MuSK and Lrp4.

No top-level findings curated for this source.

PMID:26562150

Genome-Wide Association Study of Late-Onset Myasthenia Gravis: Confirmation of TNFRSF11A and Identification of ZBTB10 and Three Distinct HLA Associations.

No top-level findings curated for this source.

PMID:27273086

Thymic Germinal Centers and Corticosteroids in Myasthenia Gravis: an Immunopathological Study in 1035 Cases and a Critical Review.

No top-level findings curated for this source.

PMID:27509100

Randomized Trial of Thymectomy in Myasthenia Gravis.

No top-level findings curated for this source.

PMID:28495048

HLA and age of onset in myasthenia gravis.

No top-level findings curated for this source.

PMID:29125185

Thymus involvement in early-onset myasthenia gravis.

No top-level findings curated for this source.

PMID:30918333

Cytometric cell-based assays for anti-striational antibodies in myasthenia gravis with myositis and/or myocarditis.

No top-level findings curated for this source.

PMID:31811563

Late-onset generalized myasthenia gravis: clinical features, treatment, and outcome.

No top-level findings curated for this source.

PMID:33458590

Myasthenia gravis: MuSK MG, late-onset MG and ocular MG.

No top-level findings curated for this source.

PMID:34400559

Myasthenia gravis genome-wide association study implicates AGRN as a risk locus.

No top-level findings curated for this source.

PMID:36074148

Receptor clustering and pathogenic complement activation in myasthenia gravis depend on synergy between antibodies with multiple subunit specificities.

No top-level findings curated for this source.

PMID:38152089

Guideline for the management of myasthenic syndromes.

No top-level findings curated for this source.

PMID:38505076

Anti-titin antibodies in a cohort of myasthenia gravis patients.

No top-level findings curated for this source.

PMID:38886398

Comparison of juvenile and adult myasthenia gravis in a French cohort with focus on thymic histology.

No top-level findings curated for this source.

PMID:39105625

Myasthenia gravis: the future is here.

No top-level findings curated for this source.

PMID:39537604

Genome-wide meta-analysis of myasthenia gravis uncovers new loci and provides insights into polygenic prediction.

No top-level findings curated for this source.

PMID:40022458

Can Non-Thymomatous Late-Onset Myasthenia Gravis Benefit From Thymectomy? A Systematic Review and Meta-Analysis.

No top-level findings curated for this source.

PMID:40117520

Single-Cell Transcriptomics Identifies a Prominent Role for the MIF-CD74 Axis in Myasthenia Gravis Thymus.

No top-level findings curated for this source.

PMID:40675734

Epidemiology of myasthenia gravis.

No top-level findings curated for this source.

PMID:40675735

Special populations in myasthenia gravis: Early, late, and very late-onset MG.

No top-level findings curated for this source.

clinicaltrials:NCT00294658

A Multi-Center, Single-Blind, Randomized Study Comparing Thymectomy to No Thymectomy in Non-Thymomatous Myasthenia Gravis (MG) Patients Receiving Prednisone

No top-level findings curated for this source.

clinicaltrials:NCT03971422

A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study Evaluating Efficacy and Safety of Rozanolixizumab in Adult Patients With Generalized Myasthenia Gravis

No top-level findings curated for this source.

clinicaltrials:NCT04524273

A Randomized, Double-blind, Multicenter, Placebo-controlled Phase 3 Study With Open-label Period to Evaluate the Efficacy and Safety of Inebilizumab in Adults With Myasthenia Gravis

No top-level findings curated for this source.

clinicaltrials:NCT04951622

Phase 3, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy, Safety, Pharmacokinetics, and Pharmacodynamics of Nipocalimab Administered to Adults With Generalized Myasthenia Gravis

No top-level findings curated for this source.

clinicaltrials:NCT06193889

KYSA-6: A Phase 2/3, Open-Label, Randomized, Controlled, Multicenter Study of KYV-101, an Autologous Fully Human Anti-CD19 Chimeric Antigen Receptor T-cell (CD19 CAR T) Therapy, Versus Ongoing Standard-Of-Care Immunosuppressive Therapy in Patients With Generalized Myasthenia Gravis

No top-level findings curated for this source.

clinicaltrials:NCT06298552

A Randomized, Double-Blinded, Placebo-Controlled, Phase 3, Parallel-Group Design Study Evaluating the Efficacy and Safety of Efgartigimod IV in Adult Participants With Acetylcholine Receptor Binding Antibody Seronegative Generalized Myasthenia Gravis

No top-level findings curated for this source.

clinicaltrials:NCT06414954

A Phase 2b, Randomised, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy, Safety, and Tolerability of 3 Dose Levels of NMD670 Over 21 Days in Adult Patients With AChR/MuSK-Ab+ Myasthenia Gravis

No top-level findings curated for this source.

url:https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/761142s004lbl.pdf

https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/761142s004lbl.pdf

No top-level findings curated for this source.

url:https://www.jnjlabels.com/package-insert/product-monograph/prescribing-information/IMAAVY-pi.pdf

https://www.jnjlabels.com/package-insert/product-monograph/prescribing-information/IMAAVY-pi.pdf

No top-level findings curated for this source.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK559331/

Myasthenia Gravis - StatPearls - NCBI Bookshelf

No top-level findings curated for this source.

Deep Research

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (1)

Create: Adult-Onset Myasthenia Gravis (MONDO:0018324) · 2026-08-19T16:36:53Z · View source

New entry for MONDO:0018324 (adult-onset myasthenia gravis, ORPHA:391490), curated on the AGE-AT-ONSET axis to complement the existing serotype-stratified Myasthenia_Gravis.yaml (MONDO:0009688). That file was deliberately NOT edited: PR #6885 is in flight on it. Scope decision (recorded in the entry notes and the PR body): the entry carries EOMG/LOMG/VLOMG subtypes, onset-stratified thymic pathology (tertiary-lymphoid-organ conversion of the hyperplastic thymus vs thymic atrophy), onset-stratified immunogenetics (HLA-B*08 / DRB1*03 / TNIP1 in EOMG vs TNFRSF11A / ZBTB10 and directionally reversed MHC effects in LOMG), the striational antibody profile of late onset, the divergent EOMG/LOMG incidence trajectories, and the age-bounded (MGTX, 18-65 years) thymectomy evidence. None of that exists on the parent entry. Shared serotype and effector biology is not re-derived. A CONTROVERSY discussion records the opposing continuum reading (PMID:22476514) rather than asserting the two-disorder model, and a KNOWLEDGE_GAP discussion records that the late-onset initiating event is unidentified. Deep research: falcon (research/Adult-Onset_Myasthenia_Gravis-deep-research-falcon.md). Its own reference-validation block reports 16/16 references resolved, confabulation_rate 0.0, 1/1 quoted claims valid, needs_review true on a single advisory off-topic flag for DOI:10.3390/jcm13010236 - a Ferrara MG incidence study that was read and not cited. The report was used as corroboration only; every snippet in this entry was quoted from a PubMed abstract fetched directly with just fetch-reference. NEC check: just preflight-dr returned SKIP (MONDO records no causal gene for this autoimmune class), so the manual CLAUDE.md section 2b fallback was performed. OAK confirms MONDO:0018324 is a defined class (myasthenia gravis and has-onset HP:0003581 Adult onset) with an Orphanet:391490 xref and no OMIM xref of its own; the top gene mentions in the report are MG autoantigens and susceptibility loci (LRP4, C5, AGRN, PTPN22, TNFRSF11A), and the report explicitly scopes itself away from congenital myasthenic syndromes. No drift onto CMS. One snippet was initially mis-stitched from line-wrapped efetch terminal output (PMID:38886398) and was caught by the reference validator, then corrected against the cached text rather than paraphrased. Validation actually run and read: just validate (schema + terms + references) passed; just validate-disorders passed with 83/83 snippets verified against cached references; just check-title-snippets clean (no new title-quoting snippets); just check-duplicate-keys clean; just check-term-cache-integrity clean; targeted pytest tests/test_data.py -k Adult-Onset_Myasthenia passed 16/16. The whole-suite pytest run has one unrelated failure in Travelers_Diarrhea.yaml which is pre-existing on origin/main and untouched by this branch.

Falcon ▸

Adult-Onset Myasthenia Gravis: Comprehensive Disease-Characteristics Report

Edison Scientific Literature 53 citations 2026-08-19T09:20:52.693615

Adult-Onset Myasthenia Gravis: Comprehensive Disease-Characteristics Report

Scope. This report concerns acquired adult-onset autoimmune myasthenia gravis (MG), not congenital myasthenic syndromes (CMS), Lambert–Eaton myasthenic syndrome, or transient neonatal MG. Evidence is labeled as human clinical, human genetic/computational, model-organism, or in vitro. Unless otherwise stated, facts are aggregated disease-level knowledge rather than observations from an individual electronic health record.

Executive summary

Adult-onset MG is a chronic, heterogeneous, T-cell-dependent, autoantibody-mediated disorder of the postsynaptic neuromuscular junction (NMJ). Its defining manifestation is fluctuating, fatigable weakness affecting ocular, bulbar, axial, limb, and sometimes respiratory muscles. Approximately 80% of generalized cases have acetylcholine-receptor antibodies (AChR-Ab); MuSK antibodies account for about 5%–8% of AChR-negative cases, while LRP4-associated and seronegative disease are less common. The 2024 JCI review accurately summarizes the spectrum as weakness “ranging from limited ocular muscle involvement to life-threatening respiratory failure.” Published June 2024; DOI/URL. (kaminski2024myastheniagravisthe pages 1-2)

The disease is not ordinarily monogenic. HLA and immune-regulatory loci confer polygenic susceptibility, whereas pathogenic germline variants in CHRNE, RAPSN, DOK7, MUSK, LRP4, AGRN, and related genes cause CMS and should not be misclassified as causal variants for autoimmune adult-onset MG. Treatment has shifted from nonspecific immunosuppression toward antibody-endotype-directed complement C5 inhibition, FcRn blockade, and B-cell depletion. Nevertheless, conventional therapy, thymectomy in selected AChR-positive disease, and IVIG/plasma exchange in crisis remain central. (OpenTargets Search: myasthenia gravis, kaminski2024myastheniagravisthe pages 1-2, wiendl2023guidelineforthe pages 2-3)

1. Disease information

Definition and classification

MG is an acquired autoimmune disorder in which antibodies against postsynaptic proteins reduce the safety factor for neuromuscular transmission. Clinical classification integrates:

distribution: ocular versus generalized;
onset: early-onset versus late-onset, commonly separated at 50 years, although studies use 40–60-year cutoffs;
antibody: AChR, MuSK, LRP4, or seronegative;
thymic pathology: thymoma-associated, hyperplastic, or non-thymomatous;
special trigger: immune-checkpoint-inhibitor-associated MG. (antonioni2023theincidenceof pages 1-2, kaminski2024myastheniagravisthe pages 2-4)

Identifiers and synonyms

MONDO: adult-onset myasthenia gravis MONDO:0018324; parent MG MONDO:0009688.
ICD-10-CM: G70.0, myasthenia gravis without acute exacerbation; more specific national extensions distinguish exacerbation/crisis.
ICD-11: classified under myasthenia gravis within disorders of the neuromuscular junction.
MeSH: Myasthenia Gravis.
Orphanet: myasthenia gravis is represented as a rare autoimmune NMJ disease; national subtype coding varies.
Common labels: autoimmune MG, acquired MG, adult MG, adult-onset MG, ocular MG, generalized MG (gMG), late-onset MG (LOMG), AChR-MG, MuSK-MG, LRP4-MG, and seronegative MG. “Late-onset” is a subtype rather than a synonym for every adult case.

The reusable ontology mapping is summarized below.

Domain	Core entity/finding	Suggested ontology identifiers/terms	Evidence/interpretive note
Disease identity	Adult-onset autoimmune myasthenia gravis	MONDO: MONDO_0018324; parent disease MONDO_0009688 myasthenia gravis; ICD-10: G70.0	Adult-onset MG is an antibody-mediated autoimmune neuromuscular junction disease; age-, antibody-, thymus-, and trigger-based subgroups are clinically meaningful (kaminski2024myastheniagravisthe pages 1-2, wiendl2023guidelineforthe pages 2-3)
Classification	Autoimmune, acquired, postsynaptic neuromuscular junction disorder	MeSH: Myasthenia Gravis; category: autoimmune disease; not congenital myasthenic syndrome	Guideline and review distinguish autoimmune MG from congenital myasthenic syndromes; routine knowledge base entry should treat adult-onset MG as acquired disease-level knowledge, not single-patient EHR-derived only (wiendl2023guidelineforthe pages 3-4, wiendl2023guidelineforthe pages 2-3)
Synonyms	Adult-onset MG; late-onset MG subset when onset ≥50 years; generalized MG / ocular MG as phenotypic forms	Labels only: adult-onset myasthenia gravis; autoimmune myasthenia gravis	Early- vs late-onset and ocular vs generalized are clinically useful sub-stratifications rather than strict synonyms (kaminski2024myastheniagravisthe pages 2-4, antonioni2023theincidenceof pages 1-2)
Core autoantibody endotypes	AChR-MG, MuSK-MG, LRP4-MG, seronegative MG	AChR antibody positive; MuSK antibody positive; LRP4 antibody positive; seronegative MG	About 80% of generalized MG and ~50% of ocular MG have AChR antibodies; MuSK antibodies occur in 5%–8% of AChR-negative patients; LRP4 is less common (kaminski2024myastheniagravisthe pages 1-2, gu2024efficacyandsafety pages 1-2)
Phenotype	Fluctuating fatigable weakness	HPO: Muscle weakness; Fatigability	Hallmark symptom complex used diagnostically and in severity scoring (kaminski2024myastheniagravisthe pages 1-2, wiendl2023guidelineforthe pages 3-4)
Phenotype	Ptosis	HPO: Ptosis	Common ocular presentation; ocular MG defined by ptosis/diplopia-limited disease (kaminski2024myastheniagravisthe pages 1-2, antonioni2023theincidenceof pages 1-2)
Phenotype	Diplopia	HPO: Diplopia	Core ocular manifestation and frequent presenting feature (kaminski2024myastheniagravisthe pages 1-2)
Phenotype	Bulbar weakness/dysphagia/dysarthria	HPO: Dysphagia; Dysarthria; Bulbar palsy	Especially prominent in MuSK-MG and severe generalized disease (vakrakou2023immunotherapiesinmuskpositive pages 1-2, kaminski2024myastheniagravisthe pages 1-2)
Phenotype	Respiratory insufficiency / myasthenic crisis	HPO: Respiratory insufficiency; Acute respiratory failure	Life-threatening generalized phenotype; crises incorporated into active/refractory disease definitions (kaminski2024myastheniagravisthe pages 1-2, wiendl2023guidelineforthe pages 3-4)
Phenotype	Generalized limb/axial weakness	HPO: Proximal muscle weakness; Generalized weakness	Generalized MG may involve ocular, bulbar, axial, limb, and respiratory muscles (kaminski2024myastheniagravisthe pages 1-2, wiendl2023guidelineforthe pages 2-3)
Burden/QoL	Persistent fatigue and reduced quality of life	MG-ADL; QMG; MG-QoL15r; EQ-5D-5L	Fatigue can persist even in pharmacologic remission and is associated with lower QoL/depressive symptoms (wiendl2023guidelineforthe pages 17-19, wiendl2023guidelineforthe pages 2-3)
Anatomy	Primary anatomical site: neuromuscular junction	UBERON: neuromuscular junction; synapse; skeletal muscle	Disease mechanism centers on the postsynaptic muscle membrane of the NMJ (kaminski2024myastheniagravisthe pages 1-2, kaminski2024myastheniagravisthe pages 2-4)
Anatomy	Postsynaptic membrane / motor end plate	UBERON labels: motor end plate; postsynaptic membrane	AChR loss, fold simplification, and MAC injury are localized here (kaminski2024myastheniagravisthe pages 2-4)
Anatomy	Thymus involvement in major subgroups	UBERON: thymus	Thymic hyperplasia and thymoma are relevant in AChR-MG; MuSK-MG generally lacks prominent thymic involvement; all patients should be imaged for thymoma (wiendl2023guidelineforthe pages 2-3, vakrakou2023immunotherapiesinmuskpositive pages 1-2)
Cell types	Autoreactive B cells / plasmablasts / plasma cells	CL: B cell; plasmablast; plasma cell	B-cell activation and autoantibody production are central upstream mechanisms; rituximab responsiveness supports B-cell contribution (vakrakou2023immunotherapiesinmuskpositive pages 1-2, kaminski2024myastheniagravisthe pages 10-11)
Cell types	CD4+ T cells / T follicular helper-like support	CL: T cell; CD4-positive, alpha-beta T cell	MG is T-cell-dependent and antibody-mediated; tolerance failure and T-cell help sustain pathogenic antibodies (kaminski2024myastheniagravisthe pages 1-2)
Cell types	Thymic epithelial cells	CL label: thymic epithelial cell	Aberrant thymic biology contributes particularly to AChR-MG and thymoma-associated MG (kaminski2024myastheniagravisthe pages 10-11, seldin2015genomewideassociationstudy pages 1-2)
Mechanism	Complement-mediated postsynaptic injury in AChR-MG	GO: complement activation; membrane attack complex assembly	AChR IgG1/IgG3 antibodies activate complement, causing MAC-mediated injury and fold loss; rationale for C5 inhibitors (kaminski2024myastheniagravisthe pages 2-4, wiendl2023guidelineforthe pages 2-3)
Mechanism	Antigenic modulation/internalization of AChR	GO: receptor-mediated endocytosis; acetylcholine receptor clustering	Cross-linking promotes AChR endocytosis/degradation, reducing receptor density (kaminski2024myastheniagravisthe pages 2-4)
Mechanism	Functional block of ACh binding	GO label: chemical synaptic transmission; acetylcholine receptor activity	Some antibodies directly block AChR function at the binding site (kaminski2024myastheniagravisthe pages 2-4)
Mechanism	MuSK-LRP4 signaling disruption	GO labels: receptor signaling pathway; neuromuscular junction development; acetylcholine receptor clustering	MuSK IgG4 antibodies interfere with LRP4-MuSK interaction and impair AChR clustering rather than complement fixation (vakrakou2023immunotherapiesinmuskpositive pages 1-2)
Mechanism	FcRn-mediated IgG recycling sustains pathogenic antibodies	Target: FCGRT; GO label: IgG receptor activity / immunoglobulin recycling	FcRn antagonists reduce circulating IgG including pathogenic autoantibodies (wiendl2023guidelineforthe pages 2-3, OpenTargets Search: myasthenia gravis)
Mechanism	Impaired neuromuscular transmission	GO: synaptic transmission, cholinergic; muscle contraction	Final common downstream pathway explaining fatigable weakness and decremental physiology (kaminski2024myastheniagravisthe pages 2-4, kaminski2024myastheniagravisthe pages 1-2)
Genetics: susceptibility, not monogenic cause	HLA region risk differs by onset subgroup	HLA-DQA1; HLA-DRB1; HLA-B; HLA-A	HLA is the dominant susceptibility region; onset-specific architecture differs between early- and late-onset disease (topaloudi2022myastheniagravisgenomewide pages 8-12, seldin2015genomewideassociationstudy pages 1-2)
Genetics: susceptibility, not monogenic cause	TNFRSF11A risk locus	HGNC: TNFRSF11A	Replicated MG susceptibility locus; not a monogenic cause of acquired adult-onset MG (topaloudi2022myastheniagravisgenomewide pages 8-12, seldin2015genomewideassociationstudy pages 1-2)
Genetics: susceptibility, not monogenic cause	PTPN22 risk variant (adult-onset association evidence)	HGNC: PTPN22	Open Targets associates PTPN22 with adult-onset MG; LOMG GWAS found suggestive rs2476601/R620W association (OpenTargets Search: myasthenia gravis, seldin2015genomewideassociationstudy pages 1-2)
Genetics: susceptibility, not monogenic cause	CTLA4, TNIP1, CHRNA1, AGRN	HGNC: CTLA4; TNIP1; CHRNA1; AGRN	These genes shape susceptibility architecture/endotypes; AGRN is biologically notable because it encodes an NMJ organizer, but this is still susceptibility rather than direct Mendelian causation for adult autoimmune MG (topaloudi2022myastheniagravisgenomewide pages 4-8, topaloudi2022myastheniagravisgenomewide pages 8-12)
Genetics: causal distinction	Adult-onset autoimmune MG is generally not caused by germline pathogenic variants in AChR-clustering genes	Distinguish from congenital myasthenic syndrome genes: CHRNE, RAPSN, DOK7, MUSK, LRP4, AGRN, COLQ, CHAT	These genes are causal in congenital myasthenic syndromes, not typical adult-onset autoimmune MG; important differential annotation in knowledge bases (OpenTargets Search: myasthenia gravis, wiendl2023guidelineforthe pages 2-3)
Environment / triggers	Infection, especially SARS-CoV-2, may trigger onset/exacerbation in some cases	Labels only: viral infection; SARS-CoV-2 infection	Epidemiologic and case-based evidence suggests possible triggering, but causality remains uncertain (antonioni2023theincidenceof pages 1-2)
Environment / triggers	Immune checkpoint inhibitor-induced MG	Label: checkpoint inhibitor-induced myasthenia gravis	Recognized distinct severe-onset subgroup in modern oncology practice (kaminski2024myastheniagravisthe pages 1-2)
Environment / triggers	Medication-related worsening	Labels only: magnesium; selected antibiotics; immune therapies	Guideline/trial eligibility language warns that concurrent medications can worsen weakness; some therapies can induce or unmask MG (NCT06298552 chunk 1, huang2023myastheniagravisnovel pages 1-3)
Diagnostics	Diagnostic framework	History of fluctuating fatigable weakness + autoantibodies and/or electrophysiology and/or pharmacologic testing	Guideline-based confirmation pathway; thymic CT/MRI recommended for all patients to evaluate thymoma (wiendl2023guidelineforthe pages 3-4, wiendl2023guidelineforthe pages 2-3)
Diagnostics	Electrodiagnostic confirmation in seronegative disease	Repetitive nerve stimulation; single-fiber EMG	In patients without positive serology, repetitive stimulation and single-fiber testing confirm diagnosis in ~90% (kaminski2024myastheniagravisthe pages 1-2)
Biomarkers	Serologic biomarkers	AChR antibody; MuSK antibody; LRP4 antibody; total IgG	Core diagnostic and treatment-stratifying biomarkers; total IgG often tracked in FcRn-therapy trials (kaminski2024myastheniagravisthe pages 1-2, NCT06298552 chunk 1)
Omics	Predictive metabolomic signature for steroid response	Histidine; free fatty acid (13:0); γ-cholestenol; guanosine	Discovery study from MGTX biospecimens found an AUC of 0.90 for a responder panel; promising but not routine clinical practice yet (sikorski2023serummetabolomicsof pages 1-2)
Standard symptomatic treatment	Pyridostigmine (acetylcholinesterase inhibitor)	NCIT label: Pyridostigmine Bromide; target/class: ACHE inhibitor	First-line symptomatic treatment for most MG; may be less useful or problematic in MuSK-MG (wiendl2023guidelineforthe pages 3-4, vakrakou2023immunotherapiesinmuskpositive pages 1-2)
Standard immunotherapy	Corticosteroids	NCIT label: Prednisone / glucocorticoid therapy	Foundational disease-modifying therapy for mild/moderate to active disease (wiendl2023guidelineforthe pages 3-4, wiendl2023guidelineforthe pages 9-10)
Steroid-sparing immunotherapy	Azathioprine, MMF, tacrolimus, cyclosporine, methotrexate	NCIT labels; classes: antimetabolite, calcineurin inhibitor, antimetabolite antifolate	Used as conventional long-term immunotherapies; azathioprine is the most established standard steroid-sparing agent in guidelines (wiendl2023guidelineforthe pages 9-10)
Rescue / crisis therapy	IVIG, plasmapheresis, immunoadsorption	NCIT labels: Immune Globulin; Plasma Exchange	Recommended for impending/manifest myasthenic crisis and severe exacerbation (wiendl2023guidelineforthe pages 3-4)
Surgery	Thymectomy for AChR-positive generalized MG and thymoma-associated MG	NCIT label: Thymectomy	MGTX showed better QMG, lower prednisone exposure, less azathioprine use, and fewer hospitalizations versus prednisone alone in nonthymomatous AChR-positive generalized MG (wolfe2016randomizedtrialof pages 1-3, wiendl2023guidelineforthe pages 2-3)
Targeted biologic	Eculizumab / ravulizumab / zilucoplan	Target: C5; class: complement inhibitor	Best mechanistic fit for AChR-positive complement-mediated MG; guideline recommends in highly active AChR-positive generalized MG (wiendl2023guidelineforthe pages 2-3, zhong2024initiationresponsemaximized pages 1-2)
Targeted biologic	Efgartigimod / rozanolixizumab	Target: FCGRT/FcRn; class: FcRn modulator/antagonist	FcRn blockade lowers pathogenic IgG broadly; major 2023-2024 therapeutic advance with strong trial activity and approvals (wiendl2023guidelineforthe pages 2-3, habib2024efficacyandsafety pages 1-2, NCT06298552 chunk 1)
Targeted biologic	Rituximab	Target: CD20; class: B-cell depletion therapy	Particularly effective in MuSK-MG and considered in seronegative/LRP4-positive/highly active disease (wiendl2023guidelineforthe pages 3-4, vakrakou2023immunotherapiesinmuskpositive pages 1-2)
Recent trial signal	Rozanolixizumab in MuSK-positive generalized MG	FcRn inhibitor; MuSK-specific subgroup efficacy	In MycarinG MuSK subgroup, MG-ADL improved versus placebo without serious TEAEs or deaths in the subgroup analysis (habib2024efficacyandsafety pages 1-2)
Active clinical development	Inebilizumab	Target: CD19; class: B-cell depletion therapy	Phase 3 MINT includes AChR- and MuSK-antibody-positive adults; reflects continued B-cell-targeted development (NCT04524273 chunk 1)
Active clinical development	KYV-101 / mivocabtagene autoleucel	Target/class: anti-CD19 CAR-T cell therapy	Phase 2/3 trial in generalized MG after failure of multiple immunosuppressive/immunomodulatory therapies (NCT06193889 chunk 1)
Active clinical development	NMD670	Class: skeletal muscle ClC-1 chloride channel inhibitor / neuromuscular function enhancer	Phase 2b symptom-focused therapy in AChR/MuSK-positive MG (NCT06414954 chunk 1)
Prevention / care considerations	Vaccination review, avoidance of precipitants, medication reconciliation	Labels only: vaccination assessment; trigger avoidance	Guideline recommends checking vaccination history before prolonged immunotherapy; tertiary prevention focuses on avoiding crises and treatment complications (wiendl2023guidelineforthe pages 9-10)

Table: This table summarizes knowledge-base-ready entities for adult-onset autoimmune myasthenia gravis, including disease identifiers, phenotypes, anatomy, mechanisms, susceptibility genes versus non-causal CMS genes, and treatment targets/classes. It is designed to support ontology mapping and evidence-linked curation.

2. Etiology, risk, protective factors, and gene–environment interaction

Primary cause

The proximal cause is loss of immune tolerance followed by production of pathogenic antibodies against NMJ proteins. AChR antibodies are usually complement-fixing IgG1/IgG3; MuSK antibodies are predominantly IgG4 and disrupt protein–protein signaling rather than fixing complement. Thymic germinal-center-like reactions and abnormal thymic epithelial biology are important in many AChR-positive cases. (vakrakou2023immunotherapiesinmuskpositive pages 1-2, kaminski2024myastheniagravisthe pages 2-4, wiendl2023guidelineforthe pages 2-3)

Genetic susceptibility

Human genetic evidence. A 2022 GWAS meta-analysis of 1,401 cases and 3,508 controls confirmed TNFRSF11A rs4369774 (OR 1.40, p=1.09×10⁻¹³), identified HLA-DQA1 rs34481484 (OR 2.11, p=3.72×10⁻⁹), and implicated CTLA4, AGRN, and ISG15. Estimated SNP heritability was 0.37 overall, 0.64 in early-onset and 0.53 in late-onset disease, supporting substantial but non-Mendelian inherited susceptibility. Published August 2022; DOI/URL. (topaloudi2022myastheniagravisgenomewide pages 8-12)

A dedicated LOMG GWAS of 532 AChR-positive cases and 2,128 controls found TNFRSF11A rs4574025 (OR 1.42, p=3.9×10⁻⁷), protective ZBTB10 rs6998967 (OR 0.53, p=8.9×10⁻¹⁰), and suggestive PTPN22 R620W/rs2476601 association (OR 1.62, p=6.5×10⁻⁶). HLA-DQA1*05:01 showed opposite effects in LOMG (OR 0.54) and early-onset MG (OR 2.82), demonstrating that onset-defined subgroups have different immunogenetic architectures. Published November 10, 2015; DOI/URL. (seldin2015genomewideassociationstudy pages 1-2)

Interpretation: these are susceptibility alleles, not clinically deterministic pathogenic variants. Penetrance, carrier frequency, anticipation, germline mosaicism, consanguinity, and Mendelian recurrence-risk concepts are therefore not applicable in the way they are for CMS. Open Targets specifically links PTPN22 to adult-onset MG and identifies therapeutically validated targets including C5, FCGRT, and ACHE; target association should not be equated with germline causation. (OpenTargets Search: myasthenia gravis)

Non-genetic risk and trigger factors

Age and sex: early adult AChR-MG has a female predominance of about 3:1 and peaks in the third decade; late-onset disease peaks around the sixth decade and has a male predominance (women:men about 2:3). MuSK-MG also has a female bias and often peaks around the fourth decade. (kaminski2024myastheniagravisthe pages 2-4)
Thymoma: a causal immune-tolerance context in a minority of generalized AChR-MG; neoplastic thymic epithelial cells may inadequately express HLA class II and AIRE-dependent self-antigens. Approximately 10% of generalized AChR-positive MG had thymoma in older European series, while one recent Ferrara cohort reported 17%. (antonioni2023theincidenceof pages 1-2, seldin2015genomewideassociationstudy pages 1-2)
Infection: respiratory and systemic infections commonly precipitate exacerbation or crisis. SARS-CoV-2-associated onset has been reported, but a population study concluded that causal evidence remains inconclusive. (antonioni2023theincidenceof pages 1-2)
Iatrogenic triggers: immune-checkpoint inhibitors can induce rapidly severe MG, sometimes with myositis/myocarditis overlap. Magnesium, aminoglycosides, fluoroquinolones, macrolides, neuromuscular blockers, and selected antiarrhythmics or beta-blockers may worsen transmission; associations vary in strength and do not imply that every exposed patient will deteriorate. (kaminski2024myastheniagravisthe pages 2-4)
Pregnancy/postpartum: disease activity may improve, worsen, or remain stable during pregnancy; postpartum exacerbation is recognized. Maternal IgG may cause transient neonatal MG, but this is passive antibody transfer, not inheritance.

Protective factors

No validated genetic protective variant or diet prevents MG. The ZBTB10 signal above is statistically protective but is not an actionable intervention. Smoking, alcohol, exercise, specific diets, or supplements have no established primary-preventive effect. Vaccination, infection control, sleep, graded exercise, and medication review are best viewed as tertiary prevention of exacerbation and treatment complications—not prevention of autoimmune onset. (seldin2015genomewideassociationstudy pages 1-2, wiendl2023guidelineforthe pages 17-19)

Gene–environment interaction

The prevailing model is polygenic immune susceptibility plus a context that disrupts tolerance—thymic pathology, infection, age-related immune remodeling, or checkpoint blockade—followed by autoreactive T/B-cell expansion. Direct, replicated locus-by-exposure interaction estimates remain sparse; most claimed environmental associations are observational or case-based rather than proven G×E effects.

3. Phenotypes

Phenotype and type	Characteristics, course, frequency	QoL/functional effect	Suggested HPO term
Fluctuating fatigable weakness—symptom/sign	Universal defining feature; worsens with repeated use and may improve with rest; minute-to-minute and week-to-month fluctuation	Limits work, mobility, self-care, and exercise	Muscle weakness; Fatigability
Ptosis/diplopia—ocular signs	May be unilateral, bilateral, or asymmetric; AChR-Ab present in about 50% of ocular MG	Driving, reading, computer use and depth perception impaired	Ptosis; Diplopia; Ophthalmoplegia
Generalized limb/axial weakness—sign	Variable proximal-predominant weakness; episodic or chronic fluctuating course	Falls, impaired transfers, walking and arm elevation	Generalized muscle weakness; Proximal muscle weakness; Axial muscle weakness
Bulbar/facial weakness—sign	Dysarthria, dysphagia, chewing fatigue and facial weakness; especially prominent in MuSK-MG	Aspiration risk, altered diet, communication and social participation	Dysphagia; Dysarthria; Facial weakness; Bulbar palsy
Neck weakness—sign	Common in MuSK and more severe generalized disease	Head drop, pain, impaired posture	Neck muscle weakness; Head drop
Respiratory weakness/crisis—sign/complication	Severe but minority phenotype; acute or subacute ventilatory failure requiring ICU monitoring and often ventilation	Life-threatening; prolonged rehabilitation may follow	Respiratory insufficiency; Acute respiratory failure
Persistent non-myasthenic fatigue—symptom	Can persist despite control of objective weakness; about one-third of patients in pharmacological remission reportedly have fatigue syndrome	Associated with lower QoL and depressive symptoms	Fatigue

These manifestations and frequencies are supported by the 2024 JCI review and 2023 guideline. The guideline emphasizes that fatigue may occur independently of neuromuscular fatigability and that only cross-sectional evidence supports its association with depression and reduced QoL. (kaminski2024myastheniagravisthe pages 1-2, wiendl2023guidelineforthe pages 17-19)

Recommended outcome annotations are MG-ADL (0–24), QMG (0–39), MGC, MG-QoL15r (0–30), MGFA class, and post-intervention status. These measure different biological or patient-centered domains and are not interchangeable. (sikorski2023serummetabolomicsof pages 1-2, NCT06298552 chunk 1)

4. Genetic and molecular information

Causal genes and variants

There is no single causal gene, canonical pathogenic variant, chromosomal abnormality, or inheritance pattern for ordinary adult autoimmune MG. Accordingly:

ACMG pathogenic/likely pathogenic/VUS classification, somatic-versus-germline status, population allele frequency, carrier frequency, karyotype, FISH, CMA, repeat-expansion, mitochondrial, WES, and WGS testing are not routine MG diagnostics.
If onset was congenital/childhood, there is a family history, fixed weakness, dysmorphism, episodic apnea, or antibody/electrophysiologic findings are atypical, evaluate CMS genes such as CHRNE, CHRNA1, CHRNB1, CHRND, RAPSN, DOK7, MUSK, LRP4, AGRN, COLQ, CHAT, GFPT1, and SCN4A. Those variants cause genetic myasthenic syndromes, not acquired autoimmune MG. (OpenTargets Search: myasthenia gravis, wiendl2023guidelineforthe pages 3-4)

Susceptibility and modifier candidates

HLA-DRB1, HLA-DQA1, HLA-B, HLA-A, TNFRSF11A, PTPN22, CTLA4, TNIP1, ZBTB10, AGRN, and ISG15 are susceptibility candidates. No modifier gene has sufficient evidence for routine severity prediction. Genetic architecture differs by age, sex, antibody status, and thymic pathology. (topaloudi2022myastheniagravisgenomewide pages 4-8, topaloudi2022myastheniagravisgenomewide pages 8-12, seldin2015genomewideassociationstudy pages 1-2)

Epigenetics and chromosomal changes

Altered miRNA expression, DNA methylation, and lymphocyte/thymic transcriptional programs have been described, but no epigenetic mark is validated for diagnosis or treatment selection. Large chromosomal abnormalities are not characteristic. Thymoma has tumor genomic alterations, but these belong to the neoplasm and are not defining germline lesions of MG.

5. Environmental information

No toxin, radiation exposure, pollution source, occupation, diet, smoking pattern, alcohol exposure, or exercise behavior has been established as a necessary or sufficient cause. The most actionable environmental information concerns exacerbation:

infection, fever, surgery, sleep deprivation and major physiological stress can increase weakness;
excessive heat may worsen transmission transiently;
medications that impair presynaptic release, postsynaptic responsiveness, or respiratory reserve require review;
immune-checkpoint blockade can induce a distinct, rapidly severe autoimmune phenotype;
evidence linking SARS-CoV-2 infection or vaccination to new-onset MG remains insufficient for causal population-level inference. In Ferrara, incidence was 2.7/100,000/year in 2008–2018 versus 2.1/100,000 during 2019–2022, a non-significant reduction rather than an increase. Published December 30, 2023; DOI/URL. (antonioni2023theincidenceof pages 1-2)

6. Mechanism and pathophysiology

Causal chain

Upstream: polygenic susceptibility/thymic abnormality or acquired trigger → defective central/peripheral tolerance → autoreactive CD4 T-cell help → B-cell, plasmablast and plasma-cell expansion → pathogenic IgG production.

Endotype-specific effector stage:

AChR-MG: IgG1/IgG3 binds clustered nicotinic AChR → classical complement activation and C5 cleavage → C5b-9 membrane-attack-complex injury; antibody cross-linking also accelerates receptor endocytosis (“antigenic modulation”), while a subset directly blocks acetylcholine binding. (kaminski2024myastheniagravisthe pages 2-4)
MuSK-MG: predominantly functionally monovalent IgG4 blocks LRP4–MuSK interaction → impaired MuSK phosphorylation and rapsyn-dependent AChR clustering. Because IgG4 does not efficiently fix complement, C5 inhibitors are mechanistically inappropriate for this endotype. The 2023 review states that IgG4 antibodies exert pathogenicity “via interfering with the interaction between their targets and binding partners.” Published July 2023; DOI/URL. (vakrakou2023immunotherapiesinmuskpositive pages 1-2)
LRP4-MG: antibodies interfere with agrin–LRP4–MuSK signaling; complement contribution is less clearly defined.

Downstream: fewer functional AChRs, damaged junctional folds and reduced sodium-channel density → smaller end-plate potentials → repeated activity lowers the end-plate potential below action-potential threshold → progressive failure of muscle-fiber recruitment → fatigable weakness, dysphagia, diplopia, or ventilatory failure. (kaminski2024myastheniagravisthe pages 2-4)

Relevant ontology suggestions

GO biological process: complement activation; membrane attack complex assembly; receptor-mediated endocytosis; regulation of acetylcholine-receptor clustering; cholinergic synaptic transmission; skeletal-muscle contraction; B-cell activation; T-cell activation; immunoglobulin production.
GO cellular component: neuromuscular junction; postsynaptic membrane; acetylcholine-gated channel complex; membrane attack complex; immunological synapse.
Cell Ontology: B cell, memory B cell, plasmablast, plasma cell, CD4-positive alpha-beta T cell, regulatory T cell, thymic epithelial cell, skeletal-muscle fiber, alpha motor neuron.

Molecular profiling and advanced technologies

Metabolomics/lipidomics—human exploratory: an MGTX-serum study found higher phospholipids associated with treatment response. Histidine, free fatty acid 13:0, γ-cholestenol and guanosine predicted a strict corticosteroid-response phenotype with AUC 0.90. The authors stress that the panel “can now undergo validation”; it is not a clinical biomarker. Published October 10, 2023; DOI/URL. (sikorski2023serummetabolomicsof pages 1-2)
Single-cell/spatial studies—human research: thymic and peripheral immune-cell studies identify heterogeneous autoreactive B/T-cell states and germinal-center niches. They refine endotyping but have no approved diagnostic use. (kaminski2024myastheniagravisthe pages 10-10, kaminski2024myastheniagravisthe pages 10-11)
Proteomics/transcriptomics: candidate cytokine, chemokine, complement and B-cell signatures are reported, but inter-cohort validation is incomplete.
Functional platforms—in vitro: cell-based antibody assays and human stem-cell-derived NMJs reproduce native antigen conformation and permit functional/pathogenicity testing and drug screening. (kaminski2024myastheniagravisthe pages 1-2)
Spatial transcriptomics, CRISPR screens, routine liquid biopsy: investigational or not established for adult MG.

7. Anatomical structures affected

Primary organ/system: peripheral neuromuscular system; voluntary skeletal muscle is functionally denervated at the NMJ despite structurally intact motor axons.
Primary site: postsynaptic motor end plate/neuromuscular junction—suggested UBERON term labels: neuromuscular junction, skeletal muscle organ, extraocular muscle, diaphragm, pharyngeal muscle and laryngeal muscle.
Secondary organ: thymus—hyperplasia or thymoma in relevant AChR-positive subtypes.
Respiratory system: diaphragm and accessory respiratory muscles are secondarily affected during severe disease; lung parenchyma is not the primary target.
Subcellular compartments: postsynaptic membrane, junctional folds, AChR complex, MuSK–LRP4 signaling complex, and complement membrane-attack complex.
Localization/lateralization: ocular findings are often asymmetric and can alternate; generalized weakness is usually bilateral but not necessarily symmetric. (kaminski2024myastheniagravisthe pages 2-4, kaminski2024myastheniagravisthe pages 1-2)

8. Temporal development and natural history

Onset may be insidious, subacute, or—especially after checkpoint inhibitors—rapid. Early adult AChR disease peaks in young women; late-onset disease increasingly affects older men, with the highest recent Ferrara incidence in people over 70. Ocular disease is often operationally classified as persistent ocular MG if it has not generalized for at least two years. (antonioni2023theincidenceof pages 1-2, kaminski2024myastheniagravisthe pages 2-4)

The course is chronic and fluctuating, with exacerbations, treatment-induced remission, pharmacologic remission, minimal manifestations, or persistent active/refractory disease. A 2024 review estimated relapse in 18%–34% and nonresponse to traditional immunosuppressants in about 10%, although definitions and cohorts vary. (zhong2024initiationresponsemaximized pages 1-2)

The greatest risk of ocular-to-generalized conversion is early in the disease course; early disease control and thymectomy, when indicated, represent important intervention windows. Abrupt withdrawal of immunotherapy can cause recurrence or crisis. Spontaneous permanent remission occurs but cannot be predicted reliably; most patients require prolonged monitoring and many require long-term immunotherapy. (wiendl2023guidelineforthe pages 3-4, wiendl2023guidelineforthe pages 9-10)

9. Inheritance, epidemiology, and population

Epidemiology

A meta-analysis cited in the Ferrara population study estimated prevalence at 7.7/100,000 and incidence at 0.5/100,000 person-years; recent annual incidence estimates commonly range from 0.3 to 3.0/100,000. A broader 2023 review estimated approximately 700,000 affected worldwide, median prevalence around 10/100,000, and regional incidence ranging from about 0.4/100,000 in Norway to 2.1/100,000 in Italy and Taiwan. Differences reflect age structure, ascertainment, diagnostic access and case definitions. (huang2023myastheniagravisnovel pages 1-3, antonioni2023theincidenceof pages 1-2)

Ferrara’s complete-enumeration study identified 106 incident cases in 2008–2018 (2.7/100,000/year) and 29 in 2019–2022 (2.1/100,000/year), with rising late-onset and declining early-onset disease. (antonioni2023theincidenceof pages 1-2)

Demographics and inheritance

Early-onset AChR-MG: women:men approximately 3:1, peak third decade.
LOMG: male predominance, peak sixth decade and increasing incidence among those over 70.
MuSK-MG: female-biased, often younger/middle adult onset, bulbar-predominant.
Thymoma MG: approximately equal sex ratio or slight male bias, peak near fifth decade. (kaminski2024myastheniagravisthe pages 2-4)

Inheritance is multifactorial/polygenic with low absolute familial recurrence, variable expression, and incomplete/age-dependent susceptibility—not autosomal dominant, recessive, X-linked, or mitochondrial. Anticipation, carrier screening, founder-mutation screening, and consanguinity effects are not established. Geographic differences in antibody and thymoma distributions occur, but variant-specific geographic prediction is not clinically mature.

10. Diagnostics

Clinical and laboratory workflow

Identify fluctuating, fatigable ocular, bulbar, limb, axial, or respiratory weakness with preserved sensation and usually normal reflexes.
Test serum AChR binding antibodies; where appropriate add blocking/modulating assays or a clustered-AChR cell-based assay.
If AChR-negative, test MuSK-Ab; then consider LRP4-Ab and specialized cell-based assays.
Perform low-frequency repetitive nerve stimulation (RNS) and/or single-fiber EMG (SFEMG), targeting clinically involved muscles. The 2024 review reports that RNS/SFEMG confirms approximately 90% of seronegative clinically suspected cases. (kaminski2024myastheniagravisthe pages 1-2)
Chest CT or MRI for every confirmed patient to evaluate thymoma. (wiendl2023guidelineforthe pages 3-4)
Assess respiratory status during bulbar/generalized deterioration using forced vital capacity, negative inspiratory force, oxygenation and blood gases; normal oxygen saturation does not exclude impending ventilatory failure.
Use MGFA class, MG-ADL, QMG, MGC and MG-QoL15r longitudinally.

The guideline’s exact summary is: “The diagnosis of MG is based on the history and physical findings of fatigable and fluctuating muscle weakness,” confirmed through autoantibodies, electrophysiology and/or pharmacological testing. Published 2023; DOI/URL. (wiendl2023guidelineforthe pages 3-4)

Imaging, biopsy, genetic and omics tests

CT/MRI evaluates thymoma but does not diagnose junctional transmission failure.
Muscle biopsy is generally unnecessary; if performed, it may be normal or nonspecific and is mainly used to investigate myopathy.
WES/WGS/panels are reserved for suspected CMS or alternative genetic neuromuscular disease.
CMA, karyotype, FISH, mtDNA and repeat-expansion tests have no routine role.
Transcriptomic, proteomic, metabolomic and epigenomic tests remain research tools. (sikorski2023serummetabolomicsof pages 1-2, wiendl2023guidelineforthe pages 3-4)

Differential diagnosis

Important mimics include Lambert–Eaton syndrome (proximal/autonomic symptoms, facilitation, often reduced reflexes), botulism (pupillary/autonomic involvement and descending paralysis), CMS, mitochondrial/chronic progressive external ophthalmoplegia, oculopharyngeal muscular dystrophy, inflammatory or checkpoint-inhibitor myositis, thyroid eye disease, brainstem stroke, multiple sclerosis, motor-neuron disease, cranial neuropathy and functional neurological disorder. MuSK-MG can resemble bulbar-onset motor-neuron disease; ICI-associated MG should prompt simultaneous creatine kinase, troponin, ECG and cardiac evaluation because of myositis/myocarditis overlap.

Screening

There is no population, newborn, carrier, prenatal, or asymptomatic genetic screening program. Targeted evaluation may be appropriate in thymoma, before/after checkpoint blockade when symptoms arise, or in relatives only if the phenotype suggests CMS rather than autoimmune MG.

11. Outcome and prognosis

Modern MG is usually treatable, and most patients achieve substantial control, but complete stable remission is less common than improvement or minimal manifestations. Survival approaches the general population in well-managed patients, although older age, respiratory crisis, aspiration, infection, thymoma, severe bulbar disease, and treatment toxicity increase risk. Contemporary literature does not support a single universal 5- or 10-year survival percentage because cohorts differ markedly.

Morbidity includes fluctuating disability, aspiration, crisis, hospitalization, falls, treatment-associated infection/metabolic disease, anxiety/depression, fatigue and impaired employment. Persistent fatigue can occur in approximately one-third of pharmacologically remitted patients and correlates with poorer QoL. (wiendl2023guidelineforthe pages 17-19)

Poorer prognosis is associated with delayed recognition, severe baseline MGFA class, recurrent crisis, thymoma, older age/comorbidity, MuSK bulbar/respiratory predominance, and insufficient treatment response. AChR antibody concentration alone correlates imperfectly with clinical severity because antibody epitope, subclass and effector mechanism vary. (kaminski2024myastheniagravisthe pages 2-4)

12. Treatment

Staged clinical strategy

Symptomatic: pyridostigmine (ACHE inhibition; NCIt term label: pyridostigmine bromide), adjusted to function and tolerability. MuSK-MG may respond poorly and can worsen with excessive cholinesterase inhibition.
Conventional disease modification: prednisone/prednisolone, usually with steroid-sparing azathioprine; alternatives include mycophenolate, tacrolimus, cyclosporine or methotrexate. Evidence for some alternatives is mixed, and onset of benefit is delayed. (wiendl2023guidelineforthe pages 9-10)
Endotype-directed therapy: C5 inhibitors for complement-mediated AChR-positive gMG; FcRn inhibitors for pathogenic-IgG reduction; rituximab particularly for MuSK-MG.
Crisis/severe exacerbation: ICU-level respiratory/bulbar surveillance, treatment of precipitant, IVIG or plasma exchange/immunoadsorption, with ventilatory and aspiration support. (wiendl2023guidelineforthe pages 3-4)

Thymectomy

Thymoma requires complete oncologic thymectomy where feasible. For non-thymomatous AChR-positive generalized MG, MGTX randomized 126 adults aged 18–65 with disease under five years. At three years, thymectomy plus prednisone versus prednisone alone reduced time-weighted QMG (6.15 vs 8.99), alternate-day prednisone (44 vs 60 mg), azathioprine use (17% vs 48%) and exacerbation hospitalization (9% vs 37%), all p<0.001. The abstract concludes: “Thymectomy improved clinical outcomes over a 3-year period.” Published August 11, 2016; PMID 27509100; DOI/URL. (wolfe2016randomizedtrialof pages 1-3)

Guidelines recommend early thymectomy—ideally within two years and no later than five years after diagnosis—for suitable 18–65-year-old AChR-positive generalized patients. It is not routinely recommended for MuSK-MG. (wiendl2023guidelineforthe pages 3-4, wiendl2023guidelineforthe pages 2-3)

Targeted therapies and 2023–2024 developments

C5 complement inhibition: eculizumab, ravulizumab, and zilucoplan prevent terminal complement/MAC injury. Their strongest rationale is AChR-positive gMG. Meningococcal vaccination and infection-risk mitigation are mandatory; breakthrough invasive infection remains possible. Zilucoplan received US approval in October 2023. (gu2024efficacyandsafety pages 1-2, kaminski2024myastheniagravisthe pages 2-4)
FcRn blockade: efgartigimod and rozanolixizumab accelerate pathogenic IgG clearance. IV and subcutaneous efgartigimod formulations and rozanolixizumab expanded practical treatment options during 2023–2024. Typical concerns include headache and infection; FcRn blockade lowers total IgG but is not antigen-specific. (zhong2024initiationresponsemaximized pages 1-2, habib2024efficacyandsafety pages 1-2, wiendl2023guidelineforthe pages 2-3)
MuSK-MG: rituximab is often used earlier because conventional therapy and IVIG may be less effective. Plasma exchange is frequently effective. Rozanolixizumab is approved for AChR- or MuSK-antibody-positive gMG in the US. (vakrakou2023immunotherapiesinmuskpositive pages 1-2, habib2024efficacyandsafety pages 1-2)

In the 21-patient MuSK subgroup of phase III MycarinG, day-43 MG-ADL changes were −7.28 with 7 mg/kg, −4.16 with 10 mg/kg and +2.28 with placebo; differences from placebo were −9.56 and −6.45. Treatment-emergent adverse events occurred in 80.0%, 62.5% and 37.5%, respectively, but there were no serious events or deaths. The small subgroup warrants cautious interpretation. Published 2024; NCT03971422; DOI/URL. (habib2024efficacyandsafety pages 1-2)

A 2024 network meta-analysis of 21 RCTs, 13 drugs and 1,657 patients ranked batoclimab highest for QMG/MGC, rozanolixizumab highest for MG-ADL, and eculizumab highest for MG-QoL15r; indirect SUCRA rankings should not be interpreted as head-to-head superiority because populations and regimens differed. Published October 2024; DOI/URL. (gu2024efficacyandsafety pages 1-2)

Current experimental applications

Inebilizumab/CD19 depletion: phase III MINT, NCT04524273, 238 AChR- or MuSK-positive adults, with MG-ADL at week 26 as primary outcome. (NCT04524273 chunk 1)
Efgartigimod in AChR-binding-seronegative gMG: ADAPT SERON, phase III, NCT06298552, 119 participants. (NCT06298552 chunk 1)
NMD670: phase IIb SYNAPSE-MG, NCT06414954, estimated 84 participants; a muscle chloride-channel-directed symptomatic approach assessed over 21 days. (NCT06414954 chunk 1)
Anti-CD19 CAR-T: KYV-101/mivocabtagene autoleucel, phase II/III KYSA-6, NCT06193889, estimated 66 treatment-refractory participants. This is an experimental immune-reset strategy, not established care. (NCT06193889 chunk 1)
Antigen-specific/CAAR-T and RNA/gene approaches: preclinical or early clinical; no approved gene, RNA, stem-cell, or regenerative therapy exists for autoimmune MG. (vakrakou2023immunotherapiesinmuskpositive pages 1-2, keritam2024aclinicalperspective pages 13-13)

Rehabilitation and supportive care

Use individualized aerobic and resistance exercise below the threshold that provokes prolonged weakness; respiratory, swallowing, speech, occupational and physical therapy are indicated by phenotype. Manage aspiration risk, nutrition, sleep, mood, osteoporosis, infection risk and steroid metabolic toxicity. Mechanical ptosis aids, prisms or occlusion may help refractory ocular symptoms. (wiendl2023guidelineforthe pages 17-19)

No validated CPIC/PharmGKB genotype-guided treatment algorithm exists. TPMT/NUDT15 testing may guide azathioprine safety according to general pharmacogenetic practice, but it predicts metabolism/toxicity rather than MG response.

13. Prevention

Primary prevention: none established; MG is not preventable through routine genetic screening, diet or vaccination.
Secondary prevention: no asymptomatic population screening. Prompt recognition of ptosis, diplopia, bulbar fatigue or respiratory symptoms reduces diagnostic delay.
Tertiary prevention: medication reconciliation; infection prevention; completion of indicated vaccines before prolonged immunotherapy; meningococcal vaccination/prophylaxis for C5 blockade; gradual—not abrupt—immunotherapy taper; perioperative planning; crisis education; swallowing and respiratory monitoring. The guideline specifically recommends assessing and completing vaccination history before prolonged immunotherapy. (wiendl2023guidelineforthe pages 9-10)
Immunization: non-live vaccines are generally appropriate, but timing should account for B-cell-depleting treatment and other immunosuppression. Vaccination-associated MG reports do not outweigh the recognized risk of infection-triggered exacerbation at the population level.
Counseling: ordinary autoimmune MG does not justify carrier or prenatal testing. Counsel women about pregnancy, medication safety, postpartum exacerbation and transient neonatal MG risk.

14. Natural disease in other species

Naturally occurring acquired autoimmune MG occurs most importantly in dogs (Canis lupus familiaris; NCBI Taxon 9615) and more rarely cats (Felis catus; Taxon 9685). Dogs develop AChR-antibody-associated focal or generalized weakness; megaesophagus with regurgitation and aspiration pneumonia is particularly important and differs from typical human presentation. Thymoma-associated MG occurs in dogs and cats. Some canine breed predispositions are reported, but breed effects vary geographically and are not equivalent to a single orthologous causal mutation.

The same postsynaptic AChR/complement biology and response to anticholinesterase or immunomodulatory treatment make canine disease comparatively informative. However, prominent canine megaesophagus, breed structure, species-specific immune responses and differences in treatment constrain direct extrapolation. Autoimmune MG is not infectious or zoonotic and has no cross-species transmission risk.

15. Model organisms and experimental systems

Active experimental autoimmune MG (EAMG): mice, rats and rabbits immunized with purified AChR or AChR peptides develop AChR antibodies, complement-mediated endplate injury, decrement and weakness. This is useful for tolerance, complement and therapeutic studies but compresses the chronic, heterogeneous human disease into an induced response.
Passive-transfer EAMG: transfer of patient or monoclonal AChR/MuSK antibodies into rodents isolates antibody effector mechanisms and permits causal testing. It does not reproduce thymic initiation, long-term T/B-cell evolution or the full human antibody repertoire.
MuSK models: active immunization or passive IgG transfer reproduces impaired AChR clustering and bulbar/generalized weakness; species and IgG-subclass biology can alter complement and Fc effects.
Genetic models: knockout/knock-in disruption of Musk, Lrp4, Agrn, Rapsn, or Dok7 elucidates NMJ development but models CMS/developmental failure more directly than acquired autoimmunity.
In vitro human systems: clustered-AChR cell assays, myotubes, motor-neuron–muscle co-cultures, iPSC-derived NMJs and microfluidic/organoid-like platforms permit patient-IgG testing and therapeutic screening. The 2024 JCI review notes both “robust animal models since the 1970s” and newer human stem-cell-derived NMJ platforms. (kaminski2024myastheniagravisthe pages 1-2)

Relevant resources include MGI, IMPC, IMSR/MMRRC/EMMA for mouse strains, RGD for rats, Cellosaurus for cell lines, and GEO/SRA/Single Cell Portal for omics datasets.

Evidence limitations and expert interpretation

Adult-onset MG is an umbrella of biologically distinct endotypes; aggregate prevalence, response and prognosis estimates should not be applied indiscriminately to AChR-, MuSK-, LRP4-, thymoma-, ICI-associated or seronegative disease.
Recent network meta-analyses offer useful indirect comparisons but are vulnerable to heterogeneous enrollment, background therapy, outcome timing and antibody subtype. (gu2024efficacyandsafety pages 1-2, zhong2024initiationresponsemaximized pages 1-2)
Antibody positivity supports diagnosis but does not alone establish current activity; titer–severity correlation is imperfect. Conversely, negative conventional serology does not exclude MG. (kaminski2024myastheniagravisthe pages 2-4, kaminski2024myastheniagravisthe pages 1-2)
Genetics and omics presently support mechanistic stratification and target discovery, not routine prediction of individual onset, prognosis, or drug choice. The promising metabolomic AUC of 0.90 requires external validation. (topaloudi2022myastheniagravisgenomewide pages 8-12, sikorski2023serummetabolomicsof pages 1-2)
The authoritative 2023 guideline considers rapid achievement of complete disease control a central goal while emphasizing antibody status, thymic pathology, age, activity and patient-reported outcomes. Precision biologics should complement—not replace—careful diagnosis, crisis prevention, conventional immunotherapy and rehabilitation. (wiendl2023guidelineforthe pages 3-4, wiendl2023guidelineforthe pages 2-3)

References

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References checked	16
Resolved	16
Unresolved (possible confabulation)	0
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Quoted claims checked	1
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Quoted claims not found in source	0
References weighed for topical relevance	16
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References that may not be about this subject

These identifiers resolve, so they are not fabrications, but the records they resolve to share almost none of this report's vocabulary. That is a clue and not a verdict - a paper can be relevant in ways its title and abstract do not spell out - so read them before deciding:

DOI:10.3390/jcm13010236 (5 mentions) - The Incidence of Myasthenia Gravis in the Province of Ferrara, Italy, in the Period of 2008–2022: An Update on a 40-Year Observation and the Influence of the COVID-19 Pandemic
shared terms: clinical

Weighed against this report's own most characteristic terms: disease, clinical, genetic, treatment, gene, achr, autoimmune, guideline, generalized, risk, musk, respiratory, weakness, thymic, causal, antibody, patient, effect, complement, muscle.

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Adult-Onset Myasthenia Gravis: Comprehensive Disease-Characteristics Report

Executive summary

1. Disease information

Definition and classification

Identifiers and synonyms

2. Etiology, risk, protective factors, and gene–environment interaction

Primary cause

Genetic susceptibility

Non-genetic risk and trigger factors

Protective factors

Gene–environment interaction

3. Phenotypes

4. Genetic and molecular information

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Thymectomy

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