DIRA

1. Disease Information

Overview. DIRA is a monogenic autoinflammatory disorder of skin and bone. Affected neonates/infants present with sterile multifocal osteomyelitis, periostitis, and pustular dermatitis with systemic inflammation, in the absence of infection, high-titer autoantibodies, or autoreactive T cells [Human clinical, PMID 19494218; Review PMID 40060136].

Key identifiers. - MONDO: MONDO:0013021 - OMIM: #612852 (disease); gene IL1RN 147679 - Orphanet: ORPHA:361 ("Deficiency of interleukin-1 receptor antagonist") - ICD-11: 4A60.x (autoinflammatory disorders) — DIRA has no unique legacy ICD-10 code; typically coded under M08/M86 (osteomyelitis) or L98 historically - MeSH: DIRA is captured under "Hereditary Autoinflammatory Diseases" (MeSH D056660); MeSH descriptor used in the systematic review was "interleukin-1 receptor antagonist deficiency" (PMID 40060136) - HGNC: IL1RN = HGNC:6000; UniProt:* P18510

Synonyms / alternative names. Deficiency of interleukin-1 receptor antagonist; IL-1RA deficiency; IL-1 receptor antagonist deficiency; DIRA; osteomyelitis, sterile multifocal, with periostitis and pustulosis (OMPP).

Information source. Disease-level knowledge derives from aggregated primary case reports and small case series plus one PRISMA systematic review (18 studies, 2009–2024; PMID 40060136) — not from large EHR/registry datasets, reflecting the disease's rarity (~30–60 reported genetically confirmed patients worldwide as of the mid-2020s).

2. Etiology

Primary cause — genetic. DIRA is caused by autosomal recessive, biallelic loss-of-function mutations in IL1RN (2q14.1, within the 2q13 IL-1 gene cluster). "DIRA is developed from the loss-of-function biallelic mutations of the IL1RN gene that encodes IL-1 receptor antagonist (IL-1RA), leading to the unchecked pro-inflammatory signaling and subsequent systemic inflammation" [Review, PMID 38398338].

Genetic risk factors. - Causal variants: homozygous or compound-heterozygous null IL1RN alleles (nonsense, frameshift, large genomic deletions). Founder alleles cluster geographically (see §9). - Modifier genes: In the mouse model, disease penetrance/expressivity is strongly background-dependent and governed by QTLs (chromosome 1 major locus; candidate genes Mr1, Pla2g4a, Fasl, Prg4, Ptgs2) [Model organism, PMID 21414240, 22820384, 22942082]. Human modifiers are not yet defined.

Environmental risk factors. None established as causal. Consanguinity and descent from a founder population increase the chance of being homozygous (see §9). Sex: reported male predominance [Review, PMID 40060136], mechanism unknown (not X-linked; IL1RN is autosomal, so this is an observational skew).

Protective factors. Heterozygous carriers are asymptomatic — "heterozygous carriers were asymptomatic, with no cytokine abnormalities in vitro" [Human clinical/In vitro, PMID 19494218]. No environmental protective factors are described. The single functional protective "factor" is a wild-type IL1RN allele.

Gene–environment interactions. Not specifically characterized in humans. In Il1rn-null mice, the intestinal microbiome modulates disease: dysbiosis (↑Helicobacter, ↓Ruminococcus/Prevotella) promotes IL-17/TLR4-dependent arthritis, indicating a microbiome × genotype interaction [Model organism, PMID 28645307]. Whether infections trigger human DIRA flares is inferred but not proven.

3. Phenotypes

DIRA is dominated by bone, skin, and systemic inflammatory phenotypes with neonatal onset and severe, chronic/episodic course; frequencies below are qualitative/derived from the small literature (PMID 19494218, 40060136, 38398338).

Supporting quotes: "neonatal onset of sterile multifocal osteomyelitis, periostitis, and pustulosis" [PMID 19494218]; "most common symptoms were fever, followed by osteoarticular manifestations (arthralgia, muscle contracture, fracture, osteolytic lesions, and osteomyelitis), nail changes, pneumonia, venous thrombosis" [PMID 40060136]; skin biopsy shows "neutrophil infiltration in the epidermis and subepidermal pustular dermatosis" [PMID 26100510].

Onset variability. Although classically neonatal, late-onset DIRA occurs (first symptoms at age 1–12 years) with milder or atypical presentations [Human clinical, PMID 26100510, 31467740].

Quality-of-life impact. No formal EQ-5D/SF-36/PROMIS data exist for this ultra-rare disease. Qualitatively, untreated DIRA causes severe pain, feeding difficulty, disability from bone deformity/fracture, and high mortality; effective IL-1 blockade dramatically improves QoL and prevents irreversible complications [Review, PMID 32882069].

4. Genetic / Molecular Information

Causal gene. IL1RN (HGNC:6000; NCBI Gene 3557; Ensembl ENSG00000136689; OMIM 147679), chromosome 2q14.1, encoding IL-1 receptor antagonist (IL-1RA; UniProt P18510)*, a secreted competitive antagonist of IL1R1.

Pathogenic variants (all loss-of-function; germline; ACMG "Pathogenic"): - p.E77X (nonsense) — Newfoundland founder allele [PMID 19494218, 21792839] - 2-bp deletion (frameshift) — Netherlands founder allele [PMID 19494218] - Lebanese frameshift (consanguineous family) [PMID 19494218] - ~175-kb genomic deletion at 2q13 removing IL1RN + five other IL-1-family genes — Puerto Rican founder allele [PMID 22431714, 22431772] - c.140delC / p.T47TfsX4 (novel frameshift) in compound het with E77X [PMID 21792839] - p.Asp72_Ile76del (in-frame 15-bp deletion) — recurrent in Brazilian patients; p.Q45* (rs1019766125) nonsense [PMID 32819369] - 22,216-bp deletion spanning the first four IL1RN exons — Indian patient, likely founder [PMID 28503715] - p.R26X (nonsense) — late-onset Turkish patient [PMID 26100510]

Variant classes: nonsense, frameshift, in-frame deletion, and large structural/genomic deletions. Because large deletions are common, copy-number–aware testing (SNP array/CMA or MLPA) is required in addition to sequencing.

Allele frequency. Individually ultra-rare in gnomAD; founder alleles are enriched in specific populations (e.g., high carrier frequency of the 175-kb deletion in Puerto Ricans — "A high carrier frequency of the 175-kb DIRA-associated genomic deletion in the Puerto Rican population…" [PMID 22431714]).

Somatic vs germline: exclusively germline, biallelic, recessive.

Functional consequence: Loss of function. "The IL1RN mutations resulted in a truncated protein that is not secreted, thereby rendering cells hyperresponsive to interleukin-1beta stimulation" [In vitro/Human, PMID 19494218]. One most-upstream premature stop codon variant is hypomorphic due to translation reinitiation, softening the phenotype [In vitro, PMID 32185578]. No dominant-negative or gain-of-function mechanism.

Modifier genes: human modifiers undefined; strong QTL modifiers in mice (§2, §15).

Epigenetic information: No DIRA-specific DNA-methylation/histone data available (not applicable/unknown).

Chromosomal abnormalities: the disease-relevant "chromosomal" lesion is the contiguous-gene 2q13 microdeletion (structural variant) that includes IL1RN [PMID 22431714].

GO/molecular annotations: IL1RN — GO:0005152 (IL-1 receptor antagonist activity), GO:0005615 (extracellular space), GO:0002526 (acute inflammatory response, negative regulation).

5. Environmental Information

• Environmental / toxic / occupational factors: none causal (monogenic disease).
• Lifestyle factors: not applicable (neonatal onset).
• Infectious agents: DIRA inflammation is sterile — lesions are culture-negative with no organisms on histology [Review, PMID 21788901, 39757386]. Infection is a key differential to exclude, not a cause. In the mouse model, the commensal microbiome modulates disease severity [Model organism, PMID 28645307], suggesting microbial context may influence expressivity but is not the trigger.

6. Mechanism / Pathophysiology

Ordered causal chain (initiating lesion → clinical manifestation)

1. Biallelic null IL1RN mutation (nonsense/frameshift/deletion) leads to absent or truncated IL-1RA that is not secreted [In vitro, PMID 19494218].
2. Loss of secreted IL-1RA results in loss of competitive antagonism at the type I IL-1 receptor (IL1R1) on target cells.
3. Unopposed IL-1α and IL-1β bind IL1R1 + accessory protein IL1RAP, leading to recruitment of MyD88 and IRAK4/IRAK1–TRAF6 (canonical IL-1 signaling; GO:0070498).
4. This results in sustained activation of NF-κB and MAPK — demonstrated as "significantly enhanced and prolonged" nuclear translocation of NF-κB p65 in IL-1RA-deficient tissue [Model organism/In vitro, PMID 16622029].
5. NF-κB activation drives transcription of IL-6, IL-8/CXCL8, CXCL1(KC)/CXCL2(MIP-2), TNF-α, and G-CSF [Model organism, PMID 16622029; In vitro comparison PMID 33314777].
6. Chemokine/cytokine output leads to massive neutrophil recruitment — "IL-1β is the pivotal cytokine… responsible for the exaggerated production of cytokines and chemokines that induce the recruitment of neutrophils" [Review, PMID 29742056].
7. Branch A — Skin: neutrophils accumulate subcorneally producing pustulosis/psoriasiform dermatitis with "neutrophil-rich microabscesses… beneath the stratum corneum" [Model organism, PMID 15086551] → clinical pustular rash.
8. Branch B — Bone: IL-1 activates osteoclastogenic mediators and inflammatory macrophages (elevated caspase-1/IL-1β secretion shown in DIRA monocytes/macrophages) leading to osteoclast/osteoblast dysregulation, osteolysis, and periosteal new bone → multifocal osteomyelitis + periostitis [In vitro, PMID 33314777].
9. Branch C — Systemic/vascular: circulating IL-1/IL-6 produce fever, acute-phase response (↑CRP/ESR), and predispose to thrombosis/vasculitis (aortitis in the mouse model) [Model organism, PMID 39600116; Human PMID 40060136].
10. Interrupting step 2–3 pharmacologically (anakinra/rilonacept/canakinumab) restores antagonism/ligand neutralization and results in rapid clinical remission [Human clinical, PMID 19494218, 38398338] — closing the causal loop and confirming IL-1 as the driver.

Upstream vs downstream. Upstream/primary: IL1RN LOF → unopposed IL1R1 signaling → NF-κB. Downstream/effector: chemokine amplification, neutrophil influx, osteoclast activation, tissue injury.

Cellular processes: innate immune activation, chronic sterile inflammation (GO:0006954), neutrophil chemotaxis (GO:0030593), NF-κB signaling (GO:0007249), osteoclast differentiation (GO:0030316). Cell types (CL): neutrophils CL:0000775, monocytes/macrophages CL:0000235, keratinocytes CL:0000312, osteoclasts CL:0000092, osteoblasts CL:0000062, fibroblast/synoviocytes. Protein dysfunction: loss of function of secreted IL-1RA (misprocessed/non-secreted truncation) [PMID 19494218]. Metabolic changes: none disease-specific. Chemical entities (CHEBI): IL-1β and IL-1α (proteins); therapeutic small-molecule/biologic antagonists; reactive mediators nitric oxide (CHEBI:16480), prostaglandins via PTGS2/COX-2. Molecular profiling: no large-scale omics datasets specific to DIRA patients (GEO/PRIDE/MetaboLights: none dedicated). Mechanistic transcriptomics comes from Il1rn-KO mice and comparative monocyte studies (PMID 33314777, 39600116).

7. Anatomical Structures Affected

• Primary organs: Bone / skeletal system (UBERON:0002481 bone tissue; ribs UBERON:0002228; clavicle UBERON:0001105; long bones/metaphyses; vertebrae UBERON:0002412) and skin (UBERON:0002097; epidermis UBERON:0001003; nail UBERON:0001705).
• Secondary / systemic involvement: joints (UBERON:0000982), lungs/respiratory system (interstitial pneumonitis; UBERON:0002048), vasculature (arteries/veins; thrombosis, aortitis UBERON:0000947), liver/spleen (hepatosplenomegaly), CNS rarely.
• Body systems: musculoskeletal, integumentary, immune/hematologic, respiratory, cardiovascular.
• Tissue types: connective/osseous tissue, epithelial (epidermis, nail matrix), synovium, vascular endothelium.
• Cell populations: neutrophils (CL:0000775), macrophages (CL:0000235), keratinocytes (CL:0000312), osteoclasts (CL:0000092).
• Subcellular (GO CC): extracellular space (GO:0005615, site of missing IL-1RA); plasma-membrane receptor complex IL1R1/IL1RAP (GO:0045323); nucleus (NF-κB translocation, GO:0005634).
• Localization / lateralization: multifocal and bilateral/asymmetric bone lesions; diffuse/generalized skin pustulosis. Characteristic sites: ribs, clavicles, long-bone metaphyses, vertebrae, periarticular bone [Human clinical, PMID 28503715 "sterile multifocal osteomyelitis including ribs and clavicles"].

8. Temporal Development

• Onset: typically congenital/neonatal (first days–weeks of life), acute-to-subacute; variable, with recognized late-onset forms (1–12 years) [PMID 19494218, 26100510, 31467740].
• Progression: chronic, progressive or episodic/relapsing systemic inflammation with flares; untreated disease escalates to organ failure. Progression rate can be rapid in neonates (respiratory insufficiency, sepsis-like deterioration) [PMID 37575641, 39757386].
• Duration: chronic, lifelong — requires continuous therapy; no spontaneous cure.
• Remission pattern: treatment-induced (IL-1 blockade); relapse on drug withdrawal. Spontaneous remission is not characteristic.
• Critical period / window of opportunity: early initiation of anakinra (ideally before irreversible bone/organ damage) is the decisive intervention window — "It is imperative to recognize this disease early to achieve adequate response and remission" [PMID 37575641].

9. Inheritance and Population

• Inheritance: Autosomal recessive [PMID 19494218].
• Penetrance: essentially complete in biallelic-null genotypes (hypomorphic reinitiation alleles can attenuate; PMID 32185578).
• Expressivity: variable (neonatal severe → late-onset milder), influenced by residual protein and presumed modifiers.
• Carriers: asymptomatic, no in-vitro cytokine abnormality [PMID 19494218].
• Founder effects (variant geography): Newfoundland (E77X), Netherlands (2-bp del), Puerto Rico (175-kb 2q13 deletion; high local carrier frequency), Lebanon (frameshift), Brazil (p.Asp72_Ile76del), India (22.5-kb deletion) [PMID 19494218, 22431714, 32819369, 28503715].
• Consanguinity: contributory (e.g., Lebanese consanguineous family) [PMID 19494218].
• Anticipation / germline mosaicism: not described / not applicable.
• Epidemiology: ultra-rare; ~30–60 genetically confirmed cases reported worldwide; precise prevalence/incidence not established (Orphanet lists prevalence as unknown/<1/1,000,000). Systematic review: 18 eligible studies over 15 years (PMID 40060136).
• Sex ratio: reported male-predominant (~observational; PMID 40060136); disease gene is autosomal.
• Age distribution: overwhelmingly infants; clinical recognition often around ~4 years in the aggregate literature (PMID 40060136), reflecting diagnostic delay.

10. Diagnostics

• Laboratory (LOINC): markedly elevated CRP (LOINC 1988-5) and ESR (LOINC 4537-7); neutrophilic leukocytosis, thrombocytosis, anemia of inflammation [PMID 19494218, 26100510]. HPO: HP:0011227, HP:0001974, HP:0001894, HP:0001903.
• Imaging (RadLex/Radiopaedia): radiographs show osteolytic and/or sclerotic lesions, periosteal new bone, rib/clavicle/long-bone widening, vertebral involvement, heterotopic ossification; MRI / whole-body MRI is the sensitivity gold standard and detects clinically silent lesions — "MRI is more sensitive for detecting CNO and is considered the gold standard for monitoring the disease" [PMID 30031498]; "Whole body MRI is helpful in detecting asymptomatic lesions" [PMID 21788901].
• Histopathology: skin — subepidermal/subcorneal neutrophilic pustular dermatosis [PMID 26100510]; bone — sterile osteomyelitis with "predominant neutrophil infiltration in the absence of autoantibodies and autoreactive T cells" [PMID 21788901]. SNOMED: sterile/chronic nonbacterial osteomyelitis.
• Genetic testing (definitive): single-gene IL1RN sequencing or NGS autoinflammatory panels / WES, plus CMA/SNP-array or MLPA to capture large deletions (e.g., 175-kb, 22.5-kb) [PMID 22431714, 28503715]. WGS captures both SNVs and structural variants. GTR: IL1RN-testing labs available.
• Functional/biomarker confirmation: demonstration of absent secreted IL-1RA and IL-1β hyperresponsiveness of patient cells [In vitro, PMID 19494218].
• Clinical criteria: no formal consensus criteria; diagnosis = compatible skin/bone/systemic phenotype + biallelic IL1RN LOF variants (± dramatic anakinra response, sometimes used empirically before genetics; PMID 37575641).
• Differential diagnosis: infectious osteomyelitis; CRMO/CNO; Majeed syndrome (LPIN2); NOMID/CAPS (NLRP3); DITRA (IL36RN)/generalized pustular psoriasis; PAPA (PSTPIP1); cherubism; neonatal sepsis; Langerhans cell histiocytosis [PMID 21788901, 39757386, 33314777]. Discriminator: sterile, antibiotic-unresponsive, anakinra-responsive disease with biallelic IL1RN variants.
• Screening: targeted cascade/carrier testing in founder populations and relatives; consider IL1RN testing (incl. CNV) in any neonate with unexplained pustulosis in high-carrier regions [PMID 22431714]. Not on standard newborn-screening panels.

11. Outcome / Prognosis

• Untreated: life-threatening; high morbidity/mortality with respiratory insufficiency, thrombosis, sepsis-like deterioration, multi-organ failure [PMID 38398338, 37575641, 39757386].
• Treated: excellent, durable remission with IL-1 blockade — "Patients treated with anakinra responded rapidly" [PMID 19494218]; ~88% complete remission on continued anakinra with mean Hb +3.18 g/dL, ESR −53.4 mm/h, CRP −135.45 mg/L [PMID 38398338].
• Life expectancy: near-normal with early, sustained treatment; historically poor if undiagnosed.
• Complications to prevent (tertiary prevention): bone deformity, pathologic fracture, growth impairment, respiratory failure, thrombosis; chronic autoinflammation carries a theoretical AA amyloidosis risk [Review, PMID 32882069].
• Prognostic factors: time-to-diagnosis / time-to-anakinra (earlier = better), severity/extent of organ involvement, treatment adherence, and residual protein function (hypomorphic alleles milder; PMID 32185578).
• Prognostic biomarkers: CRP/ESR normalization tracks treatment response; no validated molecular predictor beyond genotype.

12. Treatment

Pharmacotherapy — IL-1 blockade (mechanism-based, first-line): - Anakinra (recombinant IL-1RA; blocks IL1R1) — first-line, lifesaving; rapid response, ~88% remission [PMID 19494218, 38398338]. NCIT:C1960. ATC L04AC03. Adverse events: injection-site reactions; rarely anaphylaxis, manageable by desensitization [PMID 28503715]. - Rilonacept (IL-1 "trap" fusion protein neutralizing IL-1α/β) — effective alternative [PMID 32819369]. NCIT:C48411. - Canakinumab (anti-IL-1β mAb) — successful in a late-onset case at 150 mg SC q6 weeks [PMID 26100510]; but because DIRA involves unopposed IL-1α as well as IL-1β, selective anti-IL-1β can be insufficient or trigger flares in some patients [PMID 32819369]. NCIT:C71708. - Adalimumab (anti-TNF) — effective in one late-onset case [PMID 31467740]. Corticosteroids give partial/incomplete control [PMID 32819369].

Pharmacogenomics: none established; therapy is genotype-rational (replace/antagonize IL-1) rather than metabolizer-guided.

Advanced therapeutics: No approved gene therapy, cell therapy, or RNA therapy for DIRA; loss-of-function biology makes gene replacement a conceptually attractive future approach (not yet clinical).

Surgical/interventional: supportive orthopedic management of fractures/deformity; not curative.

Supportive & rehabilitative: pain control, wound/skin care, physical therapy for musculoskeletal sequelae, nutritional support.

Experimental / trials: no DIRA-specific registered pivotal trials (ultra-rare); management is guideline/expert-based and extrapolated from IL-1-mediated autoinflammation.

Treatment strategy: empiric anakinra may be started on strong clinical suspicion before genetic confirmation in a deteriorating neonate [PMID 37575641], then transition/optimize once genotype known; continuous lifelong IL-1 blockade with dose titration to CRP/ESR and clinical control.

13. Prevention

• Primary prevention: not possible (germline monogenic). Genetic counseling for at-risk families; carrier/cascade testing; prenatal testing or preimplantation genetic diagnosis feasible when familial variant is known (incl. CNV assays for deletions) [inferred from PMID 22431714, 28503715].
• Secondary prevention: early recognition and prompt IL-1 blockade to abort organ damage; targeted testing of neonates with unexplained pustulosis in founder populations (e.g., Puerto Rico) [PMID 22431714, 37575641].
• Tertiary prevention: sustained IL-1 blockade to prevent flares, bone deformity, thrombosis, and possible amyloidosis [PMID 32882069].
• Immunization / public-health / behavioral / environmental measures: not applicable to this monogenic disease.
• Counseling: autosomal-recessive 25% recurrence risk per pregnancy for carrier couples; asymptomatic-carrier reassurance.

14. Other Species / Natural Disease

• Taxonomy: experimental disease in Mus musculus (NCBI:txid10090); no reported spontaneous natural DIRA-equivalent in companion animals or wildlife (OMIA: not established).
• Orthologous gene: mouse Il1rn (NCBI Gene 16181); human IL1RN (3557) — evolutionarily conserved IL-1 antagonism.
• Natural disease / veterinary relevance: no recognized naturally occurring animal DIRA; not zoonotic; no cross-species transmission (genetic disease).
• Comparative biology: Il1rn-null mice reproduce the core biology (IL-1-driven sterile inflammation of skin, joints, bone, arteries), confirming mechanistic conservation, but disease pattern is strain/background-dependent [Model organism, PMID 15086551, 21414240].

15. Model Organisms

• Principal model: IL-1Ra (Il1rn) knockout mouse [Model organism]. "Interleukin-1 receptor antagonist knockout (IL-1Ra KO) mice spontaneously develop aortitis, arthritis and dermatitis, and are employed as a model for human inflammatory diseases" [PMID 39600116].
• Genetic model types: constitutive knockout (BALB/c, DBA/1, C57BL/6 backgrounds); congenic QTL strains; transferable T-cell disease (into nude mice) [PMID 39600116, 21414240].
• Phenotype recapitulation (strengths): IL-1-dependent arthritis, psoriasiform pustular dermatitis with subcorneal neutrophil microabscesses, arterial inflammation/aortitis, and bone changes — mirroring human skin+bone+systemic disease [PMID 15086551, 16622029, 39191800, 39600116].
• Limitations: disease penetrance is background-dependent (BALB/c susceptible, C57BL/6 resistant), governed by QTLs (chr 1 major locus; candidates Mr1, Pla2g4a, Fasl, Prg4, Ptgs2) and by the microbiome — features not central to the human monogenic disease [PMID 21414240, 22820384, 22942082, 28645307]; mice do not fully replicate neonatal multifocal osteomyelitis.
• Applications: dissecting IL-1→NF-κB→neutrophil biology, osteoimmunology, microbiome–autoinflammation interactions, and preclinical IL-1-blockade/target validation (e.g., PLD1 inhibition; PMID 23689131).
• Resources: MGI, IMSR (Il1rn alleles); Alliance of Genome Resources.

Supported vs Refuted Hypotheses

Supported: - H1: DIRA is caused by biallelic LOF IL1RN variants producing non-secreted IL-1RA and IL-1 hyperresponsiveness — strongly supported [PMID 19494218]. - H2: Unopposed IL-1 → NF-κB → CXC-chemokine/neutrophil axis drives pustulosis and sterile osteomyelitis — supported [PMID 16622029, 29742056, 15086551, 33314777]. - H3: IL-1 blockade (anakinra) achieves rapid, durable remission — supported (~88% remission) [PMID 38398338, 19494218]. - H4: Founder alleles explain geographic clustering — supported [PMID 22431714, 28503715, 32819369].

Refuted / not supported: - That selective IL-1β blockade is uniformly sufficient — not supported; it can be insufficient/flare-inducing because IL-1α is also unopposed [PMID 32819369]. - That an environmental/infectious agent causes DIRA — refuted; disease is sterile and monogenic [PMID 21788901].

Limitations and Future Directions

• Ultra-rarity → no prevalence/incidence figures, no QoL instruments, no controlled trials; evidence is aggregated case-level.
• Human modifiers, epigenetics, and omics are essentially unstudied; mouse QTL/microbiome findings need human validation.
• Future: DIRA registries and natural-history studies; prospective comparison of anakinra vs rilonacept vs canakinumab; gene-replacement/editing as a potential curative approach; standardized diagnostic criteria and inclusion of IL1RN (with CNV detection) in relevant newborn/at-risk screening.

Key References (PMIDs)

19494218 (landmark discovery), 40060136 (systematic review), 38398338 (anakinra meta-analysis), 22431714 & 22431772 (Puerto Rican 175-kb deletion), 28503715 (Indian 22.5-kb deletion), 21792839 (compound het E77X + c.140delC), 32819369 (Brazilian variants; IL-1β-blockade caveat), 26100510 (late-onset R26X, canakinumab), 31467740 (late-onset, adalimumab), 32185578 (hypomorphic reinitiation allele), 16622029 (NF-κB mechanism), 29742056 & 27890235 (IL-1β/neutrophil dermatologic mechanism), 15086551 (psoriasiform KO skin), 39600116 (KO multi-organ inflammation), 39191800 (KO bone), 21414240/22820384/22942082 (QTL modifiers), 28645307 (microbiome), 33314777 (DIRA vs Majeed/NOMID monocyte/osteoclast biology), 21788901 & 30031498 & 39757386 (sterile osteomyelitis/imaging/DDx), 37575641 (early recognition), 32882069 (SAID/amyloidosis).

Artifacts

• OpenScientist final report
• OpenScientist final report