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Classifications

Harrison's Part

Mechanistic Nosology

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Mechanistic Hypotheses

2

Canonical SAA Overproduction Model

canonical_saa_overproduction CANONICAL

Evidence balance 2 support

Chronic inflammation drives IL-6-dependent hepatic SAA overproduction; a sustained high plasma SAA concentration is the rate-limiting upstream lesion that permits proteolytic processing, misfolding, and cross-beta fibril deposition. The corollary - that lowering SAA arrests and can reverse the process - is the basis of all current therapy.

Show evidence (2 references)

PMID:25387054 SUPPORT Other

"In AA amyloidosis, the expression of cytokines, particularly interleukin 6, leads to overproduction of serum amyloid A (SAA) by the liver. A chronically high plasma concentration of SAA results in the aggregation of amyloid into cross-β-sheet fibrillar deposits by mechanisms not fully understood."

States the cytokine-to-precursor-to-fibril chain that defines the canonical hypothesis group. Evidence source is OTHER because this is a review.

PMID:17554117 SUPPORT Human Clinical

"Mortality, amyloid burden, and renal prognosis all significantly correlated with the SAA concentration during follow-up."

A 374-patient natural-history cohort provides the human dose-response evidence that circulating precursor concentration governs amyloid burden and outcome, the central prediction of this model.

Nucleation-Dependent Seeding Model

nucleation_seeding_model CANONICAL

Evidence balance 2 support

Fibril formation is nucleation dependent rather than simply concentration dependent: a preformed fibrillar nucleus recruits and templates conversion of further native molecules. This helps explain why only a minority of patients with equivalent chronic inflammation develop amyloidosis, and why amyloid-enhancing factor collapses the induction lag phase in animal models. The evidence for exogenous or heterologous seeds acting as a human risk factor is experimental, not clinical.

Show evidence (2 references)

PMID:25387054 SUPPORT Other

"Generation of amyloid fibrils is nucleation dependent, and once formed, fibrils recruit and catalyze the conversion of native molecules."

States the nucleation-and-templating mechanism that distinguishes this model from simple mass-action aggregation. Evidence source is OTHER because this is a review.

PMID:15829582 SUPPORT Model Organism

"Our results show that these protein fibrils exert amyloid-accelerating properties in the murine experimental AA amyloidosis, suggesting that such environment factors may be important risk factors in amyloidogenesis."

Demonstrates cross-seeding by heterologous (silk, Sup35, curli) fibrils in the murine model, supporting seeding as a mechanism. Marked PARTIAL because the extension to human environmental risk is proposed by the authors, not demonstrated; evidence source is MODEL_ORGANISM (mouse).

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Discussions and Knowledge Gaps

3

Why do only a minority of patients with equivalently sustained, equivalently high SAA concentrations develop AA amyloidosis?

KNOWLEDGE GAP OPEN saa_threshold_vs_deposition_mechanism

Attached to

pathophysiology#Glycosaminoglycan-Assisted Fibril Nucleation and Extracellular Deposition

Chronic SAA elevation is necessary but demonstrably not sufficient: most patients with long-standing rheumatoid arthritis or FMF never develop amyloidosis despite decades of raised SAA. SAA1 genotype explains part of the variance and nucleation-dependence supplies a plausible stochastic mechanism, but the field's own reviews state that the conversion step is not fully understood. Resolving this would determine whether risk stratification can ever go beyond measuring the precursor.

Proposed experiments

Prospective cohort with matched cumulative SAA exposure stratified by SAA1 genotype

exp_aa_matched_saa_exposure_genotype_cohort

Recruit patients with chronic inflammatory disease and serially quantified SAA, compute a cumulative SAA exposure integral for each, and stratify by SAA1 genotype. Screen prospectively for subclinical amyloid so that incidence can be regressed on cumulative exposure within genotype strata. The design isolates the question of whether genotype shifts the exposure threshold or instead changes the probability of conversion at a given exposure.

Supporting outcome

A genotype-dependent shift in the exposure-incidence curve would support SAA1 acting on the proteolysis and misfolding step rather than on precursor supply.

Refuting outcome

Superimposable exposure-incidence curves across genotypes would refute a genotype-dependent threshold model and point to an unmeasured host factor.

Detection of endogenous nucleating seed before clinically apparent deposition

exp_aa_pre_clinical_seed_detection

Apply high-sensitivity amyloid-seeding assays to accessible tissue (fat aspirate, minor salivary gland) from patients with sustained high SAA but no clinical amyloidosis, to test whether a subclinical nucleating seed precedes and predicts overt disease.

Supporting outcome

Seeding activity detectable before overt disease, and predictive of later amyloidosis, would support the nucleation-dependent seeding model as the rate-limiting stochastic step.

Refuting outcome

Absence of detectable seeding activity in patients who subsequently develop amyloidosis would argue against a detectable pre-clinical seed.

Show evidence (1 reference)

PMID:25387054 SUPPORT Other

"A chronically high plasma concentration of SAA results in the aggregation of amyloid into cross-β-sheet fibrillar deposits by mechanisms not fully understood."

The authoritative review explicitly states that the mechanism converting high SAA into deposits is incompletely understood, which is the gap recorded here. Evidence source is OTHER (review).

Can established AA amyloid deposits be actively cleared, rather than merely allowed to regress by withdrawing the precursor?

KNOWLEDGE GAP OPEN no_deposit_clearing_therapy

Attached to

pathophysiology#Progressive Multi-Organ Amyloid Accumulation

All available management works upstream, by lowering SAA; regression then depends on endogenous clearance, which is slow and incomplete once organ damage is established. The two direct attacks on the deposit - eprodisate against glycosaminoglycan-assisted polymerization, and SAP depletion plus anti-SAP antibody against existing deposits - both reached clinical trials and neither is available. This is the field's principal unmet need and the reason treatment timing dominates outcome.

Show evidence (2 references)

PMID:38568326 SUPPORT Other

"There is yet no treatment option for the clearance of amyloid fibril deposits; therefore, the management strategy primarily aims to reduce serum amyloid A protein."

States directly that no deposit-clearing therapy exists and that management is therefore confined to precursor reduction. Evidence source is OTHER because this is a review.

PMID:26176329 SUPPORT Human Clinical

"We conducted an open-label, single-dose-escalation, phase 1 trial involving 15 patients with systemic amyloidosis."

The anti-SAP approach reached a 15-patient phase 1 trial in systemic amyloidosis, showing clearance is achievable in principle. Marked PARTIAL because the trial was small, open-label, not AA-specific, excluded patients with cardiac involvement, and the programme was subsequently discontinued.

Is MICA a modifier locus for amyloidosis risk in familial Mediterranean fever, as sometimes summarized?

INTERPRETATION OPEN mica_not_a_modifier_locus

Attached to

pathophysiology#Sustained Elevation of Circulating Serum Amyloid A

Recorded to stop a specific error being reintroduced. The deep-research report for this entry stated that MICA polymorphisms have been reported as a modifying factor for amyloidosis risk in FMF alongside MEFV and SAA1, citing PMID:15018633. That paper reports the opposite: it tested the MICA exon 5 polymorphism precisely because MICA modifies FMF attack frequency and age of onset, and found no association with renal amyloidosis, while confirming the SAA1 association in the same cohort. MICA is therefore deliberately absent from this entry's genetic section - not overlooked. The paper reports the amyloidosis null without proposing an explanation for it; the two explanations it does offer - a weak MICA effect masked by stronger MEFV and SAA1 effects, or a population-dependent effect - are given for its separate failure to replicate the earlier MICA associations with attack frequency and age of onset, and should not be transferred to the amyloidosis result.

Show evidence (2 references)

PMID:15018633 REFUTE Human Clinical

"Moreover, no specific MICA genotype or allele was significantly associated with the development of amyloidosis"

Directly refutes a MICA-amyloidosis association in the cohort that tested it, which is why MICA is not curated as a susceptibility or modifier locus here.

PMID:15018633 SUPPORT Human Clinical

"no association was found between the MICA gene exon 5 polymorphism and the development of renal amyloidosis in FMF patients, whereas the alpha allele and the alpha/alpha genotype of the SAA1 gene were associated with this severe phenotype"

The authors' own conclusion, contrasting the null MICA result with the positive SAA1 result in the same patients - the asymmetry that justifies curating SAA1 but not MICA.

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Pathophysiology

9

Chronic Inflammatory, Autoinflammatory, or Infectious Stimulus

The proximal trigger is a persistent inflammatory drive of any cause: inflammatory arthritis (rheumatoid arthritis, ankylosing spondylitis, juvenile idiopathic arthritis), a monogenic autoinflammatory syndrome (familial Mediterranean fever, TRAPS, CAPS, mevalonate kinase deficiency), chronic infection (tuberculosis, leprosy, osteomyelitis, bronchiectasis), inflammatory bowel disease, or vasculitis. The specific disease is interchangeable; what matters mechanistically is the duration and magnitude of the cytokine drive it sustains. A substantial minority of cases remain idiopathic, with no overt trigger identified.

inflammatory response GO:0006954 ↑ INCREASED Temporal: CHRONIC

Downstream

IL-6-Driven Hepatic Acute-Phase Response Sustained cytokine release, principally IL-6, acts on hepatocytes to induce the acute-phase programme.

Show evidence (2 references)

PMID:25387054 SUPPORT Other

"Therefore, AA amyloidosis can be thought of as a consequence of long-standing inflammatory disease."

Frames chronic inflammatory disease as the upstream trigger of the whole chain. Evidence source is OTHER because this is a review.

PMID:17714761 SUPPORT Human Clinical

"The amyloidogenic disease was a chronic infection (40.8%), a chronic inflammation (38%), a tumor (9.9%), a hereditary disease (9.9%), or was undetermined in 1.4% of cases."

Quantifies the heterogeneous trigger diseases in a renal AA amyloidosis series, supporting the trigger node as an aetiology-agnostic entry point.

IL-6-Driven Hepatic Acute-Phase Response

Interleukin-6 (with contributions from IL-1beta and TNF) drives hepatocyte transcription and secretion of SAA1 and SAA2 as HDL-associated acute-phase apolipoproteins. In an ordinary self-limited acute-phase response this is physiological and transient; here it is unremitting. Adipose tissue is a second, non-hepatic source of SAA, which is how obesity feeds this node in the absence of a classical inflammatory disease.

hepatocyte CL:0000182

acute-phase response GO:0006953 ↑ INCREASED interleukin-6-mediated signaling pathway GO:0070102 ↑ INCREASED

Downstream

Sustained Elevation of Circulating Serum Amyloid A Unremitting hepatic (and adipose) SAA output raises and holds the plasma SAA concentration far above its physiological baseline.

Show evidence (2 references)

PMID:25387054 SUPPORT Other

"In AA amyloidosis, the expression of cytokines, particularly interleukin 6, leads to overproduction of serum amyloid A (SAA) by the liver."

Names IL-6 as the principal cytokine driving hepatic SAA overproduction, the amplifier step. Evidence source is OTHER because this is a review.

PMID:16737350 SUPPORT Human Clinical

"We demonstrate that A-SAA was highly and selectively expressed in human adipocytes."

Establishes adipose tissue as an additional, extrahepatic source of acute-phase SAA. Marked PARTIAL because the study characterizes SAA biology in obesity and does not itself study amyloidosis.

Sustained Elevation of Circulating Serum Amyloid A

The amyloidogenic precursor of this disease. Unlike AL (a clonal light chain) or ATTR (a destabilized or wild-type transthyretin), the AA precursor is a structurally normal protein whose only abnormality is chronic excess. Prolonged rather than transient elevation is the rate-limiting requirement: the concentration-duration product, not any single peak, determines amyloidogenic risk. This node is the disease's therapeutic target, and the quantitative relationship between achieved SAA level and outcome is the best-documented dose-response in systemic amyloidosis.

protein folding GO:0006457 ⚠ ABNORMAL

Downstream

Proteolytic Processing and Beta-Sheet Misfolding of SAA Excess circulating precursor is the substrate on which proteolysis and conformational conversion act.

Show evidence (2 references)

PMID:17554117 SUPPORT Human Clinical

"Deposition of amyloid fibrils derived from circulating acute-phase reactant serum amyloid A protein (SAA) causes systemic AA amyloidosis, a serious complication of many chronic inflammatory disorders."

Identifies circulating SAA as the precursor from which the fibrils derive, the substituted precursor node of the amyloidogenesis module.

PMID:17554117 SUPPORT Human Clinical

"The risk of death was 17.7 times as high among patients with SAA concentrations in the highest eighth, or octile, (>or=155 mg per liter) as among those with concentrations in the lowest octile (<4 mg per liter)"

Quantifies the precursor-concentration-to-outcome gradient in humans, establishing that the level of this node, not merely its presence, drives disease.

Proteolytic Processing and Beta-Sheet Misfolding of SAA

SAA is cleaved to an N-terminal fragment (predominantly residues 1-76, losing the C-terminal region) and converts from its native alpha-helical fold into beta-sheet-rich, aggregation-prone species. C-terminal truncation is not incidental: it destabilizes the alpha-helical structure and markedly accelerates fibril formation relative to the full-length protein. Genetic variation in SAA1 acts at exactly this step, by changing how readily the precursor is cleaved.

proteolysis GO:0006508 ↑ INCREASED protein folding GO:0006457 ⚠ ABNORMAL

Downstream

Glycosaminoglycan-Assisted Fibril Nucleation and Extracellular Deposition Misfolded beta-sheet species are the monomeric input to nucleation and fibril elongation.

Show evidence (3 references)

PMID:17554116 SUPPORT Human Clinical

"Amyloid A (AA) amyloidosis is a complication of chronic inflammatory conditions that develops when proteolytic fragments of serum amyloid A protein (SAA) are deposited in tissues as amyloid fibrils."

Establishes that it is proteolytic fragments of SAA, not the intact protein, that form the deposited fibrils.

PMID:29288051 SUPPORT In Vitro

"Although the full-length SAA is 104 amino acids long, the C-terminal-truncated SAA lacking mainly residues 77-104 is predominantly deposited in AA amyloidosis."

Identifies the specific truncated species that predominates in deposits, defining the processed form that misfolds. Evidence source is IN_VITRO (recombinant peptide biophysics).

PMID:29288051 SUPPORT In Vitro

"Circular dichroism (CD) measurements demonstrated that the C-terminal truncation induces a reduced α-helical structure of the SAA molecule."

Direct biophysical evidence that truncation destabilizes the native fold, the conformational conversion this node describes.

Glycosaminoglycan-Assisted Fibril Nucleation and Extracellular Deposition

The central effector and rate-limiting convergence step. Misfolded SAA fragments nucleate and elongate into insoluble cross-beta amyloid fibrils that deposit in the extracellular space. Heparan sulfate is a potent amyloid agonist here rather than a passive co-deposit: it remodels HDL-associated SAA at mildly acidic pH, induces non-native beta-sheet, and binds synergistically to forming amyloid. Serum amyloid P component binds and stabilizes the deposits against clearance. This accessory-molecule dependence is the rationale for eprodisate and for anti-SAP strategies, and it is the node that conforms to the shared amyloidogenesis module.

amyloid fibril formation GO:1990000 ↑ INCREASED

glycosaminoglycan binding GO:0005539

extracellular region GO:0005576

Downstream

Progressive Multi-Organ Amyloid Accumulation Continued nucleation and elongation converts fibril formation into a growing tissue burden.

Show evidence (4 references)

PMID:25387054 SUPPORT Other

"Central to amyloid formation is an increase in the frequency of the β-sheet structure, leading to hydrogen bonding between misfolded monomers and creating a fibril that is comparably resistant to degradation."

Describes the beta-sheet fibril assembly and its protease resistance, the central effector step. Evidence source is OTHER because this is a review.

PMID:19549924 SUPPORT In Vitro

"HS causes the remodeling of HDL-SAA at mildly acidic pH, producing SAA-rich aggregates."

Direct evidence that heparan sulfate actively promotes conversion of HDL-borne SAA into aggregates, supporting the glycosaminoglycan-assisted mechanism. Evidence source is IN_VITRO (biochemical and cell-culture assays).

PMID:39954777 SUPPORT In Vitro

"HS/heparin can promote amyloidogenesis by inducing non-native β-sheet and apparently causing liquid droplet formation in SAA in solution."

Contemporary biophysical evidence that heparan sulfate induces the non-native beta-sheet conformation feeding fibril formation. Evidence source is IN_VITRO (recombinant SAA spectroscopy and ELISA).

+ 1 more reference

Progressive Multi-Organ Amyloid Accumulation

Fibrils accumulate as a growing extracellular amyloid burden. Because the precursor is circulating, deposition is systemic and bilateral, but the distribution is characteristic: kidney (glomerular mesangium and capillary walls, plus vascular deposits), liver, spleen, and adrenal gland are the dominant sites, with perivascular deposition common across organs. Unlike the deposits of AL and ATTR, this burden is genuinely dynamic - it regresses when the precursor supply is withdrawn, which is why this node is not a therapeutic dead end.

kidney UBERON:0002113 liver UBERON:0002107 spleen UBERON:0002106

Downstream

Glomerular Filtration Barrier Disruption Mesangial and capillary-wall amyloid physically disrupts the filtration apparatus.

Extrarenal Organ Dysfunction Amyloid infiltration of liver, spleen, gut, and endocrine organs disturbs their architecture and function.

Show evidence (2 references)

PMID:28828707 SUPPORT Human Clinical

"AA amyloidosis shows vascular deposits in addition to the glomerular deposits"

Documents the characteristic combined glomerular-plus-vascular deposition pattern that distinguishes AA from other renal amyloid types.

PMID:17554117 SUPPORT Human Clinical

"Amyloid deposits regressed in 60% of patients who had a median SAA concentration of less than 10 mg per liter, and survival among these patients was superior to survival among those in whom amyloid deposits did not regress (P=0.04)."

Establishes that the accumulated amyloid burden is reversible when the precursor is suppressed, and that regression carries a survival benefit - the key clinical property of this node.

Glomerular Filtration Barrier Disruption

Amyloid expanding the mesangium and infiltrating the glomerular capillary wall breaches the filtration barrier, producing non-selective proteinuria. Glomerular (rather than purely vascular) involvement is the histological determinant of the clinical picture and of renal outcome; a vascular-predominant pattern presents with less proteinuria. Tubular atrophy and the abundance and distribution of glomerular deposits predict renal survival.

glomerular mesangial cell CL:1000742 podocyte CL:0000653

renal glomerulus UBERON:0000074

Downstream

Progressive Kidney Failure Sustained proteinuria and nephron loss drive progressive decline in glomerular filtration rate.

Show evidence (2 references)

PMID:17714761 SUPPORT Human Clinical

"the glomerular involvement appeared as the determining histological factor for clinical manifestations and outcome of renal AA amyloidosis"

Identifies glomerular amyloid involvement as the histological determinant of the clinical syndrome, supporting this node as the effector linking deposition to renal disease.

PMID:17714761 SUPPORT Human Clinical

"Tubular atrophy, abundance, and distribution pattern of glomerular amyloid deposits at the time of biopsy were independent predictors of renal outcome."

Links the quantitative glomerular amyloid burden to renal prognosis, supporting a dose-dependent barrier-disruption mechanism.

Progressive Kidney Failure

The dominant clinical consequence. Proteinuria progresses to nephrotic-range proteinuria and nephrotic syndrome, then to declining glomerular filtration rate and end-stage kidney disease requiring dialysis or transplantation. Renal dysfunction, not cardiac or neurological involvement, defines the course of AA amyloidosis - the principal clinical contrast with AL amyloidosis.

Show evidence (2 references)

PMID:17554117 SUPPORT Human Clinical

"Median survival after diagnosis was 133 months; renal dysfunction was the predominant disease manifestation."

Establishes renal dysfunction as the dominant manifestation and provides the survival benchmark for this consequence node.

PMID:17554116 SUPPORT Human Clinical

"Amyloid deposition in the kidney causes progressive deterioration in renal function."

States the deposition-to-renal-failure causal link this node represents.

Extrarenal Organ Dysfunction

Amyloid infiltration outside the kidney. Hepatic and splenic deposition is frequent and often functionally silent, detected radiologically or as raised alkaline phosphatase rather than as liver failure. Gastrointestinal deposition causes chronic diarrhoea and malabsorption. Adrenal and thyroid infiltration occurs. Cardiac involvement and peripheral neuropathy are comparatively uncommon in AA - a point of clinical contrast with AL amyloidosis rather than a feature of this disease.

Show evidence (1 reference)

PMID:38568326 SUPPORT Other

"Amyloid A (AA) amyloidosis is an organ- or life-threatening complication of chronic inflammatory disorders."

Supports multi-organ, potentially life-threatening involvement as the clinical consequence of the deposition chain. Evidence source is OTHER because this is a review.

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Histopathology

3

Congo Red-Positive Amyloid Deposition

Acellular Congo red-positive extracellular deposits showing apple-green birefringence under polarized light. This confirms amyloid but does not identify the precursor; typing is a separate and mandatory step.

Show evidence (1 reference)

PMID:28828707 SUPPORT Human Clinical

"Renal amyloidosis is characterized by acellular Congo red positive deposits in the glomeruli, interstitium and/or arteries."

Defines the Congo red-positive histological finding and its renal distribution.

Glomerular-Predominant Deposition Pattern

Amyloid deposits are distributed within the glomerulus in mesangial segmental, mesangial nodular, mesangiocapillary, or hilar patterns. A glomerular form predominates over a purely vascular form, and this distinction determines the clinical presentation, with proteinuria dominating the glomerular form.

Show evidence (1 reference)

PMID:17714761 SUPPORT Human Clinical

"The distribution pattern of glomerular amyloid deposits was mesangial segmental (14.7%), mesangial nodular (26.5%), mesangiocapillary (32.3%), and hilar (26.5%). Glomerular form was observed in 80.9% of cases and vascular form in 19.1%."

Quantifies the glomerular deposition patterns and the glomerular-to-vascular ratio in a 68-case renal AA series.

Amyloid-Associated Giant Cell and Inflammatory Reaction

A local inflammatory reaction to the deposits themselves - multinucleated giant cells and glomerular inflammatory infiltrate, sometimes with crescents - is present in a substantial minority of biopsies. The authors propose it reflects an immune response directed against AA fibrils that may contribute to amyloid resolution, which is mechanistically interesting because macrophage-mediated clearance is exactly the effector arm exploited by anti-SAP antibody therapy.

Show evidence (1 reference)

PMID:17714761 SUPPORT Human Clinical

"AA amyloidosis-related inflammation was noted in 30 patients (44.1%) and appeared as a multinucleated giant cell reaction (27.9%) or a glomerular inflammatory infiltrate (25%), including glomerular crescents (17.6%)."

Quantifies the amyloid-associated inflammatory reaction and its giant-cell component in the same 68-case series.

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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

14

Blood 1

Gastrointestinal Hemorrhage HP:0002239

Show evidence (1 reference)

PMID:38568326 SUPPORT Human Clinical

"episodes of upper and lower gastrointestinal bleeding"

Names episodes of upper and lower gastrointestinal bleeding among the frequently encountered presenting symptoms.

Cardiovascular 1

Splenomegaly HP:0001744

Show evidence (2 references)

PMID:38568326 SUPPORT Human Clinical

"Hepato- and splenomegaly commonly manifests during disease progression, whereas splenic rupture is exceptionally rare"

Directly documents splenomegaly as a common manifestation of human AA amyloidosis, replacing the model-organism-only support this phenotype previously carried.

PMID:26176329 SUPPORT Model Organism

"In murine amyloid A type amyloidosis, the binding of these antibodies to the residual SAP in amyloid deposits activates complement and triggers the rapid clearance of amyloid by macrophage-derived multinucleated giant cells."

Supplementary model-organism support: the murine AA amyloidosis model on which anti-SAP therapy was built deposits amyloid in spleen and liver. Retained alongside, not in place of, the human evidence above.

Digestive 3

Hepatomegaly HP:0002240

Show evidence (2 references)

PMID:38568326 SUPPORT Human Clinical

"Hepato- and splenomegaly commonly manifests during disease progression, whereas splenic rupture is exceptionally rare"

Directly documents hepatomegaly as a common manifestation of human AA amyloidosis during disease progression.

PMID:38568326 SUPPORT Human Clinical

"While splenic and hepatic amyloid deposition is commonly detected in serum amyloid P (SAP) scintigraphy, its clinical relevance is limited"

Records the important caveat that hepatic deposition is frequently imaged but usually not clinically consequential, so this phenotype should not be read as hepatic failure. Marked PARTIAL because it qualifies rather than strengthens the association.

Chronic Diarrhea FREQUENT HP:0002014

Temporal: CHRONIC

Show evidence (1 reference)

PMID:38568326 SUPPORT Human Clinical

"Approximately 30% of cases have gastrointestinal involvement. The predominant symptom is diarrhea that is frequently unresponsive to standard treatment"

Quantifies gastrointestinal involvement at approximately 30%, mapping to the FREQUENT band (30-79%), and names diarrhoea as its predominant and treatment-refractory symptom.

Malabsorption HP:0002024

Show evidence (1 reference)

PMID:38568326 SUPPORT Human Clinical

"Other frequently encountered presenting symptoms include weight loss, abdominal pain, malabsorption, macroglossia, gastroesophageal reflux, esophageal dysmotility, gastric polyps, and episodes of upper and lower gastrointestinal bleeding"

Lists malabsorption among the frequently encountered presenting gastrointestinal symptoms of AA amyloidosis.

Genitourinary 3

Proteinuria VERY_FREQUENT HP:0000093

Show evidence (2 references)

PMID:17714761 SUPPORT Human Clinical

"The clinical presentation of glomerular and vascular forms was distinct with a clear predominance of proteinuria in glomerular form."

Documents proteinuria as the predominant clinical presentation of the glomerular form, which was present in 80.9% of this renal AA series, supporting the VERY_FREQUENT band.

PMID:38568326 SUPPORT Other

"the prevailing symptoms frequently involve the emergence of proteinuria and gradual reduction in kidney function, apparent in over 90% of patients upon their initial presentation"

Directly quantifies proteinuria and declining kidney function at over 90% of patients at initial presentation, which is the primary support for the VERY_FREQUENT band (80-100%). Evidence source is OTHER because this is a review.

Renal Insufficiency FREQUENT HP:0000083

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:17714761 SUPPORT Human Clinical

"Nephrotic syndrome and renal insufficiency were noted in 63.1% and 75% of patients, respectively."

Directly quantifies renal insufficiency at 75%, mapping to the FREQUENT band (30-79%).

End-Stage Kidney Disease FREQUENT Stage 5 chronic kidney disease HP:0003774

Show evidence (1 reference)

PMID:17714761 SUPPORT Human Clinical

"At the end of follow-up, 26 patients (38.2%) showed end-stage renal disease."

Directly quantifies progression to end-stage renal disease at 38.2%, mapping to the FREQUENT band (30-79%).

Metabolism 2

Peripheral Edema HP:0000969

Show evidence (1 reference)

PMID:17714761 SUPPORT Human Clinical

"Nephrotic syndrome and renal insufficiency were noted in 63.1% and 75% of patients, respectively."

Oedema is a defining component of the nephrotic syndrome documented in 63.1% of this series. Marked PARTIAL because the abstract reports the syndrome rather than oedema as a separately counted finding.

Hypoalbuminemia HP:0003073

Show evidence (1 reference)

PMID:17714761 SUPPORT Human Clinical

"Nephrotic syndrome and renal insufficiency were noted in 63.1% and 75% of patients, respectively."

Hypoalbuminaemia is a defining component of the nephrotic syndrome documented here. Marked PARTIAL because the abstract reports the syndrome rather than albumin values directly.

Growth 1

Weight Loss HP:0001824

Show evidence (1 reference)

PMID:38568326 SUPPORT Human Clinical

"Other frequently encountered presenting symptoms include weight loss, abdominal pain, malabsorption, macroglossia, gastroesophageal reflux, esophageal dysmotility, gastric polyps, and episodes of upper and lower gastrointestinal bleeding"

Lists weight loss among the frequently encountered presenting symptoms of AA amyloidosis.

Other 3

Nephrotic Syndrome FREQUENT HP:0000100

Show evidence (1 reference)

PMID:17714761 SUPPORT Human Clinical

"Nephrotic syndrome and renal insufficiency were noted in 63.1% and 75% of patients, respectively."

Directly quantifies nephrotic syndrome at 63.1%, which maps to the FREQUENT band (30-79%).

Elevated Alkaline Phosphatase OCCASIONAL Elevated circulating alkaline phosphatase concentration HP:0003155

Show evidence (2 references)

PMID:38568326 SUPPORT Human Clinical

"Elevated serum alkaline phosphatase (ALP) levels are noted in 5% of patients"

Directly quantifies elevated ALP at 5% of patients, mapping to the OCCASIONAL band (5-29%).

PMID:38568326 SUPPORT Human Clinical

"this may more accurately reflect underlying disease activity rather than amyloid deposition given that ALP functions as an acute-phase reactant"

Records the interpretive caveat that the ALP rise may track inflammatory activity rather than hepatic amyloid. Marked PARTIAL because it qualifies the attribution of the finding.

Elevated Acute-Phase Reactants VERY_FREQUENT Elevated circulating C-reactive protein concentration HP:0011227

Show evidence (1 reference)

PMID:17554117 SUPPORT Human Clinical

"The median SAA concentration during follow-up was 6 mg per liter in patients in whom renal function improved and 28 mg per liter in those in whom it deteriorated (P<0.001)."

Documents elevated acute-phase SAA in this cohort and ties the level to renal outcome. Elevation is intrinsic to the disease definition (an unremitting acute-phase response), supporting the VERY_FREQUENT band.

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Genetic Associations

3

SAA1

Gene: SAA1 hgnc:10513 relationship_type: SUSCEPTIBILITY

Show evidence (3 references)

PMID:12687559 SUPPORT Human Clinical

"the presence of the SAAalpha/alpha genotype (OR 2.99, 95% CI 1.47-6.09)"

Quantifies the independent association of the amyloidogenic SAA1 alpha/alpha genotype with renal amyloidosis in a 277-patient FMF cohort.

PMID:29364741 SUPPORT Human Clinical

"Finally, the SAA1 polymorphism was confirmed as a susceptibility factor for AA amyloidosis irrespective of the type of the disease."

Confirms SAA1 polymorphism as a susceptibility factor across trigger diseases, supporting the SUSCEPTIBILITY relationship type.

PMID:18815155 SUPPORT In Vitro

"These results may explain the higher risk of amyloidosis in patients with a SAA1.1/1.1 genotype vs SAA1.5/1.5 or SAA1.1/1.5 genotype."

Provides the mechanistic basis for the SAA1 risk association, namely isoform-dependent susceptibility to MMP-1 cleavage, linking the susceptibility locus to the proteolytic-processing pathophysiology node. Evidence source is IN_VITRO (immunoblotting and MALDI-TOF of recombinant isoforms).

MEFV

Gene: MEFV hgnc:6998 relationship_type: SUSCEPTIBILITY

Show evidence (3 references)

PMID:12687559 SUPPORT Human Clinical

"Logistic regression analysis showed that homozygosity for the M694V allele"

Identifies M694V homozygosity as independently associated with renal amyloidosis in a 277-patient FMF cohort; the same sentence reports the odds ratio of 4.27 (95% CI 2.01-9.07), the strongest single MEFV genotype association.

PMID:12687559 SUPPORT Human Clinical

"Overall, disease severity and the development of amyloidosis in FMF are differentially affected by genetic variations within and outside the MEFV gene."

The authors' conclusion that MEFV variation contributes to amyloidosis risk alongside loci outside MEFV, which is exactly the two-locus (MEFV plus SAA1) susceptibility model curated here.

PMID:15018633 SUPPORT Human Clinical

"Amyloidosis in familial Mediterranean fever patients: correlation with MEFV genotype and SAA1 and MICA polymorphisms effects."

Independent study correlating MEFV genotype with amyloidosis risk in FMF, corroborating MEFV as a susceptibility locus acting through the trigger disease.

SAA2

Gene: SAA2 hgnc:10514 relationship_type: SUSCEPTIBILITY

Show evidence (2 references)

PMID:38568326 SUPPORT Other

"SAA1 and SAA2 are both acute-phase proteins and associated with AA amyloidosis."

Directly associates SAA2, alongside SAA1, with AA amyloidosis. Evidence source is OTHER because this is a review.

PMID:38568326 SUPPORT Other

"Inducible expression of SAA1 and SAA2 by proinflammatory cytokines during acute-phase response impacts the serum concentration of SAA"

Links SAA2 expression to the cytokine-driven acute-phase node that sets circulating precursor concentration. Marked PARTIAL because it describes the shared regulatory mechanism rather than an SAA2-specific amyloidosis risk estimate. Evidence source is OTHER (review).

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Medical Actions

7

Colchicine (Familial Mediterranean Fever)

Action: Pharmacotherapy NCIT:C15986

Agent: colchicine CHEBI:23359

First-line and foundational therapy for FMF, suppressing the inflammatory attacks that drive SAA production and thereby preventing amyloidosis. In patients who already have established amyloid nephropathy, the therapeutic dose is above 1.5 mg/day and efficacy depends critically on starting before renal function is lost - the effect is confined to patients whose serum creatinine is still below 1.5 mg/dL. This is the clearest demonstration in the disease that treatment timing, not just treatment choice, determines outcome.

Mechanism Target:

INHIBITS Chronic Inflammatory, Autoinflammatory, or Infectious Stimulus — Suppressing FMF inflammatory attacks removes the cytokine drive at the trigger node, preventing the downstream acute-phase SAA surge.

Show evidence (4 references)

PMID:7986228 SUPPORT Human Clinical

"The therapeutic dosage of colchicine for amyloidosis of FMF is > 1.5 mg/day. This dosage is effective only in patients with initial serum creatinine levels < 1.5 mg/dl."

Defines both the effective colchicine dose and the renal-function window within which it works, in 68 FMF patients with amyloidosis followed at least 5 years.

PMID:7986228 SUPPORT Human Clinical

"At the end of the study period, kidney disease had worsened in 31 patients and remained stable in 22. Proteinuria had regressed in 15 patients."

Documents stabilization or regression of proteinuria in a substantial share of colchicine-treated patients. Marked PARTIAL because this is an uncontrolled retrospective series without a comparator arm, and disease still worsened in the largest single group.

PMID:38568326 SUPPORT Other

"In a study examining 960 patients with FMF without evidence of amyloidosis at baseline, the cumulative rate of proteinuria after 11 years was reported as 1.7% in colchicine-compliant patients while 48.9% in the non-compliants"

The strongest available prevention signal in this disease: a roughly 29-fold difference in 11-year cumulative proteinuria between colchicine-compliant and non-compliant FMF patients, which is what justifies colchicine as prophylaxis rather than only as rescue therapy. Evidence source is OTHER because the figures are reported in a review summarizing the primary cohort.

+ 1 more reference

Anti-TNF-alpha Therapy

Action: Pharmacotherapy NCIT:C15986

Agent: infliximab NCIT:C1789 etanercept NCIT:C2381 adalimumab NCIT:C65216

TNF inhibitors (infliximab, etanercept, adalimumab) treat AA amyloidosis by controlling the underlying inflammatory arthropathy, and are the mainstay for the rheumatoid-arthritis and spondyloarthritis-driven disease that accounts for much of the Western caseload. Results are more mixed than with IL-6 blockade - in a head-to-head retrospective comparison tocilizumab was superior for lowering SAA and improving kidney function - and, as with colchicine, benefit depends on starting before renal function is lost.

Mechanism Target:

INHIBITS Chronic Inflammatory, Autoinflammatory, or Infectious Stimulus — Neutralizing TNF-alpha suppresses the inflammatory arthropathy at the trigger node, reducing the cytokine drive to hepatic SAA production.

Show evidence (3 references)

PMID:38568326 SUPPORT Other

"In a retrospective series including 15 patients treated with anti-TNF, amyloidosis progressed in seven patients (46.7%), stabilized in five (33.3%), and regression of proteinuria occurred in three (20%) in 10 months"

Quantifies outcomes on anti-TNF therapy. Marked PARTIAL deliberately: amyloidosis still progressed in the largest single group, so this series does not establish efficacy. Evidence source is OTHER because the figures are reported in a review summarizing the primary series.

PMID:38568326 SUPPORT Other

"in a multicenter study in which 36 patients with AA amyloidosis treated with anti-TNF therapy were followed prospectively for 5 years, > 50% decrease in proteinuria was observed in more than half of the patients"

The stronger of the two datasets - prospective, multicentre, 5-year follow-up - showing a substantial proteinuria response in the majority. Evidence source is OTHER because the figures are reported in a review summarizing the primary study.

PMID:38568326 SUPPORT Other

"a retrospective analysis including 42 patients with AA amyloidosis demonstrated that tocilizumab was superior to anti-TNFs in terms of obtaining a decrease in SAA, improvement in kidney function, and suppression of the disease activity"

Records the comparative result that places anti-TNF below IL-6 blockade on the biochemical and renal endpoints, which is why this entry does not present anti-TNF as first choice. Marked PARTIAL because it is a retrospective, non-randomized comparison. Evidence source is OTHER (review).

Interleukin-6 Receptor Blockade (Tocilizumab)

Action: Pharmacotherapy NCIT:C15986

Agent: tocilizumab NCIT:C84217

Tocilizumab blocks the IL-6 receptor and so acts directly on the cytokine that drives hepatic SAA production - mechanistically the most targeted of the available anti-inflammatory options, since it inhibits the exact signalling axis that supplies the precursor. SAA falls within days and amyloid deposits regress or stabilize. Infection is the predominant adverse effect.

Mechanism Target:

INHIBITS IL-6-Driven Hepatic Acute-Phase Response — IL-6 receptor blockade removes the principal signal inducing hepatocyte SAA transcription, collapsing precursor supply at the amplifier node.

Show evidence (3 references)

PMID:26120866 SUPPORT Human Clinical

"Whole-cohort median pre-treatment SAA fell from 70 to 4 mg/L within 10 days of the first dose; this response has been maintained over an on-treatment follow-up period of 23 months (p<0.0001). AA amyloid deposits either regressed or remained stable."

Directly demonstrates rapid, sustained SAA suppression and amyloid regression or stabilization on IL-6 blockade, validating the acute-phase node as the drug target.

PMID:26120866 SUPPORT Human Clinical

"This small series shows that in patients with treatment-refractory chronic inflammatory conditions TCZ can be effective in suppressing inflammation, and in those with AA amyloidosis, can lead to regression of amyloid deposits."

The authors' own conclusion, recorded with its stated limitation. Marked PARTIAL because this is an uncontrolled 20-patient case series, of whom 70% had AA amyloidosis, and the authors call for longer follow-up.

PMID:41670232 SUPPORT Human Clinical

"Steroid pulse therapy, followed by tocilizumab, a IL-6 receptor inhibitor, in combination with oral glucocorticoids dramatically improved kidney and cardiac manifestations with reduction in systemic inflammation."

Corroborates organ-level benefit of IL-6 blockade in biopsy-proven AA amyloidosis. Marked PARTIAL because it is a single case report with concomitant glucocorticoid therapy.

Interleukin-1 Blockade (Canakinumab, Anakinra)

Action: Pharmacotherapy NCIT:C15986

Agent: canakinumab NCIT:C80971 anakinra NCIT:C38717

IL-1 blockade targets the inflammasome-driven cytokine cascade upstream of IL-6, and is the principal option in colchicine-resistant or colchicine-intolerant FMF and in the other monogenic autoinflammatory syndromes (TRAPS, CAPS, mevalonate kinase deficiency) that drive AA amyloidosis. Note that the randomized evidence recorded here establishes control of the trigger diseases; randomized evidence for amyloid or renal outcomes on IL-1 blockade in established AA amyloidosis is not available.

Mechanism Target:

INHIBITS Chronic Inflammatory, Autoinflammatory, or Infectious Stimulus — Neutralizing IL-1beta suppresses inflammasome-driven autoinflammatory disease activity at the trigger node, removing the drive to the hepatic acute-phase response.

Show evidence (1 reference)

PMID:29768139 SUPPORT Human Clinical

"In this trial, canakinumab was effective in controlling and preventing flares in patients with colchicine-resistant familial Mediterranean fever, mevalonate kinase deficiency, and TRAPS."

Randomized trial evidence that canakinumab controls the autoinflammatory trigger diseases. Marked PARTIAL because the trial endpoint was control of the trigger disease, not amyloid burden or renal outcome in AA amyloidosis.

Kidney Transplantation

Action: Kidney Transplantation NCIT:C15265

The preferred renal replacement modality for AA amyloidosis with kidney failure, and no longer the poor-prognosis option it once was: contemporary multicentre outcomes approach those of other causes of end-stage kidney disease. Amyloid recurrence in the allograft has become rare where the underlying inflammatory disease is controlled with modern agents. Because excess post-transplant mortality is driven by cardiovascular disease, pre-transplant cardiac assessment matters.

Show evidence (2 references)

PMID:37741608 SUPPORT Human Clinical

"Patient survival rates were 94.0% (95% CI, 89.1-99.2) at 1 year and 85.5% (77.8-94.0) at 5 years after transplantation."

Provides contemporary patient-survival outcomes after kidney transplantation in 86 patients across 26 French centres.

PMID:38568326 SUPPORT Other

"Kidney transplantation is preferred in patients with kidney failure, and the recurrence of amyloidosis in the allograft has become rare as transplant recipients have started to benefit from the new agents."

States the preference for transplantation and the modern rarity of allograft recurrence. Evidence source is OTHER because this is a review.

Dialysis

Action: Dialysis NCIT:C15221

Haemodialysis or peritoneal dialysis for established kidney failure. It is a suitable modality, but survival on dialysis is poor relative to transplantation, and worse where cardiac amyloid is present: cardiovascular deposition plus nephrotic syndrome makes these patients prone to intradialytic hypotension. This is the practical reason transplantation is preferred where the patient is a candidate.

Show evidence (2 references)

PMID:38568326 SUPPORT Other

"Dialysis modalities and kidney transplantation are both suitable for patients suffering from AA amyloidosis and kidney failure"

Establishes dialysis as an accepted renal replacement modality in AA amyloidosis. Evidence source is OTHER because this is a review.

PMID:38568326 SUPPORT Other

"Still, survival is poor among patients on dialysis, especially when cardiac involvement is prevalent"

Records the poor survival on dialysis and its dependence on cardiac involvement, the caveat that makes transplantation preferred. Marked PARTIAL because it qualifies rather than supports the intervention. Evidence source is OTHER (review).

Eprodisate (Investigational, Not Approved)

Action: Pharmacotherapy NCIT:C15986

A glycosaminoglycan mimetic designed to disrupt the SAA-glycosaminoglycan interaction that promotes fibril polymerization - the only agent to have been tested in a randomized trial against the deposition step itself rather than against the upstream inflammation. It slowed the decline in renal function but did not significantly affect progression to end-stage renal disease or mortality, and it was not approved. It is recorded here because it is the direct clinical test of the glycosaminoglycan-dependence mechanism curated in the pathophysiology, and because its failure is part of why no deposit-clearing therapy exists.

Mechanism Target:

INHIBITS Glycosaminoglycan-Assisted Fibril Nucleation and Extracellular Deposition — Competes with glycosaminoglycan binding to amyloidogenic SAA, inhibiting fibril polymerization and tissue deposition at the central effector node.

Show evidence (2 references)

PMID:17554116 SUPPORT Human Clinical

"Eprodisate is a member of a new class of compounds designed to interfere with interactions between amyloidogenic proteins and glycosaminoglycans and thereby inhibit polymerization of amyloid fibrils and deposition of the fibrils in tissues."

States the drug's mechanism of action against the glycosaminoglycan-assisted fibril formation node.

PMID:17554116 SUPPORT Human Clinical

"The drug had no significant effect on progression to end-stage renal disease (hazard ratio, 0.54; P=0.20) or risk of death (hazard ratio, 0.95; P=0.94)."

Records the negative results on the hard endpoints alongside the positive renal-function-slope result, which is why the drug was not approved. Marked PARTIAL to avoid overstating benefit.

🌍

Environmental Factors

1

Obesity and adipose-derived serum amyloid A

Obesity is an independently identified susceptibility factor for idiopathic AA amyloidosis, meaning cases with no classical inflammatory trigger. The proposed mechanism is direct rather than merely correlative: adipocytes are themselves a major site of acute-phase SAA expression, so adipose mass supplies precursor and sustains low-grade systemic inflammation independently of the hepatic acute-phase response. This is the plausible explanation for a substantial share of idiopathic disease in an ageing, increasingly obese population.

Show evidence (1 reference)

PMID:29364741 SUPPORT Human Clinical

"Obesity, age and the SAA1 polymorphism are susceptibility factors for idiopathic AA amyloidosis."

Directly states obesity as a susceptibility factor for idiopathic AA amyloidosis in a 146-patient study with two control groups.

Mechanism Target:

PREDISPOSES IL-6-Driven Hepatic Acute-Phase Response — Adipose tissue contributes acute-phase SAA and pro-inflammatory cytokines, adding to the systemic precursor supply modelled at this node even without a classical inflammatory disease.

Show evidence (1 reference)

PMID:16737350 SUPPORT Human Clinical

"A-SAA mRNA levels and A-SAA secretion from adipose tissue were significantly correlated with body mass index (r = 0.47; p = 0.028 and r = 0.80; p = 0.0002, respectively)."

Quantifies the correlation between adiposity and adipose SAA output, supporting the route by which obesity feeds the acute-phase precursor node.

🔬

Biochemical Markers

1

Serum Amyloid A (INCREASED)

Show evidence (2 references)

PMID:17554117 SUPPORT Human Clinical

"The effects of renal dysfunction dominate the course of AA amyloidosis, which is associated with a relatively favorable outcome in patients with SAA concentrations that remain in the low-normal range (<4 mg per liter)."

Establishes the prognostic threshold that makes SAA an actionable treat-to-target biomarker.

PMID:26120866 SUPPORT Human Clinical

"The main aim of treatment is to suppress inflammation thereby inhibiting serum amyloid A protein (SAA), which is the precursor of AA amyloid fibrils, to prevent or halt amyloid deposition."

States explicitly that SAA is both the fibril precursor and the treatment target, the dual role this biochemical entry records.

🔬

Diagnosis

2

Tissue Biopsy with Amyloid Typing

Histopathological demonstration of amyloid is the diagnostic gold standard, but Congo red positivity alone is insufficient - the fibril protein must be typed. Immunohistochemistry with anti-AA antibody, or laser microdissection with mass spectrometry where available, distinguishes AA from AL, ATTR, and the rarer hereditary types. Getting this wrong has direct therapeutic consequences, since AL requires anti-plasma-cell therapy and AA requires suppression of inflammation.

Show evidence (2 references)

PMID:38568326 SUPPORT Other

"Histopathological examination is the gold standard of diagnosis, but magnetic resonance imaging can be used to detect cardiac involvement."

Establishes histopathology as the diagnostic gold standard. Evidence source is OTHER because this is a review.

PMID:28828707 SUPPORT Human Clinical

"accurate typing of non-AL amyloidosis then requires immunohistochemical or laser microdissection/mass spectrometry studies of the Congo red positive deposits"

States the requirement for immunohistochemical or mass-spectrometric typing beyond Congo red staining.

Serum Amyloid A and C-Reactive Protein Monitoring

Serial measurement of SAA (with CRP as a widely available surrogate) is used both to stratify risk in patients with known inflammatory disease and to titrate therapy. Because the treat-to-target threshold is defined numerically, this is a monitoring test with a therapeutic decision attached rather than a purely diagnostic one.

Show evidence (1 reference)

PMID:17554117 SUPPORT Human Clinical

"The SAA concentration was measured serially, and the amyloid burden was estimated with the use of whole-body serum amyloid P component scintigraphy."

Documents serial SAA measurement (alongside SAP scintigraphy) as the monitoring strategy in the definitive natural-history cohort.

📈

Progression

4

Subclinical amyloid deposition

Amyloid accumulates during years to decades of uncontrolled inflammation before any renal abnormality is detectable. This is the window in which surveillance of at-risk patients (established FMF, other periodic fever syndromes, long-standing inflammatory arthritis) by urinalysis and SAA can change the outcome.

Show evidence (1 reference)

PMID:25387054 SUPPORT Other

"Therefore, AA amyloidosis can be thought of as a consequence of long-standing inflammatory disease."

Supports a prolonged latent phase driven by long-standing inflammation preceding clinical presentation. Evidence source is OTHER (review).

Proteinuric and nephrotic phase

Proteinuria appears and progresses to nephrotic-range, with nephrotic syndrome in roughly two-thirds and renal insufficiency in three-quarters of patients in biopsy-based series.

Show evidence (1 reference)

PMID:17714761 SUPPORT Human Clinical

"Nephrotic syndrome and renal insufficiency were noted in 63.1% and 75% of patients, respectively."

Quantifies the proteinuric and nephrotic phase in a renal AA amyloidosis series.

Amyloid storm (rare acute FMF-associated variant)

A minority of FMF patients depart from the indolent course entirely and present with an acute illness: heavy proteinuria, high inflammatory markers, and progression to kidney failure within weeks rather than years, typically precipitated by a superimposed infection. Curated as a distinct trajectory rather than a severity grade, because the timescale (weeks) and the infection trigger are qualitatively different from the usual course.

Show evidence (2 references)

PMID:38568326 SUPPORT Other

"While the majority of cases follow an indolent course, a subset of individuals with FMF might undergo acute illness, marked by substantial proteinuria, elevated inflammatory markers, and rapid progression to kidney failure within weeks."

Defines the amyloid storm presentation and contrasts it with the indolent majority course. Evidence source is OTHER because this is a review.

PMID:38568326 SUPPORT Other

"These infrequent instances are named “amyloid storm,” which is thought to be precipitated by superimposed infections or other triggering events"

Names the entity and its precipitating trigger. Evidence source is OTHER because this is a review.

Progressive renal decline to end-stage kidney disease

Untreated, creatinine clearance falls at roughly 15 mL/min/1.73 m2 per year - the placebo-arm rate in the eprodisate trial, which is the best available quantitative natural-history benchmark. Median survival after diagnosis in the era before widespread biologic therapy was 133 months.

Show evidence (2 references)

PMID:17554116 SUPPORT Human Clinical

"The mean rates of decline in creatinine clearance were 10.9 and 15.6 ml per minute per 1.73 m(2) of body-surface area per year in the eprodisate and the placebo groups, respectively (P=0.02)."

The placebo arm provides the quantitative rate of untreated renal decline cited for this phase.

PMID:17554117 SUPPORT Human Clinical

"Median survival after diagnosis was 133 months"

Provides the median survival benchmark for the progressive phase.

📊

Prevalence

2

Patients with rheumatoid arthritis, studies published before 2010

Point Prevalence 20950.0 per 100,000 (16700.0–25200.0) >1 in 1,000

Prevalence of AA amyloidosis among patients with rheumatoid arthritis, not a general-population rate. The source reports a range of 16.7%-25.2%; the normalized value is the midpoint of that range expressed per 100,000.

Show evidence (1 reference)

PMID:40516176 SUPPORT Human Clinical

"AAA prevalence rates in rheumatoid arthritis ranged from 16.7 % to 25.2 % before 2010"

Systematic review reporting the historical prevalence range of AA amyloidosis within rheumatoid arthritis cohorts.

Patients with rheumatoid arthritis, studies published after 2010

Point Prevalence 700.0 per 100,000 >1 in 1,000

Prevalence among rheumatoid arthritis patients in the biologic-therapy era. The roughly 30-fold fall relative to the pre-2010 estimate is the epidemiological signature of effective upstream inflammation control, and is the strongest population-level evidence that AA amyloidosis is a preventable complication.

Show evidence (1 reference)

PMID:40516176 SUPPORT Human Clinical

"decreased to 0.7 % after 2010, which suggests a potential positive role of biologic therapies"

Documents the post-2010 prevalence and attributes the decline to biologic therapy for the underlying inflammatory disease.

🔀

Differential Diagnoses

1

Conditions with similar clinical presentations that must be differentiated from AA Amyloidosis:

Systemic AL Amyloidosis MONDO:0017816

Overlapping Features The other major systemic amyloidosis and the principal differential. AL is a clonal plasma-cell disorder whose precursor is a monoclonal immunoglobulin light chain; AA's precursor is a normal acute-phase protein present in excess. The distinction is not academic - AL requires anti-plasma-cell therapy while AA requires suppression of inflammation - and it cannot be made on Congo red staining alone.

Distinguishing Features

Cardiac involvement, peripheral neuropathy, carpal tunnel syndrome, and macroglossia are common in AL and comparatively uncommon in AA.
Renal involvement dominates the clinical course of AA amyloidosis.
AL shows light-chain restriction on immunofluorescence, whereas Congo red positivity with negative immunofluorescence points to a non-AL type.
A detectable monoclonal protein does not by itself establish AL, since monoclonal gammopathy is common in the affected age group.

Show evidence (2 references)

PMID:28828707 SUPPORT Human Clinical

"The detection of Congo red positive deposits coupled with negative immunofluorescence studies is highly suggestive of non-AL amyloidosis."

Provides the immunofluorescence-based discriminator between AL and non-AL (including AA) renal amyloidosis.

PMID:38568326 SUPPORT Other

"While cardiac infiltration is extensively documented in various amyloidosis types, it is a relatively rare cause of heart failure in AA amyloidosis"

Supports the single most useful clinical discriminator recorded above: a patient with systemic amyloidosis and heart failure is far more likely to have AL or ATTR than AA. Evidence source is OTHER because this is a review.

🔬

Clinical Trials

1

NCT00035334 PHASE_III COMPLETED

Multicenter, randomized, double-blind, placebo-controlled trial of eprodisate versus placebo for 24 months in 183 patients with AA amyloidosis and kidney involvement, with a composite renal-function-or-death primary endpoint.

Target Phenotypes: Renal insufficiency HP:0000083 Proteinuria HP:0000093

Show evidence (1 reference)

PMID:17554116 SUPPORT Human Clinical

"We randomly assigned 183 patients from 27 centers to receive eprodisate or placebo for 24 months."

Describes the trial design and enrolment registered as NCT00035334.

🐁

Animal Models

1

Wild-type mice given an inflammatory stimulus, with or without amyloid-enhancing factor Mus musculus Induced (non-transgenic) AA amyloidosis model

AA amyloidosis is unusual among systemic amyloidoses in having a reliable induced rodent model that needs no transgene: a chronic inflammatory stimulus (casein, silver nitrate) raises murine SAA and produces amyloid deposits, and co-administration of amyloid-enhancing factor - an extract of amyloid-laden tissue from a previously affected animal - collapses the induction lag phase to days. That lag-phase collapse is the direct experimental evidence for the nucleation-dependent seeding arm of this entry's mechanistic hypotheses, and the same system demonstrated cross-seeding by heterologous non-mammalian fibrils. Limitation: the model depends on an exogenous inflammatory stimulus and an exogenous seed rather than on spontaneous chronic autoimmune disease, so it does not reproduce the decades-long, SAA1-genotype-modulated human natural history.

Species

Mus musculus

Genotype

Wild-type mice given an inflammatory stimulus, with or without amyloid-enhancing factor

Show evidence (2 references)

PMID:15829582 SUPPORT Model Organism

"Preformed amyloid-like fibrils act as nuclei in amyloid fibril formation in vitro, and AA amyloid fibrils and synthetic amyloid-like fibrils also may serve as seed for fibril formation in vivo."

States the seeding principle the murine induction model is used to test, and that preformed fibrils act as nuclei in vivo.

PMID:15829582 SUPPORT Model Organism

"We studied three such naturally occurring protein fibrils: silk from Bombyx mori, Sup35 from Saccharomyces cerevisiae, and curli from Escherichia coli."

Describes the specific heterologous fibrils tested in the murine model, documenting the experimental design underlying the cross-seeding result.

{ }

Source YAML

click to show

name: AA Amyloidosis
creation_date: "2026-08-08T00:00:00Z"
category: Complex
disease_term:
  preferred_term: AA amyloidosis
  term:
    id: MONDO:0019439
    label: AA amyloidosis
parents:
- Amyloidosis
description: >-
  Systemic AA amyloidosis is an acquired systemic amyloidosis that complicates
  long-standing inflammatory, autoinflammatory, or chronic infectious disease. It
  is the one systemic amyloidosis whose amyloidogenic precursor is not a mutant
  or clonal protein but a normal acute-phase reactant present in excess:
  cytokine-driven (principally interleukin-6-driven) hepatic overproduction of
  serum amyloid A protein (SAA) sustains a chronically high plasma SAA
  concentration, from which proteolytically processed, C-terminally truncated
  fragments misfold into cross-beta amyloid fibrils and deposit extracellularly.
  Because the precursor is supplied by inflammation rather than by a genetic
  lesion in the precursor itself, the disease is both preventable and partly
  reversible: durable suppression of SAA halts deposition and can permit
  regression of existing deposits. The clinical picture is dominated by renal
  involvement - proteinuria progressing to nephrotic syndrome and end-stage
  kidney disease - with hepatic, splenic, adrenal, and gastrointestinal
  deposition also common. Cardiac involvement, peripheral neuropathy, and
  macroglossia, prominent in AL amyloidosis, are comparatively uncommon in AA and
  are useful discriminators.
synonyms:
- secondary amyloidosis
- reactive systemic amyloidosis
- inflammatory amyloidosis
- amyloid A amyloidosis
- serum amyloid A amyloidosis
prevalence:
- population: Patients with rheumatoid arthritis, studies published before 2010
  measure_type: POINT_PREVALENCE
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 20950.0
  rate_low: 16700.0
  rate_high: 25200.0
  notes: >-
    Prevalence of AA amyloidosis among patients with rheumatoid arthritis, not a
    general-population rate. The source reports a range of 16.7%-25.2%; the
    normalized value is the midpoint of that range expressed per 100,000.
  evidence:
  - reference: PMID:40516176
    reference_title: "AA amyloidosis in inflammatory joint diseases: A systematic review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      AAA prevalence rates in rheumatoid arthritis ranged from 16.7 % to 25.2 %
      before 2010
    explanation: >-
      Systematic review reporting the historical prevalence range of AA
      amyloidosis within rheumatoid arthritis cohorts.
- population: Patients with rheumatoid arthritis, studies published after 2010
  measure_type: POINT_PREVALENCE
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 700.0
  notes: >-
    Prevalence among rheumatoid arthritis patients in the biologic-therapy era.
    The roughly 30-fold fall relative to the pre-2010 estimate is the
    epidemiological signature of effective upstream inflammation control, and is
    the strongest population-level evidence that AA amyloidosis is a preventable
    complication.
  evidence:
  - reference: PMID:40516176
    reference_title: "AA amyloidosis in inflammatory joint diseases: A systematic review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      decreased to 0.7 % after 2010, which suggests a potential positive role of
      biologic therapies
    explanation: >-
      Documents the post-2010 prevalence and attributes the decline to biologic
      therapy for the underlying inflammatory disease.
mechanistic_hypotheses:
- hypothesis_group_id: canonical_saa_overproduction
  hypothesis_label: Canonical SAA Overproduction Model
  status: CANONICAL
  description: >-
    Chronic inflammation drives IL-6-dependent hepatic SAA overproduction; a
    sustained high plasma SAA concentration is the rate-limiting upstream lesion
    that permits proteolytic processing, misfolding, and cross-beta fibril
    deposition. The corollary - that lowering SAA arrests and can reverse the
    process - is the basis of all current therapy.
  evidence:
  - reference: PMID:25387054
    reference_title: "AA amyloidosis: pathogenesis and targeted therapy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      In AA amyloidosis, the expression of cytokines, particularly interleukin 6,
      leads to overproduction of serum amyloid A (SAA) by the liver. A
      chronically high plasma concentration of SAA results in the aggregation of
      amyloid into cross-β-sheet fibrillar deposits by mechanisms not fully
      understood.
    explanation: >-
      States the cytokine-to-precursor-to-fibril chain that defines the canonical
      hypothesis group. Evidence source is OTHER because this is a review.
  - reference: PMID:17554117
    reference_title: "Natural history and outcome in systemic AA amyloidosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mortality, amyloid burden, and renal prognosis all significantly correlated
      with the SAA concentration during follow-up.
    explanation: >-
      A 374-patient natural-history cohort provides the human dose-response
      evidence that circulating precursor concentration governs amyloid burden
      and outcome, the central prediction of this model.
- hypothesis_group_id: nucleation_seeding_model
  hypothesis_label: Nucleation-Dependent Seeding Model
  status: CANONICAL
  description: >-
    Fibril formation is nucleation dependent rather than simply concentration
    dependent: a preformed fibrillar nucleus recruits and templates conversion of
    further native molecules. This helps explain why only a minority of patients
    with equivalent chronic inflammation develop amyloidosis, and why
    amyloid-enhancing factor collapses the induction lag phase in animal models.
    The evidence for exogenous or heterologous seeds acting as a human risk
    factor is experimental, not clinical.
  evidence:
  - reference: PMID:25387054
    reference_title: "AA amyloidosis: pathogenesis and targeted therapy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Generation of amyloid fibrils is nucleation dependent, and once formed,
      fibrils recruit and catalyze the conversion of native molecules.
    explanation: >-
      States the nucleation-and-templating mechanism that distinguishes this
      model from simple mass-action aggregation. Evidence source is OTHER because
      this is a review.
  - reference: PMID:15829582
    reference_title: "Protein fibrils in nature can enhance amyloid protein A amyloidosis in mice: Cross-seeding as a disease mechanism."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Our results show that these protein fibrils exert amyloid-accelerating
      properties in the murine experimental AA amyloidosis, suggesting that such
      environment factors may be important risk factors in amyloidogenesis.
    explanation: >-
      Demonstrates cross-seeding by heterologous (silk, Sup35, curli) fibrils in
      the murine model, supporting seeding as a mechanism. Marked PARTIAL because
      the extension to human environmental risk is proposed by the authors, not
      demonstrated; evidence source is MODEL_ORGANISM (mouse).
pathophysiology:
- name: Chronic Inflammatory, Autoinflammatory, or Infectious Stimulus
  description: >-
    The proximal trigger is a persistent inflammatory drive of any cause:
    inflammatory arthritis (rheumatoid arthritis, ankylosing spondylitis,
    juvenile idiopathic arthritis), a monogenic autoinflammatory syndrome
    (familial Mediterranean fever, TRAPS, CAPS, mevalonate kinase deficiency),
    chronic infection (tuberculosis, leprosy, osteomyelitis, bronchiectasis),
    inflammatory bowel disease, or vasculitis. The specific disease is
    interchangeable; what matters mechanistically is the duration and magnitude
    of the cytokine drive it sustains. A substantial minority of cases remain
    idiopathic, with no overt trigger identified.
  role: trigger
  biological_scale: ORGANISM
  biological_processes:
  - preferred_term: inflammatory response
    term:
      id: GO:0006954
      label: inflammatory response
    modifier: INCREASED
    temporality: CHRONIC
  evidence:
  - reference: PMID:25387054
    reference_title: "AA amyloidosis: pathogenesis and targeted therapy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Therefore, AA amyloidosis can be thought of as a consequence of
      long-standing inflammatory disease.
    explanation: >-
      Frames chronic inflammatory disease as the upstream trigger of the whole
      chain. Evidence source is OTHER because this is a review.
  - reference: PMID:17714761
    reference_title: "Clinical and histological characteristics of renal AA amyloidosis: a retrospective study of 68 cases with a special interest to amyloid-associated inflammatory response."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The amyloidogenic disease was a chronic infection (40.8%), a chronic
      inflammation (38%), a tumor (9.9%), a hereditary disease (9.9%), or was
      undetermined in 1.4% of cases.
    explanation: >-
      Quantifies the heterogeneous trigger diseases in a renal AA amyloidosis
      series, supporting the trigger node as an aetiology-agnostic entry point.
  downstream:
  - target: IL-6-Driven Hepatic Acute-Phase Response
    causal_link_type: DIRECT
    description: >-
      Sustained cytokine release, principally IL-6, acts on hepatocytes to induce
      the acute-phase programme.
- name: IL-6-Driven Hepatic Acute-Phase Response
  description: >-
    Interleukin-6 (with contributions from IL-1beta and TNF) drives hepatocyte
    transcription and secretion of SAA1 and SAA2 as HDL-associated acute-phase
    apolipoproteins. In an ordinary self-limited acute-phase response this is
    physiological and transient; here it is unremitting. Adipose tissue is a
    second, non-hepatic source of SAA, which is how obesity feeds this node in
    the absence of a classical inflammatory disease.
  role: amplifier
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  biological_processes:
  - preferred_term: acute-phase response
    term:
      id: GO:0006953
      label: acute-phase response
    modifier: INCREASED
  - preferred_term: interleukin-6-mediated signaling pathway
    term:
      id: GO:0070102
      label: interleukin-6-mediated signaling pathway
    modifier: INCREASED
  evidence:
  - reference: PMID:25387054
    reference_title: "AA amyloidosis: pathogenesis and targeted therapy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      In AA amyloidosis, the expression of cytokines, particularly interleukin 6,
      leads to overproduction of serum amyloid A (SAA) by the liver.
    explanation: >-
      Names IL-6 as the principal cytokine driving hepatic SAA overproduction,
      the amplifier step. Evidence source is OTHER because this is a review.
  - reference: PMID:16737350
    reference_title: "Acute-phase serum amyloid A: an inflammatory adipokine and potential link between obesity and its metabolic complications."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We demonstrate that A-SAA was highly and selectively expressed in human
      adipocytes.
    explanation: >-
      Establishes adipose tissue as an additional, extrahepatic source of
      acute-phase SAA. Marked PARTIAL because the study characterizes SAA biology
      in obesity and does not itself study amyloidosis.
  downstream:
  - target: Sustained Elevation of Circulating Serum Amyloid A
    causal_link_type: DIRECT
    description: >-
      Unremitting hepatic (and adipose) SAA output raises and holds the plasma
      SAA concentration far above its physiological baseline.
- name: Sustained Elevation of Circulating Serum Amyloid A
  description: >-
    The amyloidogenic precursor of this disease. Unlike AL (a clonal light chain)
    or ATTR (a destabilized or wild-type transthyretin), the AA precursor is a
    structurally normal protein whose only abnormality is chronic excess.
    Prolonged rather than transient elevation is the rate-limiting requirement:
    the concentration-duration product, not any single peak, determines
    amyloidogenic risk. This node is the disease's therapeutic target, and the
    quantitative relationship between achieved SAA level and outcome is the
    best-documented dose-response in systemic amyloidosis.
  conforms_to: amyloidogenesis#Amyloidogenic Precursor Protein
  role: trigger
  biological_scale: MOLECULAR
  biological_processes:
  - preferred_term: protein folding
    term:
      id: GO:0006457
      label: protein folding
    modifier: ABNORMAL
  evidence:
  - reference: PMID:17554117
    reference_title: "Natural history and outcome in systemic AA amyloidosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Deposition of amyloid fibrils derived from circulating acute-phase reactant
      serum amyloid A protein (SAA) causes systemic AA amyloidosis, a serious
      complication of many chronic inflammatory disorders.
    explanation: >-
      Identifies circulating SAA as the precursor from which the fibrils derive,
      the substituted precursor node of the amyloidogenesis module.
  - reference: PMID:17554117
    reference_title: "Natural history and outcome in systemic AA amyloidosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The risk of death was 17.7 times as high among patients with SAA
      concentrations in the highest eighth, or octile, (>or=155 mg per liter) as
      among those with concentrations in the lowest octile (<4 mg per liter)
    explanation: >-
      Quantifies the precursor-concentration-to-outcome gradient in humans,
      establishing that the level of this node, not merely its presence, drives
      disease.
  downstream:
  - target: Proteolytic Processing and Beta-Sheet Misfolding of SAA
    causal_link_type: DIRECT
    description: >-
      Excess circulating precursor is the substrate on which proteolysis and
      conformational conversion act.
- name: Proteolytic Processing and Beta-Sheet Misfolding of SAA
  description: >-
    SAA is cleaved to an N-terminal fragment (predominantly residues 1-76, losing
    the C-terminal region) and converts from its native alpha-helical fold into
    beta-sheet-rich, aggregation-prone species. C-terminal truncation is not
    incidental: it destabilizes the alpha-helical structure and markedly
    accelerates fibril formation relative to the full-length protein. Genetic
    variation in SAA1 acts at exactly this step, by changing how readily the
    precursor is cleaved.
  conforms_to: amyloidogenesis#Protein Misfolding and Beta-Sheet Oligomerization
  role: amplifier
  biological_scale: MOLECULAR
  biological_processes:
  - preferred_term: proteolysis
    term:
      id: GO:0006508
      label: proteolysis
    modifier: INCREASED
  - preferred_term: protein folding
    term:
      id: GO:0006457
      label: protein folding
    modifier: ABNORMAL
  evidence:
  - reference: PMID:17554116
    reference_title: "Eprodisate for the treatment of renal disease in AA amyloidosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Amyloid A (AA) amyloidosis is a complication of chronic inflammatory
      conditions that develops when proteolytic fragments of serum amyloid A
      protein (SAA) are deposited in tissues as amyloid fibrils.
    explanation: >-
      Establishes that it is proteolytic fragments of SAA, not the intact
      protein, that form the deposited fibrils.
  - reference: PMID:29288051
    reference_title: "Acceleration of amyloid fibril formation by carboxyl-terminal truncation of human serum amyloid A."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Although the full-length SAA is 104 amino acids long, the
      C-terminal-truncated SAA lacking mainly residues 77-104 is predominantly
      deposited in AA amyloidosis.
    explanation: >-
      Identifies the specific truncated species that predominates in deposits,
      defining the processed form that misfolds. Evidence source is IN_VITRO
      (recombinant peptide biophysics).
  - reference: PMID:29288051
    reference_title: "Acceleration of amyloid fibril formation by carboxyl-terminal truncation of human serum amyloid A."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Circular dichroism (CD) measurements demonstrated that the C-terminal
      truncation induces a reduced α-helical structure of the SAA molecule.
    explanation: >-
      Direct biophysical evidence that truncation destabilizes the native fold,
      the conformational conversion this node describes.
  downstream:
  - target: Glycosaminoglycan-Assisted Fibril Nucleation and Extracellular Deposition
    causal_link_type: DIRECT
    description: >-
      Misfolded beta-sheet species are the monomeric input to nucleation and
      fibril elongation.
- name: Glycosaminoglycan-Assisted Fibril Nucleation and Extracellular Deposition
  description: >-
    The central effector and rate-limiting convergence step. Misfolded SAA
    fragments nucleate and elongate into insoluble cross-beta amyloid fibrils
    that deposit in the extracellular space. Heparan sulfate is a potent amyloid
    agonist here rather than a passive co-deposit: it remodels HDL-associated SAA
    at mildly acidic pH, induces non-native beta-sheet, and binds synergistically
    to forming amyloid. Serum amyloid P component binds and stabilizes the
    deposits against clearance. This accessory-molecule dependence is the
    rationale for eprodisate and for anti-SAP strategies, and it is the node that
    conforms to the shared amyloidogenesis module.
  conforms_to: amyloidogenesis#Amyloid Fibril Formation and Extracellular Deposition
  role: central_effector
  biological_scale: MOLECULAR
  cellular_components:
  - preferred_term: extracellular region
    term:
      id: GO:0005576
      label: extracellular region
  biological_processes:
  - preferred_term: amyloid fibril formation
    term:
      id: GO:1990000
      label: amyloid fibril formation
    modifier: INCREASED
  molecular_functions:
  - preferred_term: glycosaminoglycan binding
    term:
      id: GO:0005539
      label: glycosaminoglycan binding
  evidence:
  - reference: PMID:25387054
    reference_title: "AA amyloidosis: pathogenesis and targeted therapy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Central to amyloid formation is an increase in the frequency of the β-sheet
      structure, leading to hydrogen bonding between misfolded monomers and
      creating a fibril that is comparably resistant to degradation.
    explanation: >-
      Describes the beta-sheet fibril assembly and its protease resistance, the
      central effector step. Evidence source is OTHER because this is a review.
  - reference: PMID:19549924
    reference_title: "Heparan sulfate promotes the aggregation of HDL-associated serum amyloid A: evidence for a proamyloidogenic histidine molecular switch."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      HS causes the remodeling of HDL-SAA at mildly acidic pH, producing SAA-rich
      aggregates.
    explanation: >-
      Direct evidence that heparan sulfate actively promotes conversion of
      HDL-borne SAA into aggregates, supporting the glycosaminoglycan-assisted
      mechanism. Evidence source is IN_VITRO (biochemical and cell-culture
      assays).
  - reference: PMID:39954777
    reference_title: "Serum Amyloid A Binding to Glycosaminoglycans is Synergistic with Amyloid Formation: Therapeutic Targeting in the Inflammation-linked Amyloidosis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      HS/heparin can promote amyloidogenesis by inducing non-native β-sheet and
      apparently causing liquid droplet formation in SAA in solution.
    explanation: >-
      Contemporary biophysical evidence that heparan sulfate induces the
      non-native beta-sheet conformation feeding fibril formation. Evidence
      source is IN_VITRO (recombinant SAA spectroscopy and ELISA).
  - reference: PMID:26176329
    reference_title: "Therapeutic Clearance of Amyloid by Antibodies to Serum Amyloid P Component."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The amyloid fibril deposits that cause systemic amyloidosis always contain
      the nonfibrillar normal plasma protein, serum amyloid P component (SAP).
    explanation: >-
      Establishes SAP as an invariant component of the deposits, the second
      accessory molecule stabilizing them.
  downstream:
  - target: Progressive Multi-Organ Amyloid Accumulation
    causal_link_type: DIRECT
    description: >-
      Continued nucleation and elongation converts fibril formation into a
      growing tissue burden.
- name: Progressive Multi-Organ Amyloid Accumulation
  description: >-
    Fibrils accumulate as a growing extracellular amyloid burden. Because the
    precursor is circulating, deposition is systemic and bilateral, but the
    distribution is characteristic: kidney (glomerular mesangium and capillary
    walls, plus vascular deposits), liver, spleen, and adrenal gland are the
    dominant sites, with perivascular deposition common across organs. Unlike the
    deposits of AL and ATTR, this burden is genuinely dynamic - it regresses when
    the precursor supply is withdrawn, which is why this node is not a
    therapeutic dead end.
  conforms_to: amyloidogenesis#Progressive Tissue Amyloid Accumulation
  role: effector
  biological_scale: TISSUE
  locations:
  - preferred_term: kidney
    term:
      id: UBERON:0002113
      label: kidney
  - preferred_term: liver
    term:
      id: UBERON:0002107
      label: liver
  - preferred_term: spleen
    term:
      id: UBERON:0002106
      label: spleen
  evidence:
  - reference: PMID:28828707
    reference_title: "Pathology and diagnosis of renal non-AL amyloidosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      AA amyloidosis shows vascular deposits in addition to the glomerular
      deposits
    explanation: >-
      Documents the characteristic combined glomerular-plus-vascular deposition
      pattern that distinguishes AA from other renal amyloid types.
  - reference: PMID:17554117
    reference_title: "Natural history and outcome in systemic AA amyloidosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Amyloid deposits regressed in 60% of patients who had a median SAA
      concentration of less than 10 mg per liter, and survival among these
      patients was superior to survival among those in whom amyloid deposits did
      not regress (P=0.04).
    explanation: >-
      Establishes that the accumulated amyloid burden is reversible when the
      precursor is suppressed, and that regression carries a survival benefit -
      the key clinical property of this node.
  downstream:
  - target: Glomerular Filtration Barrier Disruption
    causal_link_type: DIRECT
    description: >-
      Mesangial and capillary-wall amyloid physically disrupts the filtration
      apparatus.
  - target: Extrarenal Organ Dysfunction
    causal_link_type: DIRECT
    description: >-
      Amyloid infiltration of liver, spleen, gut, and endocrine organs disturbs
      their architecture and function.
- name: Glomerular Filtration Barrier Disruption
  description: >-
    Amyloid expanding the mesangium and infiltrating the glomerular capillary
    wall breaches the filtration barrier, producing non-selective proteinuria.
    Glomerular (rather than purely vascular) involvement is the histological
    determinant of the clinical picture and of renal outcome; a
    vascular-predominant pattern presents with less proteinuria. Tubular atrophy
    and the abundance and distribution of glomerular deposits predict renal
    survival.
  conforms_to: amyloidogenesis#Organ Dysfunction
  role: effector
  biological_scale: TISSUE
  cell_types:
  - preferred_term: glomerular mesangial cell
    term:
      id: CL:1000742
      label: glomerular mesangial cell
  - preferred_term: podocyte
    term:
      id: CL:0000653
      label: podocyte
  locations:
  - preferred_term: renal glomerulus
    term:
      id: UBERON:0000074
      label: renal glomerulus
  evidence:
  - reference: PMID:17714761
    reference_title: "Clinical and histological characteristics of renal AA amyloidosis: a retrospective study of 68 cases with a special interest to amyloid-associated inflammatory response."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the glomerular involvement appeared as the determining histological factor
      for clinical manifestations and outcome of renal AA amyloidosis
    explanation: >-
      Identifies glomerular amyloid involvement as the histological determinant
      of the clinical syndrome, supporting this node as the effector linking
      deposition to renal disease.
  - reference: PMID:17714761
    reference_title: "Clinical and histological characteristics of renal AA amyloidosis: a retrospective study of 68 cases with a special interest to amyloid-associated inflammatory response."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Tubular atrophy, abundance, and distribution pattern of glomerular amyloid
      deposits at the time of biopsy were independent predictors of renal
      outcome.
    explanation: >-
      Links the quantitative glomerular amyloid burden to renal prognosis,
      supporting a dose-dependent barrier-disruption mechanism.
  downstream:
  - target: Progressive Kidney Failure
    causal_link_type: DIRECT
    description: >-
      Sustained proteinuria and nephron loss drive progressive decline in
      glomerular filtration rate.
- name: Progressive Kidney Failure
  description: >-
    The dominant clinical consequence. Proteinuria progresses to nephrotic-range
    proteinuria and nephrotic syndrome, then to declining glomerular filtration
    rate and end-stage kidney disease requiring dialysis or transplantation.
    Renal dysfunction, not cardiac or neurological involvement, defines the
    course of AA amyloidosis - the principal clinical contrast with AL
    amyloidosis.
  conforms_to: amyloidogenesis#Organ Dysfunction
  role: consequence
  biological_scale: ORGANISM
  evidence:
  - reference: PMID:17554117
    reference_title: "Natural history and outcome in systemic AA amyloidosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Median survival after diagnosis was 133 months; renal dysfunction was the
      predominant disease manifestation.
    explanation: >-
      Establishes renal dysfunction as the dominant manifestation and provides
      the survival benchmark for this consequence node.
  - reference: PMID:17554116
    reference_title: "Eprodisate for the treatment of renal disease in AA amyloidosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Amyloid deposition in the kidney causes progressive deterioration in renal
      function.
    explanation: >-
      States the deposition-to-renal-failure causal link this node represents.
- name: Extrarenal Organ Dysfunction
  description: >-
    Amyloid infiltration outside the kidney. Hepatic and splenic deposition is
    frequent and often functionally silent, detected radiologically or as raised
    alkaline phosphatase rather than as liver failure. Gastrointestinal
    deposition causes chronic diarrhoea and malabsorption. Adrenal and thyroid
    infiltration occurs. Cardiac involvement and peripheral neuropathy are
    comparatively uncommon in AA - a point of clinical contrast with AL
    amyloidosis rather than a feature of this disease.
  conforms_to: amyloidogenesis#Organ Dysfunction
  role: consequence
  biological_scale: ORGANISM
  evidence:
  - reference: PMID:38568326
    reference_title: "AA Amyloidosis: A Contemporary View."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Amyloid A (AA) amyloidosis is an organ- or life-threatening complication of
      chronic inflammatory disorders.
    explanation: >-
      Supports multi-organ, potentially life-threatening involvement as the
      clinical consequence of the deposition chain. Evidence source is OTHER
      because this is a review.
phenotypes:
- category: Renal
  name: Proteinuria
  description: >-
    Non-selective proteinuria from glomerular amyloid deposition is the earliest
    and commonest manifestation, and the finding on which surveillance of at-risk
    patients is based. It is frequently nephrotic-range at presentation.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Proteinuria
    term:
      id: HP:0000093
      label: Proteinuria
  evidence:
  - reference: PMID:17714761
    reference_title: "Clinical and histological characteristics of renal AA amyloidosis: a retrospective study of 68 cases with a special interest to amyloid-associated inflammatory response."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The clinical presentation of glomerular and vascular forms was distinct
      with a clear predominance of proteinuria in glomerular form.
    explanation: >-
      Documents proteinuria as the predominant clinical presentation of the
      glomerular form, which was present in 80.9% of this renal AA series,
      supporting the VERY_FREQUENT band.
  - reference: PMID:38568326
    reference_title: "AA Amyloidosis: A Contemporary View."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      the prevailing symptoms frequently involve the emergence of proteinuria and
      gradual reduction in kidney function, apparent in over 90% of patients upon
      their initial presentation
    explanation: >-
      Directly quantifies proteinuria and declining kidney function at over 90%
      of patients at initial presentation, which is the primary support for the
      VERY_FREQUENT band (80-100%). Evidence source is OTHER because this is a
      review.
- category: Renal
  name: Nephrotic Syndrome
  description: >-
    Heavy proteinuria with hypoalbuminaemia, oedema, and dyslipidaemia. Reported
    in roughly two-thirds of patients with renal AA amyloidosis.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Nephrotic syndrome
    term:
      id: HP:0000100
      label: Nephrotic syndrome
  evidence:
  - reference: PMID:17714761
    reference_title: "Clinical and histological characteristics of renal AA amyloidosis: a retrospective study of 68 cases with a special interest to amyloid-associated inflammatory response."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Nephrotic syndrome and renal insufficiency were noted in 63.1% and 75% of
      patients, respectively.
    explanation: >-
      Directly quantifies nephrotic syndrome at 63.1%, which maps to the FREQUENT
      band (30-79%).
- category: Renal
  name: Renal Insufficiency
  description: >-
    Reduced glomerular filtration rate accompanying or following the proteinuric
    phase, present in three-quarters of patients in biopsy-based series.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Renal insufficiency
    term:
      id: HP:0000083
      label: Renal insufficiency
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:17714761
    reference_title: "Clinical and histological characteristics of renal AA amyloidosis: a retrospective study of 68 cases with a special interest to amyloid-associated inflammatory response."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Nephrotic syndrome and renal insufficiency were noted in 63.1% and 75% of
      patients, respectively.
    explanation: >-
      Directly quantifies renal insufficiency at 75%, mapping to the FREQUENT
      band (30-79%).
- category: Renal
  name: End-Stage Kidney Disease
  description: >-
    Progression to dialysis-dependent kidney failure, reached by a substantial
    minority within the follow-up period of biopsy cohorts. It is the principal
    determinant of morbidity and of the need for renal replacement therapy or
    transplantation.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Stage 5 chronic kidney disease
    term:
      id: HP:0003774
      label: Stage 5 chronic kidney disease
  evidence:
  - reference: PMID:17714761
    reference_title: "Clinical and histological characteristics of renal AA amyloidosis: a retrospective study of 68 cases with a special interest to amyloid-associated inflammatory response."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      At the end of follow-up, 26 patients (38.2%) showed end-stage renal disease.
    explanation: >-
      Directly quantifies progression to end-stage renal disease at 38.2%,
      mapping to the FREQUENT band (30-79%).
- category: Constitutional
  name: Peripheral Edema
  description: >-
    Oedema secondary to nephrotic-range proteinuria and hypoalbuminaemia; often
    the symptom that brings the patient to medical attention.
  phenotype_term:
    preferred_term: Edema
    term:
      id: HP:0000969
      label: Edema
  evidence:
  - reference: PMID:17714761
    reference_title: "Clinical and histological characteristics of renal AA amyloidosis: a retrospective study of 68 cases with a special interest to amyloid-associated inflammatory response."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Nephrotic syndrome and renal insufficiency were noted in 63.1% and 75% of
      patients, respectively.
    explanation: >-
      Oedema is a defining component of the nephrotic syndrome documented in
      63.1% of this series. Marked PARTIAL because the abstract reports the
      syndrome rather than oedema as a separately counted finding.
- category: Laboratory
  name: Hypoalbuminemia
  description: >-
    Reduced serum albumin resulting from urinary protein loss; a component of the
    nephrotic syndrome and a marker of its severity.
  phenotype_term:
    preferred_term: Hypoalbuminemia
    term:
      id: HP:0003073
      label: Hypoalbuminemia
  evidence:
  - reference: PMID:17714761
    reference_title: "Clinical and histological characteristics of renal AA amyloidosis: a retrospective study of 68 cases with a special interest to amyloid-associated inflammatory response."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Nephrotic syndrome and renal insufficiency were noted in 63.1% and 75% of
      patients, respectively.
    explanation: >-
      Hypoalbuminaemia is a defining component of the nephrotic syndrome
      documented here. Marked PARTIAL because the abstract reports the syndrome
      rather than albumin values directly.
- category: Hepatosplenic
  name: Hepatomegaly
  description: >-
    Hepatic amyloid deposition, classically perisinusoidal, enlarging the liver
    as the disease progresses. Deposition is commonly detected on serum amyloid P
    component scintigraphy but its clinical relevance is limited: raised alkaline
    phosphatase is the usual laboratory correlate, and liver failure is
    infrequent.
  phenotype_term:
    preferred_term: Hepatomegaly
    term:
      id: HP:0002240
      label: Hepatomegaly
  evidence:
  - reference: PMID:38568326
    reference_title: "AA Amyloidosis: A Contemporary View."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hepato- and splenomegaly commonly manifests during disease progression,
      whereas splenic rupture is exceptionally rare
    explanation: >-
      Directly documents hepatomegaly as a common manifestation of human AA
      amyloidosis during disease progression.
  - reference: PMID:38568326
    reference_title: "AA Amyloidosis: A Contemporary View."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      While splenic and hepatic amyloid deposition is commonly detected in serum
      amyloid P (SAP) scintigraphy, its clinical relevance is limited
    explanation: >-
      Records the important caveat that hepatic deposition is frequently imaged
      but usually not clinically consequential, so this phenotype should not be
      read as hepatic failure. Marked PARTIAL because it qualifies rather than
      strengthens the association.
- category: Hepatosplenic
  name: Splenomegaly
  description: >-
    Splenic amyloid deposition involving red and white pulp, enlarging the spleen
    as the disease progresses. The spleen is one of the classic sites
    demonstrated by serum amyloid P component scintigraphy; splenic rupture is
    exceptionally rare.
  phenotype_term:
    preferred_term: Splenomegaly
    term:
      id: HP:0001744
      label: Splenomegaly
  evidence:
  - reference: PMID:38568326
    reference_title: "AA Amyloidosis: A Contemporary View."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hepato- and splenomegaly commonly manifests during disease progression,
      whereas splenic rupture is exceptionally rare
    explanation: >-
      Directly documents splenomegaly as a common manifestation of human AA
      amyloidosis, replacing the model-organism-only support this phenotype
      previously carried.
  - reference: PMID:26176329
    reference_title: "Therapeutic Clearance of Amyloid by Antibodies to Serum Amyloid P Component."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      In murine amyloid A type amyloidosis, the binding of these antibodies to
      the residual SAP in amyloid deposits activates complement and triggers the
      rapid clearance of amyloid by macrophage-derived multinucleated giant
      cells.
    explanation: >-
      Supplementary model-organism support: the murine AA amyloidosis model on
      which anti-SAP therapy was built deposits amyloid in spleen and liver.
      Retained alongside, not in place of, the human evidence above.
- category: Gastrointestinal
  name: Chronic Diarrhea
  description: >-
    Gastrointestinal amyloid deposition affects roughly 30% of patients, and
    diarrhoea is its predominant symptom. It is characteristically refractory to
    standard antidiarrhoeal treatment, which distinguishes it from incidental
    gastrointestinal upset and makes it a meaningful clinical burden.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Diarrhea
    term:
      id: HP:0002014
      label: Diarrhea
    temporality: CHRONIC
  evidence:
  - reference: PMID:38568326
    reference_title: "AA Amyloidosis: A Contemporary View."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Approximately 30% of cases have gastrointestinal involvement. The
      predominant symptom is diarrhea that is frequently unresponsive to
      standard treatment
    explanation: >-
      Quantifies gastrointestinal involvement at approximately 30%, mapping to
      the FREQUENT band (30-79%), and names diarrhoea as its predominant and
      treatment-refractory symptom.
- category: Gastrointestinal
  name: Malabsorption
  description: >-
    Amyloid infiltration of the bowel wall impairs absorption, contributing with
    chronic diarrhoea to the weight loss seen in advanced disease.
  phenotype_term:
    preferred_term: Malabsorption
    term:
      id: HP:0002024
      label: Malabsorption
  evidence:
  - reference: PMID:38568326
    reference_title: "AA Amyloidosis: A Contemporary View."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Other frequently encountered presenting symptoms include weight loss,
      abdominal pain, malabsorption, macroglossia, gastroesophageal reflux,
      esophageal dysmotility, gastric polyps, and episodes of upper and lower
      gastrointestinal bleeding
    explanation: >-
      Lists malabsorption among the frequently encountered presenting
      gastrointestinal symptoms of AA amyloidosis.
- category: Gastrointestinal
  name: Gastrointestinal Hemorrhage
  description: >-
    Upper and lower gastrointestinal bleeding from amyloid-laden, friable mucosal
    vessels.
  phenotype_term:
    preferred_term: Gastrointestinal hemorrhage
    term:
      id: HP:0002239
      label: Gastrointestinal hemorrhage
  evidence:
  - reference: PMID:38568326
    reference_title: "AA Amyloidosis: A Contemporary View."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      episodes of upper and lower gastrointestinal bleeding
    explanation: >-
      Names episodes of upper and lower gastrointestinal bleeding among the
      frequently encountered presenting symptoms.
- category: Constitutional
  name: Weight Loss
  description: >-
    Weight loss driven by gastrointestinal amyloid (malabsorption, chronic
    diarrhoea) together with the catabolic burden of the underlying chronic
    inflammatory disease and nephrotic protein loss.
  phenotype_term:
    preferred_term: Weight loss
    term:
      id: HP:0001824
      label: Weight loss
  evidence:
  - reference: PMID:38568326
    reference_title: "AA Amyloidosis: A Contemporary View."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Other frequently encountered presenting symptoms include weight loss,
      abdominal pain, malabsorption, macroglossia, gastroesophageal reflux,
      esophageal dysmotility, gastric polyps, and episodes of upper and lower
      gastrointestinal bleeding
    explanation: >-
      Lists weight loss among the frequently encountered presenting symptoms of
      AA amyloidosis.
- category: Laboratory
  name: Elevated Alkaline Phosphatase
  description: >-
    Raised serum alkaline phosphatase, present in about 5% of patients. Worth
    interpreting carefully: ALP is itself an acute-phase reactant, so an
    elevation may reflect underlying inflammatory disease activity rather than
    hepatic amyloid deposition.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Elevated circulating alkaline phosphatase concentration
    term:
      id: HP:0003155
      label: Elevated circulating alkaline phosphatase concentration
  evidence:
  - reference: PMID:38568326
    reference_title: "AA Amyloidosis: A Contemporary View."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Elevated serum alkaline phosphatase (ALP) levels are noted in 5% of
      patients
    explanation: >-
      Directly quantifies elevated ALP at 5% of patients, mapping to the
      OCCASIONAL band (5-29%).
  - reference: PMID:38568326
    reference_title: "AA Amyloidosis: A Contemporary View."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      this may more accurately reflect underlying disease activity rather than
      amyloid deposition given that ALP functions as an acute-phase reactant
    explanation: >-
      Records the interpretive caveat that the ALP rise may track inflammatory
      activity rather than hepatic amyloid. Marked PARTIAL because it qualifies
      the attribution of the finding.
- category: Laboratory
  name: Elevated Acute-Phase Reactants
  description: >-
    Raised serum amyloid A and C-reactive protein reflecting the underlying
    inflammatory drive. These are not merely diagnostic markers but the
    quantitative substrate of the disease: SAA is the precursor itself, and its
    level during follow-up predicts amyloid burden, renal outcome, and mortality.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Elevated circulating C-reactive protein concentration
    term:
      id: HP:0011227
      label: Elevated circulating C-reactive protein concentration
  evidence:
  - reference: PMID:17554117
    reference_title: "Natural history and outcome in systemic AA amyloidosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The median SAA concentration during follow-up was 6 mg per liter in
      patients in whom renal function improved and 28 mg per liter in those in
      whom it deteriorated (P<0.001).
    explanation: >-
      Documents elevated acute-phase SAA in this cohort and ties the level to
      renal outcome. Elevation is intrinsic to the disease definition (an
      unremitting acute-phase response), supporting the VERY_FREQUENT band.
genetic:
- name: SAA1
  notes: >-
    SAA1 encodes serum amyloid A1, the dominant fibril-forming precursor isoform
    in AA deposits. Its common coding polymorphisms (the SAA1.1/alpha, SAA1.3,
    and SAA1.5/gamma isoforms, differing at codons 52 and 57) are the strongest
    documented genetic modifier of amyloidosis risk among patients with an
    equivalent inflammatory burden. This is a susceptibility locus, not a causal
    gene: SAA1 genotype does not cause disease without a chronic inflammatory
    driver.
  relationship_type: SUSCEPTIBILITY
  gene_term:
    preferred_term: SAA1
    term:
      id: hgnc:10513
      label: SAA1
  evidence:
  - reference: PMID:12687559
    reference_title: "The contribution of genotypes at the MEFV and SAA1 loci to amyloidosis and disease severity in patients with familial Mediterranean fever."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the presence of the SAAalpha/alpha genotype (OR 2.99, 95% CI 1.47-6.09)
    explanation: >-
      Quantifies the independent association of the amyloidogenic SAA1
      alpha/alpha genotype with renal amyloidosis in a 277-patient FMF cohort.
  - reference: PMID:29364741
    reference_title: "Obesity is a significant susceptibility factor for idiopathic AA amyloidosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Finally, the SAA1 polymorphism was confirmed as a susceptibility factor for
      AA amyloidosis irrespective of the type of the disease.
    explanation: >-
      Confirms SAA1 polymorphism as a susceptibility factor across trigger
      diseases, supporting the SUSCEPTIBILITY relationship type.
  - reference: PMID:18815155
    reference_title: "Increased susceptibility of serum amyloid A 1.1 to degradation by MMP-1: potential explanation for higher risk of type AA amyloidosis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      These results may explain the higher risk of amyloidosis in patients with a
      SAA1.1/1.1 genotype vs SAA1.5/1.5 or SAA1.1/1.5 genotype.
    explanation: >-
      Provides the mechanistic basis for the SAA1 risk association, namely
      isoform-dependent susceptibility to MMP-1 cleavage, linking the
      susceptibility locus to the proteolytic-processing pathophysiology node.
      Evidence source is IN_VITRO (immunoblotting and MALDI-TOF of recombinant
      isoforms).
- name: MEFV
  notes: >-
    MEFV encodes pyrin and is the causal gene of familial Mediterranean fever,
    the single most important monogenic upstream trigger of AA amyloidosis
    worldwide. It contributes to AA amyloidosis indirectly, by determining the
    severity and persistence of the inflammatory drive; homozygosity for
    p.Met694Val carries the highest amyloidosis risk (odds ratio 4.27, 95% CI
    2.01-9.07 in the cited FMF cohort). Colchicine adherence markedly modifies
    this genetic risk, making it one of the clearest gene-environment
    interactions in the disease.
  relationship_type: SUSCEPTIBILITY
  gene_term:
    preferred_term: MEFV
    term:
      id: hgnc:6998
      label: MEFV
  evidence:
  - reference: PMID:12687559
    reference_title: "The contribution of genotypes at the MEFV and SAA1 loci to amyloidosis and disease severity in patients with familial Mediterranean fever."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Logistic regression analysis showed that homozygosity for the M694V allele
    explanation: >-
      Identifies M694V homozygosity as independently associated with renal
      amyloidosis in a 277-patient FMF cohort; the same sentence reports the
      odds ratio of 4.27 (95% CI 2.01-9.07), the strongest single MEFV genotype
      association.
  - reference: PMID:12687559
    reference_title: "The contribution of genotypes at the MEFV and SAA1 loci to amyloidosis and disease severity in patients with familial Mediterranean fever."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Overall, disease severity and the development of amyloidosis in FMF are
      differentially affected by genetic variations within and outside the MEFV
      gene.
    explanation: >-
      The authors' conclusion that MEFV variation contributes to amyloidosis
      risk alongside loci outside MEFV, which is exactly the two-locus
      (MEFV plus SAA1) susceptibility model curated here.
  - reference: PMID:15018633
    reference_title: "Amyloidosis in familial Mediterranean fever patients: correlation with MEFV genotype and SAA1 and MICA polymorphisms effects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Amyloidosis in familial Mediterranean fever patients: correlation with MEFV
      genotype and SAA1 and MICA polymorphisms effects.
    explanation: >-
      Independent study correlating MEFV genotype with amyloidosis risk in FMF,
      corroborating MEFV as a susceptibility locus acting through the trigger
      disease.
- name: SAA2
  notes: >-
    SAA2 is the second inducible acute-phase SAA isoform, encoded adjacent to
    SAA1 on chromosome 11p15.1, and is likewise associated with AA amyloidosis -
    although SAA1 is the isoform that predominates in the deposits themselves.
    Curated here to make the locus explicit rather than leaving the SAA gene
    cluster represented by SAA1 alone; SAA3 is a pseudogene and SAA4 is
    constitutively expressed and non-acute-phase, so neither is curated.
  relationship_type: SUSCEPTIBILITY
  gene_term:
    preferred_term: SAA2
    term:
      id: hgnc:10514
      label: SAA2
  evidence:
  - reference: PMID:38568326
    reference_title: "AA Amyloidosis: A Contemporary View."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      SAA1 and SAA2 are both acute-phase proteins and associated with AA
      amyloidosis.
    explanation: >-
      Directly associates SAA2, alongside SAA1, with AA amyloidosis. Evidence
      source is OTHER because this is a review.
  - reference: PMID:38568326
    reference_title: "AA Amyloidosis: A Contemporary View."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Inducible expression of SAA1 and SAA2 by proinflammatory cytokines during
      acute-phase response impacts the serum concentration of SAA
    explanation: >-
      Links SAA2 expression to the cytokine-driven acute-phase node that sets
      circulating precursor concentration. Marked PARTIAL because it describes
      the shared regulatory mechanism rather than an SAA2-specific amyloidosis
      risk estimate. Evidence source is OTHER (review).
environmental:
- name: Obesity and adipose-derived serum amyloid A
  description: >-
    Obesity is an independently identified susceptibility factor for idiopathic
    AA amyloidosis, meaning cases with no classical inflammatory trigger. The
    proposed mechanism is direct rather than merely correlative: adipocytes are
    themselves a major site of acute-phase SAA expression, so adipose mass
    supplies precursor and sustains low-grade systemic inflammation independently
    of the hepatic acute-phase response. This is the plausible explanation for a
    substantial share of idiopathic disease in an ageing, increasingly obese
    population.
  effect: Increases risk of idiopathic AA amyloidosis
  evidence:
  - reference: PMID:29364741
    reference_title: "Obesity is a significant susceptibility factor for idiopathic AA amyloidosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Obesity, age and the SAA1 polymorphism are susceptibility factors for
      idiopathic AA amyloidosis.
    explanation: >-
      Directly states obesity as a susceptibility factor for idiopathic AA
      amyloidosis in a 146-patient study with two control groups.
  influences_mechanisms:
  - target: IL-6-Driven Hepatic Acute-Phase Response
    environmental_effect: PREDISPOSES
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Adipose tissue contributes acute-phase SAA and pro-inflammatory cytokines,
      adding to the systemic precursor supply modelled at this node even without
      a classical inflammatory disease.
    evidence:
    - reference: PMID:16737350
      reference_title: "Acute-phase serum amyloid A: an inflammatory adipokine and potential link between obesity and its metabolic complications."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        A-SAA mRNA levels and A-SAA secretion from adipose tissue were
        significantly correlated with body mass index (r = 0.47; p = 0.028 and r
        = 0.80; p = 0.0002, respectively).
      explanation: >-
        Quantifies the correlation between adiposity and adipose SAA output,
        supporting the route by which obesity feeds the acute-phase precursor
        node.
biochemical:
- name: Serum Amyloid A
  notes: >-
    The circulating precursor protein, and the disease's single most important
    biomarker. It is unusual among biomarkers in being the pathogenic substrate
    itself rather than a downstream correlate, which is why treatment is titrated
    to SAA rather than to symptoms. Sustained suppression below roughly 10 mg/L
    is associated with amyloid regression; levels below 4 mg/L with a relatively
    favourable outcome.
  presence: INCREASED
  evidence:
  - reference: PMID:17554117
    reference_title: "Natural history and outcome in systemic AA amyloidosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The effects of renal dysfunction dominate the course of AA amyloidosis,
      which is associated with a relatively favorable outcome in patients with
      SAA concentrations that remain in the low-normal range (<4 mg per liter).
    explanation: >-
      Establishes the prognostic threshold that makes SAA an actionable
      treat-to-target biomarker.
  - reference: PMID:26120866
    reference_title: "Therapeutic blockade of interleukin-6 by tocilizumab in the management of AA amyloidosis and chronic inflammatory disorders: a case series and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The main aim of treatment is to suppress inflammation thereby inhibiting
      serum amyloid A protein (SAA), which is the precursor of AA amyloid
      fibrils, to prevent or halt amyloid deposition.
    explanation: >-
      States explicitly that SAA is both the fibril precursor and the treatment
      target, the dual role this biochemical entry records.
histopathology:
- name: Congo Red-Positive Amyloid Deposition
  description: >-
    Acellular Congo red-positive extracellular deposits showing apple-green
    birefringence under polarized light. This confirms amyloid but does not
    identify the precursor; typing is a separate and mandatory step.
  diagnostic: true
  finding_term:
    preferred_term: amyloid deposition
    term:
      id: NCIT:C54018
      label: Amyloid Deposition
  evidence:
  - reference: PMID:28828707
    reference_title: "Pathology and diagnosis of renal non-AL amyloidosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Renal amyloidosis is characterized by acellular Congo red positive deposits
      in the glomeruli, interstitium and/or arteries.
    explanation: >-
      Defines the Congo red-positive histological finding and its renal
      distribution.
- name: Glomerular-Predominant Deposition Pattern
  description: >-
    Amyloid deposits are distributed within the glomerulus in mesangial
    segmental, mesangial nodular, mesangiocapillary, or hilar patterns. A
    glomerular form predominates over a purely vascular form, and this
    distinction determines the clinical presentation, with proteinuria dominating
    the glomerular form.
  finding_term:
    preferred_term: amyloid deposition
    term:
      id: NCIT:C54018
      label: Amyloid Deposition
  evidence:
  - reference: PMID:17714761
    reference_title: "Clinical and histological characteristics of renal AA amyloidosis: a retrospective study of 68 cases with a special interest to amyloid-associated inflammatory response."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The distribution pattern of glomerular amyloid deposits was mesangial
      segmental (14.7%), mesangial nodular (26.5%), mesangiocapillary (32.3%),
      and hilar (26.5%). Glomerular form was observed in 80.9% of cases and
      vascular form in 19.1%.
    explanation: >-
      Quantifies the glomerular deposition patterns and the
      glomerular-to-vascular ratio in a 68-case renal AA series.
- name: Amyloid-Associated Giant Cell and Inflammatory Reaction
  description: >-
    A local inflammatory reaction to the deposits themselves - multinucleated
    giant cells and glomerular inflammatory infiltrate, sometimes with crescents
    - is present in a substantial minority of biopsies. The authors propose it
    reflects an immune response directed against AA fibrils that may contribute
    to amyloid resolution, which is mechanistically interesting because
    macrophage-mediated clearance is exactly the effector arm exploited by
    anti-SAP antibody therapy.
  finding_term:
    preferred_term: amyloid deposition
    term:
      id: NCIT:C54018
      label: Amyloid Deposition
  evidence:
  - reference: PMID:17714761
    reference_title: "Clinical and histological characteristics of renal AA amyloidosis: a retrospective study of 68 cases with a special interest to amyloid-associated inflammatory response."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      AA amyloidosis-related inflammation was noted in 30 patients (44.1%) and
      appeared as a multinucleated giant cell reaction (27.9%) or a glomerular
      inflammatory infiltrate (25%), including glomerular crescents (17.6%).
    explanation: >-
      Quantifies the amyloid-associated inflammatory reaction and its giant-cell
      component in the same 68-case series.
diagnosis:
- name: Tissue Biopsy with Amyloid Typing
  description: >-
    Histopathological demonstration of amyloid is the diagnostic gold standard,
    but Congo red positivity alone is insufficient - the fibril protein must be
    typed. Immunohistochemistry with anti-AA antibody, or laser microdissection
    with mass spectrometry where available, distinguishes AA from AL, ATTR, and
    the rarer hereditary types. Getting this wrong has direct therapeutic
    consequences, since AL requires anti-plasma-cell therapy and AA requires
    suppression of inflammation.
  evidence:
  - reference: PMID:38568326
    reference_title: "AA Amyloidosis: A Contemporary View."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Histopathological examination is the gold standard of diagnosis, but
      magnetic resonance imaging can be used to detect cardiac involvement.
    explanation: >-
      Establishes histopathology as the diagnostic gold standard. Evidence source
      is OTHER because this is a review.
  - reference: PMID:28828707
    reference_title: "Pathology and diagnosis of renal non-AL amyloidosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      accurate typing of non-AL amyloidosis then requires immunohistochemical or
      laser microdissection/mass spectrometry studies of the Congo red positive
      deposits
    explanation: >-
      States the requirement for immunohistochemical or mass-spectrometric typing
      beyond Congo red staining.
- name: Serum Amyloid A and C-Reactive Protein Monitoring
  description: >-
    Serial measurement of SAA (with CRP as a widely available surrogate) is used
    both to stratify risk in patients with known inflammatory disease and to
    titrate therapy. Because the treat-to-target threshold is defined
    numerically, this is a monitoring test with a therapeutic decision attached
    rather than a purely diagnostic one.
  evidence:
  - reference: PMID:17554117
    reference_title: "Natural history and outcome in systemic AA amyloidosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The SAA concentration was measured serially, and the amyloid burden was
      estimated with the use of whole-body serum amyloid P component
      scintigraphy.
    explanation: >-
      Documents serial SAA measurement (alongside SAP scintigraphy) as the
      monitoring strategy in the definitive natural-history cohort.
differential_diagnoses:
- name: Systemic AL Amyloidosis
  description: >-
    The other major systemic amyloidosis and the principal differential. AL is a
    clonal plasma-cell disorder whose precursor is a monoclonal immunoglobulin
    light chain; AA's precursor is a normal acute-phase protein present in
    excess. The distinction is not academic - AL requires anti-plasma-cell
    therapy while AA requires suppression of inflammation - and it cannot be made
    on Congo red staining alone.
  disease_term:
    preferred_term: primary systemic amyloidosis
    term:
      id: MONDO:0017816
      label: primary systemic amyloidosis
  distinguishing_features:
  - Cardiac involvement, peripheral neuropathy, carpal tunnel syndrome, and
    macroglossia are common in AL and comparatively uncommon in AA.
  - Renal involvement dominates the clinical course of AA amyloidosis.
  - AL shows light-chain restriction on immunofluorescence, whereas Congo red
    positivity with negative immunofluorescence points to a non-AL type.
  - A detectable monoclonal protein does not by itself establish AL, since
    monoclonal gammopathy is common in the affected age group.
  evidence:
  - reference: PMID:28828707
    reference_title: "Pathology and diagnosis of renal non-AL amyloidosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The detection of Congo red positive deposits coupled with negative
      immunofluorescence studies is highly suggestive of non-AL amyloidosis.
    explanation: >-
      Provides the immunofluorescence-based discriminator between AL and non-AL
      (including AA) renal amyloidosis.
  - reference: PMID:38568326
    reference_title: "AA Amyloidosis: A Contemporary View."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      While cardiac infiltration is extensively documented in various amyloidosis
      types, it is a relatively rare cause of heart failure in AA amyloidosis
    explanation: >-
      Supports the single most useful clinical discriminator recorded above: a
      patient with systemic amyloidosis and heart failure is far more likely to
      have AL or ATTR than AA. Evidence source is OTHER because this is a review.
progression:
- phase: Subclinical amyloid deposition
  notes: >-
    Amyloid accumulates during years to decades of uncontrolled inflammation
    before any renal abnormality is detectable. This is the window in which
    surveillance of at-risk patients (established FMF, other periodic fever
    syndromes, long-standing inflammatory arthritis) by urinalysis and SAA can
    change the outcome.
  evidence:
  - reference: PMID:25387054
    reference_title: "AA amyloidosis: pathogenesis and targeted therapy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Therefore, AA amyloidosis can be thought of as a consequence of
      long-standing inflammatory disease.
    explanation: >-
      Supports a prolonged latent phase driven by long-standing inflammation
      preceding clinical presentation. Evidence source is OTHER (review).
- phase: Proteinuric and nephrotic phase
  notes: >-
    Proteinuria appears and progresses to nephrotic-range, with nephrotic
    syndrome in roughly two-thirds and renal insufficiency in three-quarters of
    patients in biopsy-based series.
  evidence:
  - reference: PMID:17714761
    reference_title: "Clinical and histological characteristics of renal AA amyloidosis: a retrospective study of 68 cases with a special interest to amyloid-associated inflammatory response."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Nephrotic syndrome and renal insufficiency were noted in 63.1% and 75% of
      patients, respectively.
    explanation: >-
      Quantifies the proteinuric and nephrotic phase in a renal AA amyloidosis
      series.
- phase: Amyloid storm (rare acute FMF-associated variant)
  notes: >-
    A minority of FMF patients depart from the indolent course entirely and
    present with an acute illness: heavy proteinuria, high inflammatory markers,
    and progression to kidney failure within weeks rather than years, typically
    precipitated by a superimposed infection. Curated as a distinct trajectory
    rather than a severity grade, because the timescale (weeks) and the
    infection trigger are qualitatively different from the usual course.
  evidence:
  - reference: PMID:38568326
    reference_title: "AA Amyloidosis: A Contemporary View."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      While the majority of cases follow an indolent course, a subset of
      individuals with FMF might undergo acute illness, marked by substantial
      proteinuria, elevated inflammatory markers, and rapid progression to kidney
      failure within weeks.
    explanation: >-
      Defines the amyloid storm presentation and contrasts it with the indolent
      majority course. Evidence source is OTHER because this is a review.
  - reference: PMID:38568326
    reference_title: "AA Amyloidosis: A Contemporary View."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      These infrequent instances are named “amyloid storm,” which is thought to
      be precipitated by superimposed infections or other triggering events
    explanation: >-
      Names the entity and its precipitating trigger. Evidence source is OTHER
      because this is a review.
- phase: Progressive renal decline to end-stage kidney disease
  notes: >-
    Untreated, creatinine clearance falls at roughly 15 mL/min/1.73 m2 per year -
    the placebo-arm rate in the eprodisate trial, which is the best available
    quantitative natural-history benchmark. Median survival after diagnosis in
    the era before widespread biologic therapy was 133 months.
  evidence:
  - reference: PMID:17554116
    reference_title: "Eprodisate for the treatment of renal disease in AA amyloidosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The mean rates of decline in creatinine clearance were 10.9 and 15.6 ml per
      minute per 1.73 m(2) of body-surface area per year in the eprodisate and
      the placebo groups, respectively (P=0.02).
    explanation: >-
      The placebo arm provides the quantitative rate of untreated renal decline
      cited for this phase.
  - reference: PMID:17554117
    reference_title: "Natural history and outcome in systemic AA amyloidosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Median survival after diagnosis was 133 months
    explanation: >-
      Provides the median survival benchmark for the progressive phase.
treatments:
- name: Colchicine (Familial Mediterranean Fever)
  description: >-
    First-line and foundational therapy for FMF, suppressing the inflammatory
    attacks that drive SAA production and thereby preventing amyloidosis. In
    patients who already have established amyloid nephropathy, the therapeutic
    dose is above 1.5 mg/day and efficacy depends critically on starting before
    renal function is lost - the effect is confined to patients whose serum
    creatinine is still below 1.5 mg/dL. This is the clearest demonstration in
    the disease that treatment timing, not just treatment choice, determines
    outcome.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: colchicine
      term:
        id: CHEBI:23359
        label: colchicine
  target_mechanisms:
  - target: Chronic Inflammatory, Autoinflammatory, or Infectious Stimulus
    treatment_effect: INHIBITS
    description: >-
      Suppressing FMF inflammatory attacks removes the cytokine drive at the
      trigger node, preventing the downstream acute-phase SAA surge.
  evidence:
  - reference: PMID:7986228
    reference_title: "Colchicine treatment of AA amyloidosis of familial Mediterranean fever. An analysis of factors affecting outcome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The therapeutic dosage of colchicine for amyloidosis of FMF is > 1.5
      mg/day. This dosage is effective only in patients with initial serum
      creatinine levels < 1.5 mg/dl.
    explanation: >-
      Defines both the effective colchicine dose and the renal-function window
      within which it works, in 68 FMF patients with amyloidosis followed at
      least 5 years.
  - reference: PMID:7986228
    reference_title: "Colchicine treatment of AA amyloidosis of familial Mediterranean fever. An analysis of factors affecting outcome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      At the end of the study period, kidney disease had worsened in 31 patients
      and remained stable in 22. Proteinuria had regressed in 15 patients.
    explanation: >-
      Documents stabilization or regression of proteinuria in a substantial share
      of colchicine-treated patients. Marked PARTIAL because this is an
      uncontrolled retrospective series without a comparator arm, and disease
      still worsened in the largest single group.
  - reference: PMID:38568326
    reference_title: "AA Amyloidosis: A Contemporary View."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      In a study examining 960 patients with FMF without evidence of amyloidosis
      at baseline, the cumulative rate of proteinuria after 11 years was reported
      as 1.7% in colchicine-compliant patients while 48.9% in the non-compliants
    explanation: >-
      The strongest available prevention signal in this disease: a roughly
      29-fold difference in 11-year cumulative proteinuria between
      colchicine-compliant and non-compliant FMF patients, which is what
      justifies colchicine as prophylaxis rather than only as rescue therapy.
      Evidence source is OTHER because the figures are reported in a review
      summarizing the primary cohort.
  - reference: PMID:38568326
    reference_title: "AA Amyloidosis: A Contemporary View."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      However, evidence for its efficacy in AA amyloidosis due to causes other
      than FMF is still quite limited
    explanation: >-
      Records the scope limit deliberately encoded in this treatment's name:
      colchicine's evidence base is FMF-specific and should not be generalized to
      AA amyloidosis from other triggers. Evidence source is OTHER (review).
- name: Anti-TNF-alpha Therapy
  description: >-
    TNF inhibitors (infliximab, etanercept, adalimumab) treat AA amyloidosis by
    controlling the underlying inflammatory arthropathy, and are the mainstay for
    the rheumatoid-arthritis and spondyloarthritis-driven disease that accounts
    for much of the Western caseload. Results are more mixed than with IL-6
    blockade - in a head-to-head retrospective comparison tocilizumab was
    superior for lowering SAA and improving kidney function - and, as with
    colchicine, benefit depends on starting before renal function is lost.
  therapeutic_modality: MONOCLONAL_ANTIBODY
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: infliximab
      term:
        id: NCIT:C1789
        label: Infliximab
    - preferred_term: etanercept
      term:
        id: NCIT:C2381
        label: Etanercept
    - preferred_term: adalimumab
      term:
        id: NCIT:C65216
        label: Adalimumab
  target_mechanisms:
  - target: Chronic Inflammatory, Autoinflammatory, or Infectious Stimulus
    treatment_effect: INHIBITS
    description: >-
      Neutralizing TNF-alpha suppresses the inflammatory arthropathy at the
      trigger node, reducing the cytokine drive to hepatic SAA production.
  evidence:
  - reference: PMID:38568326
    reference_title: "AA Amyloidosis: A Contemporary View."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      In a retrospective series including 15 patients treated with anti-TNF,
      amyloidosis progressed in seven patients (46.7%), stabilized in five
      (33.3%), and regression of proteinuria occurred in three (20%) in 10
      months
    explanation: >-
      Quantifies outcomes on anti-TNF therapy. Marked PARTIAL deliberately:
      amyloidosis still progressed in the largest single group, so this series
      does not establish efficacy. Evidence source is OTHER because the figures
      are reported in a review summarizing the primary series.
  - reference: PMID:38568326
    reference_title: "AA Amyloidosis: A Contemporary View."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      in a multicenter study in which 36 patients with AA amyloidosis treated
      with anti-TNF therapy were followed prospectively for 5 years, > 50%
      decrease in proteinuria was observed in more than half of the patients
    explanation: >-
      The stronger of the two datasets - prospective, multicentre, 5-year
      follow-up - showing a substantial proteinuria response in the majority.
      Evidence source is OTHER because the figures are reported in a review
      summarizing the primary study.
  - reference: PMID:38568326
    reference_title: "AA Amyloidosis: A Contemporary View."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      a retrospective analysis including 42 patients with AA amyloidosis
      demonstrated that tocilizumab was superior to anti-TNFs in terms of
      obtaining a decrease in SAA, improvement in kidney function, and
      suppression of the disease activity
    explanation: >-
      Records the comparative result that places anti-TNF below IL-6 blockade on
      the biochemical and renal endpoints, which is why this entry does not
      present anti-TNF as first choice. Marked PARTIAL because it is a
      retrospective, non-randomized comparison. Evidence source is OTHER
      (review).
- name: Interleukin-6 Receptor Blockade (Tocilizumab)
  description: >-
    Tocilizumab blocks the IL-6 receptor and so acts directly on the cytokine
    that drives hepatic SAA production - mechanistically the most targeted of the
    available anti-inflammatory options, since it inhibits the exact signalling
    axis that supplies the precursor. SAA falls within days and amyloid deposits
    regress or stabilize. Infection is the predominant adverse effect.
  therapeutic_modality: MONOCLONAL_ANTIBODY
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: tocilizumab
      term:
        id: NCIT:C84217
        label: Tocilizumab
  target_mechanisms:
  - target: IL-6-Driven Hepatic Acute-Phase Response
    treatment_effect: INHIBITS
    description: >-
      IL-6 receptor blockade removes the principal signal inducing hepatocyte SAA
      transcription, collapsing precursor supply at the amplifier node.
  evidence:
  - reference: PMID:26120866
    reference_title: "Therapeutic blockade of interleukin-6 by tocilizumab in the management of AA amyloidosis and chronic inflammatory disorders: a case series and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Whole-cohort median pre-treatment SAA fell from 70 to 4 mg/L within 10 days
      of the first dose; this response has been maintained over an on-treatment
      follow-up period of 23 months (p<0.0001). AA amyloid deposits either
      regressed or remained stable.
    explanation: >-
      Directly demonstrates rapid, sustained SAA suppression and amyloid
      regression or stabilization on IL-6 blockade, validating the acute-phase
      node as the drug target.
  - reference: PMID:26120866
    reference_title: "Therapeutic blockade of interleukin-6 by tocilizumab in the management of AA amyloidosis and chronic inflammatory disorders: a case series and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This small series shows that in patients with treatment-refractory chronic
      inflammatory conditions TCZ can be effective in suppressing inflammation,
      and in those with AA amyloidosis, can lead to regression of amyloid
      deposits.
    explanation: >-
      The authors' own conclusion, recorded with its stated limitation. Marked
      PARTIAL because this is an uncontrolled 20-patient case series, of whom 70%
      had AA amyloidosis, and the authors call for longer follow-up.
  - reference: PMID:41670232
    reference_title: "Tocilizumab prevented the progression of AA amyloidosis derived from adult-onset Still's disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Steroid pulse therapy, followed by tocilizumab, a IL-6 receptor inhibitor,
      in combination with oral glucocorticoids dramatically improved kidney and
      cardiac manifestations with reduction in systemic inflammation.
    explanation: >-
      Corroborates organ-level benefit of IL-6 blockade in biopsy-proven AA
      amyloidosis. Marked PARTIAL because it is a single case report with
      concomitant glucocorticoid therapy.
- name: Interleukin-1 Blockade (Canakinumab, Anakinra)
  description: >-
    IL-1 blockade targets the inflammasome-driven cytokine cascade upstream of
    IL-6, and is the principal option in colchicine-resistant or
    colchicine-intolerant FMF and in the other monogenic autoinflammatory
    syndromes (TRAPS, CAPS, mevalonate kinase deficiency) that drive AA
    amyloidosis. Note that the randomized evidence recorded here establishes
    control of the trigger diseases; randomized evidence for amyloid or renal
    outcomes on IL-1 blockade in established AA amyloidosis is not available.
  therapeutic_modality: MONOCLONAL_ANTIBODY
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: canakinumab
      term:
        id: NCIT:C80971
        label: Canakinumab
    - preferred_term: anakinra
      term:
        id: NCIT:C38717
        label: Anakinra
  target_mechanisms:
  - target: Chronic Inflammatory, Autoinflammatory, or Infectious Stimulus
    treatment_effect: INHIBITS
    description: >-
      Neutralizing IL-1beta suppresses inflammasome-driven autoinflammatory
      disease activity at the trigger node, removing the drive to the hepatic
      acute-phase response.
  evidence:
  - reference: PMID:29768139
    reference_title: "Canakinumab for the Treatment of Autoinflammatory Recurrent Fever Syndromes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In this trial, canakinumab was effective in controlling and preventing
      flares in patients with colchicine-resistant familial Mediterranean fever,
      mevalonate kinase deficiency, and TRAPS.
    explanation: >-
      Randomized trial evidence that canakinumab controls the autoinflammatory
      trigger diseases. Marked PARTIAL because the trial endpoint was control of
      the trigger disease, not amyloid burden or renal outcome in AA amyloidosis.
- name: Kidney Transplantation
  description: >-
    The preferred renal replacement modality for AA amyloidosis with kidney
    failure, and no longer the poor-prognosis option it once was: contemporary
    multicentre outcomes approach those of other causes of end-stage kidney
    disease. Amyloid recurrence in the allograft has become rare where the
    underlying inflammatory disease is controlled with modern agents. Because
    excess post-transplant mortality is driven by cardiovascular disease,
    pre-transplant cardiac assessment matters.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: Kidney Transplantation
    term:
      id: NCIT:C15265
      label: Kidney Transplantation
  evidence:
  - reference: PMID:37741608
    reference_title: "Kidney Transplantation in Patients With AA Amyloidosis: Outcomes in a French Multicenter Cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patient survival rates were 94.0% (95% CI, 89.1-99.2) at 1 year and 85.5%
      (77.8-94.0) at 5 years after transplantation.
    explanation: >-
      Provides contemporary patient-survival outcomes after kidney
      transplantation in 86 patients across 26 French centres.
  - reference: PMID:38568326
    reference_title: "AA Amyloidosis: A Contemporary View."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Kidney transplantation is preferred in patients with kidney failure, and
      the recurrence of amyloidosis in the allograft has become rare as
      transplant recipients have started to benefit from the new agents.
    explanation: >-
      States the preference for transplantation and the modern rarity of
      allograft recurrence. Evidence source is OTHER because this is a review.
- name: Dialysis
  description: >-
    Haemodialysis or peritoneal dialysis for established kidney failure. It is a
    suitable modality, but survival on dialysis is poor relative to
    transplantation, and worse where cardiac amyloid is present: cardiovascular
    deposition plus nephrotic syndrome makes these patients prone to
    intradialytic hypotension. This is the practical reason transplantation is
    preferred where the patient is a candidate.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: Dialysis
    term:
      id: NCIT:C15221
      label: Dialysis
  evidence:
  - reference: PMID:38568326
    reference_title: "AA Amyloidosis: A Contemporary View."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Dialysis modalities and kidney transplantation are both suitable for
      patients suffering from AA amyloidosis and kidney failure
    explanation: >-
      Establishes dialysis as an accepted renal replacement modality in AA
      amyloidosis. Evidence source is OTHER because this is a review.
  - reference: PMID:38568326
    reference_title: "AA Amyloidosis: A Contemporary View."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Still, survival is poor among patients on dialysis, especially when cardiac
      involvement is prevalent
    explanation: >-
      Records the poor survival on dialysis and its dependence on cardiac
      involvement, the caveat that makes transplantation preferred. Marked
      PARTIAL because it qualifies rather than supports the intervention.
      Evidence source is OTHER (review).
- name: Eprodisate (Investigational, Not Approved)
  description: >-
    A glycosaminoglycan mimetic designed to disrupt the SAA-glycosaminoglycan
    interaction that promotes fibril polymerization - the only agent to have been
    tested in a randomized trial against the deposition step itself rather than
    against the upstream inflammation. It slowed the decline in renal function
    but did not significantly affect progression to end-stage renal disease or
    mortality, and it was not approved. It is recorded here because it is the
    direct clinical test of the glycosaminoglycan-dependence mechanism curated in
    the pathophysiology, and because its failure is part of why no
    deposit-clearing therapy exists.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  target_mechanisms:
  - target: Glycosaminoglycan-Assisted Fibril Nucleation and Extracellular Deposition
    treatment_effect: INHIBITS
    description: >-
      Competes with glycosaminoglycan binding to amyloidogenic SAA, inhibiting
      fibril polymerization and tissue deposition at the central effector node.
  evidence:
  - reference: PMID:17554116
    reference_title: "Eprodisate for the treatment of renal disease in AA amyloidosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Eprodisate is a member of a new class of compounds designed to interfere
      with interactions between amyloidogenic proteins and glycosaminoglycans and
      thereby inhibit polymerization of amyloid fibrils and deposition of the
      fibrils in tissues.
    explanation: >-
      States the drug's mechanism of action against the
      glycosaminoglycan-assisted fibril formation node.
  - reference: PMID:17554116
    reference_title: "Eprodisate for the treatment of renal disease in AA amyloidosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The drug had no significant effect on progression to end-stage renal
      disease (hazard ratio, 0.54; P=0.20) or risk of death (hazard ratio, 0.95;
      P=0.94).
    explanation: >-
      Records the negative results on the hard endpoints alongside the positive
      renal-function-slope result, which is why the drug was not approved. Marked
      PARTIAL to avoid overstating benefit.
clinical_trials:
- name: NCT00035334
  phase: PHASE_III
  status: COMPLETED
  description: >-
    Multicenter, randomized, double-blind, placebo-controlled trial of eprodisate
    versus placebo for 24 months in 183 patients with AA amyloidosis and kidney
    involvement, with a composite renal-function-or-death primary endpoint.
  target_phenotypes:
  - preferred_term: Renal insufficiency
    term:
      id: HP:0000083
      label: Renal insufficiency
  - preferred_term: Proteinuria
    term:
      id: HP:0000093
      label: Proteinuria
  evidence:
  - reference: PMID:17554116
    reference_title: "Eprodisate for the treatment of renal disease in AA amyloidosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We randomly assigned 183 patients from 27 centers to receive eprodisate or
      placebo for 24 months.
    explanation: >-
      Describes the trial design and enrolment registered as NCT00035334.
discussions:
- discussion_id: saa_threshold_vs_deposition_mechanism
  kind: KNOWLEDGE_GAP
  prompt: >-
    Why do only a minority of patients with equivalently sustained, equivalently
    high SAA concentrations develop AA amyloidosis?
  rationale: >-
    Chronic SAA elevation is necessary but demonstrably not sufficient: most
    patients with long-standing rheumatoid arthritis or FMF never develop
    amyloidosis despite decades of raised SAA. SAA1 genotype explains part of the
    variance and nucleation-dependence supplies a plausible stochastic mechanism,
    but the field's own reviews state that the conversion step is not fully
    understood. Resolving this would determine whether risk stratification can
    ever go beyond measuring the precursor.
  attaches_to:
  - pathophysiology#Glycosaminoglycan-Assisted Fibril Nucleation and Extracellular Deposition
  status: OPEN
  proposed_experiments:
  - experiment_id: exp_aa_matched_saa_exposure_genotype_cohort
    name: Prospective cohort with matched cumulative SAA exposure stratified by SAA1 genotype
    description: >-
      Recruit patients with chronic inflammatory disease and serially quantified
      SAA, compute a cumulative SAA exposure integral for each, and stratify by
      SAA1 genotype. Screen prospectively for subclinical amyloid so that
      incidence can be regressed on cumulative exposure within genotype strata.
      The design isolates the question of whether genotype shifts the exposure
      threshold or instead changes the probability of conversion at a given
      exposure.
    supporting_outcome:
    - A genotype-dependent shift in the exposure-incidence curve would support
      SAA1 acting on the proteolysis and misfolding step rather than on precursor
      supply.
    refuting_outcome:
    - Superimposable exposure-incidence curves across genotypes would refute a
      genotype-dependent threshold model and point to an unmeasured host factor.
  - experiment_id: exp_aa_pre_clinical_seed_detection
    name: Detection of endogenous nucleating seed before clinically apparent deposition
    description: >-
      Apply high-sensitivity amyloid-seeding assays to accessible tissue (fat
      aspirate, minor salivary gland) from patients with sustained high SAA but
      no clinical amyloidosis, to test whether a subclinical nucleating seed
      precedes and predicts overt disease.
    supporting_outcome:
    - Seeding activity detectable before overt disease, and predictive of later
      amyloidosis, would support the nucleation-dependent seeding model as the
      rate-limiting stochastic step.
    refuting_outcome:
    - Absence of detectable seeding activity in patients who subsequently develop
      amyloidosis would argue against a detectable pre-clinical seed.
  evidence:
  - reference: PMID:25387054
    reference_title: "AA amyloidosis: pathogenesis and targeted therapy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      A chronically high plasma concentration of SAA results in the aggregation
      of amyloid into cross-β-sheet fibrillar deposits by mechanisms not fully
      understood.
    explanation: >-
      The authoritative review explicitly states that the mechanism converting
      high SAA into deposits is incompletely understood, which is the gap
      recorded here. Evidence source is OTHER (review).
- discussion_id: no_deposit_clearing_therapy
  kind: KNOWLEDGE_GAP
  prompt: >-
    Can established AA amyloid deposits be actively cleared, rather than merely
    allowed to regress by withdrawing the precursor?
  rationale: >-
    All available management works upstream, by lowering SAA; regression then
    depends on endogenous clearance, which is slow and incomplete once organ
    damage is established. The two direct attacks on the deposit - eprodisate
    against glycosaminoglycan-assisted polymerization, and SAP depletion plus
    anti-SAP antibody against existing deposits - both reached clinical trials
    and neither is available. This is the field's principal unmet need and the
    reason treatment timing dominates outcome.
  attaches_to:
  - pathophysiology#Progressive Multi-Organ Amyloid Accumulation
  status: OPEN
  evidence:
  - reference: PMID:38568326
    reference_title: "AA Amyloidosis: A Contemporary View."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      There is yet no treatment option for the clearance of amyloid fibril
      deposits; therefore, the management strategy primarily aims to reduce serum
      amyloid A protein.
    explanation: >-
      States directly that no deposit-clearing therapy exists and that management
      is therefore confined to precursor reduction. Evidence source is OTHER
      because this is a review.
  - reference: PMID:26176329
    reference_title: "Therapeutic Clearance of Amyloid by Antibodies to Serum Amyloid P Component."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We conducted an open-label, single-dose-escalation, phase 1 trial involving
      15 patients with systemic amyloidosis.
    explanation: >-
      The anti-SAP approach reached a 15-patient phase 1 trial in systemic
      amyloidosis, showing clearance is achievable in principle. Marked PARTIAL
      because the trial was small, open-label, not AA-specific, excluded patients
      with cardiac involvement, and the programme was subsequently discontinued.
- discussion_id: mica_not_a_modifier_locus
  kind: INTERPRETATION
  prompt: >-
    Is MICA a modifier locus for amyloidosis risk in familial Mediterranean
    fever, as sometimes summarized?
  rationale: >-
    Recorded to stop a specific error being reintroduced. The deep-research
    report for this entry stated that MICA polymorphisms have been reported as a
    modifying factor for amyloidosis risk in FMF alongside MEFV and SAA1, citing
    PMID:15018633. That paper reports the opposite: it tested the MICA exon 5
    polymorphism precisely because MICA modifies FMF attack frequency and age of
    onset, and found no association with renal amyloidosis, while confirming the
    SAA1 association in the same cohort. MICA is therefore deliberately absent
    from this entry's genetic section - not overlooked. The paper reports the
    amyloidosis null without proposing an explanation for it; the two
    explanations it does offer - a weak MICA effect masked by stronger MEFV and
    SAA1 effects, or a population-dependent effect - are given for its separate
    failure to replicate the earlier MICA associations with attack frequency and
    age of onset, and should not be transferred to the amyloidosis result.
  attaches_to:
  - pathophysiology#Sustained Elevation of Circulating Serum Amyloid A
  status: OPEN
  evidence:
  - reference: PMID:15018633
    reference_title: "Amyloidosis in familial Mediterranean fever patients: correlation with MEFV genotype and SAA1 and MICA polymorphisms effects."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Moreover, no specific MICA genotype or allele was significantly associated
      with the development of amyloidosis
    explanation: >-
      Directly refutes a MICA-amyloidosis association in the cohort that tested
      it, which is why MICA is not curated as a susceptibility or modifier locus
      here.
  - reference: PMID:15018633
    reference_title: "Amyloidosis in familial Mediterranean fever patients: correlation with MEFV genotype and SAA1 and MICA polymorphisms effects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      no association was found between the MICA gene exon 5 polymorphism and the
      development of renal amyloidosis in FMF patients, whereas the alpha allele
      and the alpha/alpha genotype of the SAA1 gene were associated with this
      severe phenotype
    explanation: >-
      The authors' own conclusion, contrasting the null MICA result with the
      positive SAA1 result in the same patients - the asymmetry that justifies
      curating SAA1 but not MICA.
animal_models:
- species: Mus musculus
  genotype: Wild-type mice given an inflammatory stimulus, with or without amyloid-enhancing factor
  category: Induced (non-transgenic) AA amyloidosis model
  description: >-
    AA amyloidosis is unusual among systemic amyloidoses in having a reliable
    induced rodent model that needs no transgene: a chronic inflammatory stimulus
    (casein, silver nitrate) raises murine SAA and produces amyloid deposits,
    and co-administration of amyloid-enhancing factor - an extract of
    amyloid-laden tissue from a previously affected animal - collapses the
    induction lag phase to days. That lag-phase collapse is the direct
    experimental evidence for the nucleation-dependent seeding arm of this
    entry's mechanistic hypotheses, and the same system demonstrated
    cross-seeding by heterologous non-mammalian fibrils. Limitation: the model
    depends on an exogenous inflammatory stimulus and an exogenous seed rather
    than on spontaneous chronic autoimmune disease, so it does not reproduce the
    decades-long, SAA1-genotype-modulated human natural history.
  associated_phenotypes:
  - Splenic, hepatic, and renal amyloid deposition
  evidence:
  - reference: PMID:15829582
    reference_title: "Protein fibrils in nature can enhance amyloid protein A amyloidosis in mice: Cross-seeding as a disease mechanism."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Preformed amyloid-like fibrils act as nuclei in amyloid fibril formation in
      vitro, and AA amyloid fibrils and synthetic amyloid-like fibrils also may
      serve as seed for fibril formation in vivo.
    explanation: >-
      States the seeding principle the murine induction model is used to test,
      and that preformed fibrils act as nuclei in vivo.
  - reference: PMID:15829582
    reference_title: "Protein fibrils in nature can enhance amyloid protein A amyloidosis in mice: Cross-seeding as a disease mechanism."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We studied three such naturally occurring protein fibrils: silk from Bombyx
      mori, Sup35 from Saccharomyces cerevisiae, and curli from Escherichia coli.
    explanation: >-
      Describes the specific heterologous fibrils tested in the murine model,
      documenting the experimental design underlying the cross-seeding result.
classifications:
  harrisons_chapter:
  - classification_value: IMMUNE_RHEUMATOLOGIC
  - classification_value: KIDNEY_URINARY_TRACT
  mechanistic_category:
  - classification_value: amyloidopathy
notes: >-
  GeneReviews baseline (curation SOP step 3b) does not apply here. AA amyloidosis
  is an acquired complication of chronic inflammation, not a Mendelian disorder,
  and a PubMed search for a GeneReviews chapter returned only chapters for the
  monogenic trigger diseases (Familial Mediterranean Fever, PMID:20301405; TNF
  Receptor-Associated Periodic Fever Syndrome, PMID:36375008), which are curated
  as separate dismech entries. Cardiac amyloidosis, peripheral neuropathy, and
  macroglossia are deliberately NOT curated as phenotypes here; they are uncommon
  in AA and are recorded instead as discriminators under the AL differential
  diagnosis. Note the nuance on macroglossia: PMID:38568326 does list it among
  the presenting gastrointestinal symptoms of AA amyloidosis, in a sentence this
  entry quotes for malabsorption and weight loss, so it is not absent from AA -
  it is merely far less frequent than in AL, which is what makes it useful as a
  discriminator rather than as an AA phenotype.

  Thyroid and adrenal involvement are likewise uncurated. The only available
  statement ("Involvements of the thyroid, adrenals, and the nervous system might
  also be encountered") carries no frequency and no specific functional claim, so
  binding it to an HPO term would assert more precision than the source supports.

  `evidence_source` convention for PMID:38568326, which appears in this file with
  two different values: `HUMAN_CLINICAL` where the review makes a direct clinical
  observation about AA amyloidosis patients, and `OTHER` where it reports the
  numbers of a specific primary series it is summarizing (the colchicine 960-patient
  cohort, the anti-TNF 15- and 36-patient studies, the 42-patient tocilizumab
  comparison), and also where it makes a general narrative or background
  statement rather than a patient-level observation. Both of the latter cases are
  secondary reporting and are marked as such; every item states its reason
  inline.

  The rare autosomal-dominant SAA1-promoter form of hereditary AA
  amyloidosis reported in Kidney International (2021) is not curated, because the
  deep-research report supplied no verifiable PMID for it; it is a candidate
  subtype if a citable identifier is confirmed.

  Two evidence choices are worth stating explicitly. First, the anti-TNF
  treatment entry and several extrarenal phenotypes are cited to the full text of
  the PMID:38568326 review rather than to the primary series it summarizes,
  because the primary PMIDs for those series could not be independently resolved;
  quoting the review verbatim is preferred here over guessing an identifier.
  Second, Eprodisate carries no `therapeutic_agent`: both NCIT eprodisate terms
  (NCIT:C166957, NCIT:C65520) exist but are outside the `ChemicalEntityTerm`
  dynamic enum, and CHEBI has no eprodisate entry, so there is no valid
  ontology binding to give it.

  Nephroprotective supportive care (ACE inhibitors / ARBs) is deliberately not
  curated as a treatment: it is standard practice for proteinuric kidney disease
  generally, but no quotable AA-specific statement was found in the cached
  sources, and a treatment entry without evidence would be worse than its
  absence.
references:
- reference: "PMID:7986228"
  title: "Colchicine treatment of AA amyloidosis of familial Mediterranean fever. An analysis of factors affecting outcome."
- reference: "PMID:12687559"
  title: "The contribution of genotypes at the MEFV and SAA1 loci to amyloidosis and disease severity in patients with familial Mediterranean fever."
- reference: "PMID:15018633"
  title: "Amyloidosis in familial Mediterranean fever patients: correlation with MEFV genotype and SAA1 and MICA polymorphisms effects."
- reference: "PMID:15829582"
  title: "Protein fibrils in nature can enhance amyloid protein A amyloidosis in mice: Cross-seeding as a disease mechanism."
- reference: "PMID:16737350"
  title: "Acute-phase serum amyloid A: an inflammatory adipokine and potential link between obesity and its metabolic complications."
- reference: "PMID:17554116"
  title: "Eprodisate for the treatment of renal disease in AA amyloidosis."
- reference: "PMID:17554117"
  title: "Natural history and outcome in systemic AA amyloidosis."
- reference: "PMID:17714761"
  title: "Clinical and histological characteristics of renal AA amyloidosis: a retrospective study of 68 cases with a special interest to amyloid-associated inflammatory response."
- reference: "PMID:18815155"
  title: "Increased susceptibility of serum amyloid A 1.1 to degradation by MMP-1: potential explanation for higher risk of type AA amyloidosis."
- reference: "PMID:19549924"
  title: "Heparan sulfate promotes the aggregation of HDL-associated serum amyloid A: evidence for a proamyloidogenic histidine molecular switch."
- reference: "PMID:25387054"
  title: "AA amyloidosis: pathogenesis and targeted therapy."
- reference: "PMID:26120866"
  title: "Therapeutic blockade of interleukin-6 by tocilizumab in the management of AA amyloidosis and chronic inflammatory disorders: a case series and review of the literature."
- reference: "PMID:26176329"
  title: "Therapeutic Clearance of Amyloid by Antibodies to Serum Amyloid P Component."
- reference: "PMID:28828707"
  title: "Pathology and diagnosis of renal non-AL amyloidosis."
- reference: "PMID:29288051"
  title: "Acceleration of amyloid fibril formation by carboxyl-terminal truncation of human serum amyloid A."
- reference: "PMID:29364741"
  title: "Obesity is a significant susceptibility factor for idiopathic AA amyloidosis."
- reference: "PMID:29768139"
  title: "Canakinumab for the Treatment of Autoinflammatory Recurrent Fever Syndromes."
- reference: "PMID:37741608"
  title: "Kidney Transplantation in Patients With AA Amyloidosis: Outcomes in a French Multicenter Cohort."
- reference: "PMID:38568326"
  title: "AA Amyloidosis: A Contemporary View."
- reference: "PMID:39954777"
  title: "Serum Amyloid A Binding to Glycosaminoglycans is Synergistic with Amyloid Formation: Therapeutic Targeting in the Inflammation-linked Amyloidosis."
- reference: "PMID:40516176"
  title: "AA amyloidosis in inflammatory joint diseases: A systematic review."
- reference: "PMID:41670232"
  title: "Tocilizumab prevented the progression of AA amyloidosis derived from adult-onset Still's disease."

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References & Deep Research

References

22

PMID:7986228

Colchicine treatment of AA amyloidosis of familial Mediterranean fever. An analysis of factors affecting outcome.