Amyloidosis in Rheumatic Disease

Amyloidosis is a group of disorders characterised by extracellular deposition of misfolded protein in an abnormal fibrillar configuration. In the context of rheumatic disease, the two clinically relevant forms are AA (secondary) amyloidosis driven by chronic systemic inflammation, and AL (primary) amyloidosis caused by monoclonal immunoglobulin light chain deposition from plasma cell dyscrasia. Both lead to progressive organ dysfunction through disruption of normal tissue architecture and can be fatal if undiagnosed.

Secondary (AA) amyloidosis remains a serious systemic complication of inadequately controlled chronic inflammatory conditions, including rheumatoid arthritis (RA), familial Mediterranean fever (FMF), juvenile idiopathic arthritis (JIA), ankylosing spondylitis (AS), and Crohn disease. The unifying mechanism is sustained elevation of serum amyloid A (SAA), an acute-phase reactant produced by the liver under interleukin-6 (IL-6) and IL-1β stimulation.

In Australia, AA amyloidosis is rare but clinically significant. The AIHW reports that amyloidosis-related hospitalisations have a mortality rate exceeding 20% within 5 years of diagnosis. FMF is relatively prevalent among Australian communities of Middle Eastern and Mediterranean descent, particularly in Lebanese, Armenian, Turkish, and Sephardic Jewish populations. RA-related AA amyloidosis has declined markedly with early aggressive disease-modifying therapy but still occurs in patients with longstanding, poorly controlled disease. The prevalence of AL amyloidosis is estimated at 8–12 per million population per year in Australia.

AA Amyloidosis (Secondary)

AA amyloidosis develops when persistent elevation of serum amyloid A (SAA) — an acute-phase apolipoprotein synthesised predominantly by hepatocytes — leads to proteolytic cleavage and misfolding into β-pleated amyloid fibrils. These fibrils deposit extracellularly in parenchymal organs and progressively replace normal tissue architecture.

The key pathological events are:

• Sustained inflammation: IL-6 and IL-1β drive hepatic SAA production. Chronic elevations (>10 mg/L persistently for months to years) are necessary but not sufficient for amyloid formation.
• Proteolytic processing: Monocyte-derived proteases cleave SAA into the N-terminal AA fragment, which is the primary constituent of AA fibrils.
• Fibril nucleation: AA fragments polymerise into cross-β fibrils. Glycosaminoglycans and serum amyloid P component (SAP) stabilise the fibril structure, resisting proteolysis.
• Organ deposition: Kidney is the predominant site (glomerular mesangium, basement membrane); liver, spleen, GI tract, and adrenal glands are also affected.

AL Amyloidosis (Primary)

AL amyloidosis results from clonal expansion of plasma cells producing monoclonal immunoglobulin light chains (typically κ or λ) that misfold and deposit as amyloid fibrils. It is classified as a plasma cell dyscrasia and may coexist with myeloma, Waldenström macroglobulinaemia, or occur in the setting of MGUS. The light chain subtype determines organ tropism: AL deposits preferentially affect the heart, kidneys, nerves, and soft tissues.

Histological Diagnosis

All amyloid subtypes share a common histological appearance:

• Congo red staining: Amyloid deposits stain salmon-pink under conventional light microscopy.
• Apple-green birefringence under polarised light: This is the defining diagnostic feature and must be demonstrated for definitive amyloid confirmation.
• Subtyping: Immunohistochemistry (anti-AA antibody, anti-κ/λ antibodies) or mass spectrometry-based proteomics should be performed on all positive biopsies to determine the amyloid fibril type — critical for guiding therapy.

AA Amyloidosis

AA amyloidosis typically presents insidiously, with renal involvement as the dominant clinical feature. Patients often have long-standing inflammatory disease and may have proteinuria detected incidentally on urinalysis.

AL Amyloidosis

AL amyloidosis has multi-organ involvement and a broader clinical spectrum. It may mimic heart failure, nephrotic syndrome, neuropathy, or chronic diarrhoea — often simultaneously.

Biopsy Strategy

Tissue biopsy remains the cornerstone of amyloidosis diagnosis. The biopsy strategy depends on the clinical scenario and the likelihood of organ involvement.

Cardiac Assessment

Laboratory Investigations

AL Amyloidosis — Revised Mayo Clinic Staging

AL amyloidosis staging uses four prognostic biomarkers:

• NT-proBNP ≥1800 pg/mL
• hs-troponin T ≥0.025 ng/mL (or hs-troponin I elevated)
• Difference in free light chains (dFLC) ≥180 mg/L

AA Amyloidosis — Renal Prognostic Stratification

The fundamental principle in AA amyloidosis management is aggressive suppression of the underlying inflammatory disease to reduce SAA levels. The therapeutic target is sustained SAA <4 mg/L (ideally <2 mg/L). Amyloid regression can occur if SAA levels are controlled, but this requires months to years of sustained remission.

Disease-Modifying Therapy for Underlying Condition

Biologic DMARDs — Anti-TNF and Anti-IL-1

When conventional DMARDs fail to control inflammation, biologic agents targeting TNF-α or IL-1 are critical in suppressing SAA production.

Colchicine — FMF-Specific

Supportive Renal Care

• ACE inhibitors / ARBs: Recommended to reduce proteinuria and slow renal progression. Start at low dose and titrate cautiously (e.g., ramipril 2.5 mg daily → 10 mg daily).
• Diuretics: Loop diuretics for oedema management (furosemide 20–80 mg PO daily).
• Renal replacement therapy: Haemodialysis or peritoneal dialysis when eGFR <10 mL/min. Renal transplantation is an option but amyloid recurrence in the graft occurs in up to 30%.
• Antiplatelet agents: Consider in patients with nephrotic syndrome (thrombotic risk).

AL amyloidosis management requires collaboration between haematology and the relevant organ specialists (cardiology, nephrology, neurology). The goals are eradication of the clonal plasma cell population, reduction of amyloidogenic light chain production, and supportive organ management.

First-Line Chemotherapy — Bortezomib/Melphalan/Dexamethasone (VMD)

Daratumumab-Based Regimens

Anti-CD38 monoclonal antibody daratumumab has transformed AL treatment. The ANDROMEDA trial demonstrated that daratumumab-bortezomib-melphalan-dexamethasone (D-VMD) achieved higher rates of complete haematological response and organ response compared to VMD alone. D-VMD is increasingly used as first-line in Australia.

Autologous Stem Cell Transplant (ASCT)

ASCT may be considered in selected patients with AL amyloidosis. Eligibility criteria are strict given the high transplant-related mortality (TRM) in patients with cardiac involvement.

Organ Support in AL

• Cardiac: Cautious diuretics (avoid hypotension); avoid digoxin and calcium channel blockers (bind to amyloid fibrils → toxicity); pacemaker/ICD for arrhythmias. Consider heart transplantation in selected patients with otherwise favourable prognosis.
• Renal: ACE inhibitors/ARBs for proteinuria; dialysis if needed. Renal transplantation with concurrent systemic therapy.
• Neuropathic: Neuropathic pain agents (gabapentin, pregabalin); physiotherapy for functional impairment; compression garments for autonomic instability.
• Nutritional: Dietitian input for malabsorption or macroglossia-related dysphagia.

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