Systemic Autoinflammatory Syndromes — Written Clinical Reasoning

SAQ 1 — Familial Mediterranean fever complicated by AA amyloidosis (20 marks, 30 minutes)

Model answer

Diagnosis and pathophysiology (4 marks) [1]

This patient has familial Mediterranean fever (FMF) complicated by AA amyloidosis. The combination of Mediterranean ancestry, recurrent brief attacks (one to two days) of fever and serositis (abdominal pain mimicking an acute abdomen), a previous negative laparotomy or appendicectomy, complete wellness between attacks, and new proteinuria is classic. The Tel Hashomer criteria — one major criterion (typical abdominal attack) or two minor criteria — establish the diagnosis with a sensitivity above 95 per cent [1].

FMF is caused by autosomal recessive mutations in MEFV, encoding pyrin, which regulates the pyrin inflammasome. Mutant pyrin constitutively activates the inflammasome, driving interleukin-1 beta and interleukin-18 release and neutrophil-mediated serositis. The peritonitis reflects neutrophil infiltration of the peritoneum during an attack. The new proteinuria reflects AA amyloid deposition in the kidney from years of persistent subclinical inflammation — the feared and preventable complication of inadequately treated FMF. [1]

Immediate management (5 marks) [1]

1. Confirm the diagnosis with MEFV genetic testing (targeted autoinflammatory gene panel), a serum amyloid A level (elevated, indicating ongoing inflammation), and a renal biopsy to confirm AA amyloidosis if the diagnosis is uncertain.
2. Start colchicine immediately — 1.5 mg orally daily (commonly 0.5 mg three times daily), titrated to the maximum tolerated dose that completely prevents attacks. The goal is complete attack prevention, not attack reduction, because colchicine prevents further AA amyloid deposition [2].
3. Do NOT perform laparotomy for an acute abdominal attack — a careful history of recurrent self-limiting attacks prevents unnecessary surgery. NSAIDs manage the acute pain.
4. Assess renal function — full renal workup with creatinine, eGFR, urinary albumin-to-creatinine ratio, and nephrology referral given the proteinuria.
5. Screen for amyloidosis complications — renal function, liver function and, if indicated, an echocardiogram for cardiac amyloid.

Long-term management and surveillance (5 marks) [1]

• Lifelong colchicine is the cornerstone. The dose is titrated to complete attack prevention, monitored by attack diary and serum amyloid A. Gastrointestinal intolerance (diarrhoea) is the main adverse effect; reduce the dose in renal impairment and monitor full blood count for myelosuppression.
• Canakinumab for colchicine-resistant FMF — for patients who do not achieve complete attack control on the maximum tolerated colchicine dose, canakinumab 150 mg subcutaneously every 8 weeks is the evidence-based IL-1 blocker, approved on the basis of the CLUSTER trial [3].
• AA amyloidosis surveillance — urinalysis for proteinuria and serum amyloid A at every follow-up visit (every 3 to 6 months). Any new proteinuria or rising serum amyloid A mandates intensification of therapy.
• Cascade family testing — siblings should be screened with a careful attack history, urinalysis and serum amyloid A, with genetic counselling and MEFV testing where indicated.
• Monitor colchicine toxicity — full blood count, liver function and renal function every 3 to 6 months. Counsel the patient on the danger of colchicine overdose (multi-organ failure) and the need for dose reduction in renal impairment.

Key differentials to exclude (3 marks) [1]

Communication and follow-up (3 marks) [1]

• Frame the diagnosis as a genuine lifelong condition with effective treatment — the shift from recurrent unexplained attacks to a named, treatable diagnosis is therapeutic for a patient who has often been dismissed for years.
• Explain the colchicine contract: the goal is complete attack prevention and amyloidosis prevention, not just fewer attacks; adherence is the single biggest determinant of long-term renal outcome.
• Address the psychosocial impact of a delayed diagnosis and a preventable complication, and the implications for siblings and future children. Genetic counselling should be offered before cascade family testing. [1]

SAQ 2 — Adult-onset Still disease and the cytokine-directed approach (10 marks, 20 minutes)

Question

A 36-year-old man presents with a two-week history of spiking evening fevers to 39.5 degrees Celsius, an evanescent salmon-pink rash on his trunk, a sore throat and a polyarthritis of the wrists and knees. His white cell count is 16,000 per cubic millimetre with 86 per cent neutrophils, ferritin is 2800 micrograms per litre, and ANA and rheumatoid factor are negative. Blood cultures, echocardiogram and CT for malignancy are negative. Outline the diagnosis, the investigations that confirm it, the cytokine-directed treatment, and the complication you must monitor for. [1]

Model answer

Diagnosis (2 marks) [1]

This patient has adult-onset Still disease (AOSD), meeting the Yamaguchi criteria: fever above 39 degrees for over a week (major), arthralgia for over two weeks (major), a typical non-pruritic salmon-pink rash (major), leukocytosis above 10,000 with 80 per cent or more neutrophils (major), sore throat (minor), and negative ANA and rheumatoid factor (minor) — five criteria with more than two major, after exclusion of infection, malignancy and autoimmune disease [4]. The ferritin above 1000 micrograms per litre with a low glycosylated fraction supports the diagnosis. AOSD is a polygenic autoinflammatory disease driven by interleukin-1 beta (fever), interleukin-6 (arthritis) and interleukin-18 (macrophage activation).

Confirmatory investigations (3 marks) [1]

• Ferritin and glycosylated ferritin — a ferritin above 1000 with a glycosylated fraction below 20 per cent supports AOSD but is not specific, so exclusion of mimics is mandatory.
• Infection exclusion — serial blood cultures, echocardiogram for endocarditis, viral serology (HIV, hepatitis, EBV, CMV, parvovirus), and a tuberculosis screen.
• Malignancy exclusion — lactate dehydrogenase, peripheral blood film, and CT of the chest, abdomen and pelvis; bone marrow biopsy if haematological malignancy is suspected.
• Autoimmune exclusion — ANA, anti-dsDNA, ANCA, rheumatoid factor and anti-CCP, complement and cryoglobulins. [1]

Cytokine-directed treatment (3 marks) [1]

1. NSAIDs and glucocorticoids for induction. Mild disease may respond to NSAIDs alone; most patients need prednisolone 0.5 to 1 mg/kg daily, tapered with a steroid-sparing agent.
2. Interleukin-1 blockade (anakinra) early. Anakinra, a recombinant IL-1 receptor antagonist (100 mg subcutaneously daily, up to 4 to 8 mg/kg daily in severe disease), produces a rapid response in the systemic phenotype and has a diagnostic-therapeutic overlap — a brisk response supports the diagnosis. Early IL-1 blockade reduces cumulative steroid exposure.
3. Interleukin-6 blockade (tocilizumab) for the articular or chronic phenotype, or when IL-1 blockade fails. Tocilizumab (8 mg/kg intravenously every 4 weeks, or 162 mg subcutaneously weekly) is particularly effective for sustained remission of the arthritis. [1]

Complication to monitor — macrophage activation syndrome (2 marks) [1]

Macrophage activation syndrome (MAS) is a feared and life-threatening complication of AOSD. It presents with persistent high fever, hepatosplenomegaly, pancytopenia, a markedly elevated ferritin (often above 10,000 micrograms per litre), hypertriglyceridaemia, hypofibrinogenaemia and elevated soluble interleukin-2 receptor. Treatment is high-dose glucocorticoids plus anakinra; etoposide is used in refractory haemophagocytic lymphohistiocytosis. MAS must be recognised early because it is rapidly fatal — a rising ferritin with falling blood counts in a febrile AOSD patient is an emergency. [1]