Systemic Autoinflammatory Syndromes — Viva

Long Case Viva Defence

Candidate's opening statement (model answer)

"Mr Yusuf Demir is a 28-year-old carpenter of Turkish ancestry presenting with a 12-year history of recurrent attacks of fever and severe abdominal pain, each lasting one to two days and resolving completely, with a previous negative laparotomy at age 20. He now presents with proteinuria on urinalysis and a serum creatinine of 130, from a baseline of 80. Between attacks he is entirely well. ^[1]

His problem list is: (1) familial Mediterranean fever, almost certainly undiagnosed for over a decade, now complicated by (2) AA amyloidosis with proteinuria and early chronic kidney disease; (3) a colchicine initiation and titration plan aimed at complete attack prevention and amyloidosis arrest; (4) genetic confirmation with MEFV testing and cascade family testing; (5) the psychosocial impact of a delayed diagnosis and a preventable complication; and (6) the implications for his siblings and future children. ^[1]

This is a chronic disease with effective treatment. My immediate management is to start colchicine 1.5 mg daily, confirm the diagnosis with MEFV genetic testing and a renal biopsy for AA amyloidosis, and arrange genetic counselling for the family." ^[1]

Examiner probing questions and model answers

Examiner: Walk me through your diagnostic reasoning in detail. ^[1]

"The combination of Mediterranean ancestry, recurrent brief attacks of fever and serositis, a previous negative laparotomy, and complete wellness between attacks is the classic presentation of familial Mediterranean fever. The attack duration of one to two days is the key discriminator — HIDS attacks last 3 to 7 days and TRAPS attacks last 1 to 3 weeks, so the brevity points strongly to FMF. The new proteinuria is the red flag: it indicates AA amyloidosis, the feared and largely preventable complication of inadequately treated FMF, in which persistent subclinical inflammation drives serum amyloid A overproduction and renal deposition. ^[1]

I would apply the Tel Hashomer criteria — one major criterion, in his case a typical abdominal attack of peritonitis, establishes the diagnosis with a sensitivity above 95 per cent and specificity above 97 per cent ^[1]. I would confirm with a targeted MEFV genetic test (looking for the common pathogenic variants such as M694V), a serum amyloid A level to document ongoing inflammation, and a renal biopsy to confirm AA amyloid deposition."

Examiner: What is the pathophysiology, and how does it explain the treatment? ^[1]

"FMF is caused by autosomal recessive mutations in MEFV, which encodes pyrin, a regulator of the pyrin inflammasome. Mutant pyrin constitutively activates the inflammasome, driving interleukin-1 beta and interleukin-18 release and neutrophil-mediated serositis — which is why he gets peritonitis (neutrophil infiltration of the peritoneum) during each attack. The episodic, self-limiting nature reflects the intermittent activation of this innate immune pathway. ^[1]

This mechanism explains the treatment. Colchicine works by inhibiting microtubule-dependent inflammasome assembly and neutrophil function, which is why it prevents attacks. The therapeutic target is complete attack prevention, because persistent subclinical inflammation — even without overt attacks — drives serum amyloid A overproduction and AA amyloidosis. For patients who do not achieve complete control on the maximum tolerated colchicine dose, canakinumab targets the interleukin-1 beta that the mutant pyrin inflammasome overproduces ^[2][3]."

Examiner: Why was the diagnosis missed for 12 years, and what does that tell you about the disease? ^[1]

"FMF attacks mimic an acute surgical abdomen — severe diffuse abdominal pain with guarding and rigidity — which is why he had a negative laparotomy. The episodic nature and full inter-attack wellness, plus low awareness among non-specialists, drive diagnostic delay. The average delay from symptom onset to diagnosis in FMF is several years, and many patients accumulate unnecessary investigations and surgeries in that time. ^[1]

The lesson is that any patient of Mediterranean ancestry with recurrent self-limiting attacks of fever and abdominal pain, particularly with a prior negative laparotomy or appendicectomy, should be assessed for FMF with a serum amyloid A level, a urinalysis for proteinuria, and a targeted genetic panel. Early diagnosis and colchicine prevent AA amyloidosis entirely." ^[1]

Examiner: What is your surveillance plan once colchicine is started? ^[1]

"My surveillance plan has three arms. First, attack surveillance — the patient keeps a symptom diary and we aim for zero attacks; any breakthrough attack mandates colchicine dose escalation up to the maximum tolerated dose (typically 2 mg daily), and canakinumab if control is still incomplete. ^[1]

Second, AA amyloidosis surveillance — urinalysis for proteinuria and a serum amyloid A level every 3 to 6 months. Any new proteinuria or rising serum amyloid A is an indication to intensify therapy, because the amyloidosis is the principal cause of death in untreated FMF. ^[1]

Third, colchicine toxicity surveillance — full blood count, liver function and renal function every 3 to 6 months, with dose reduction in renal impairment. I would counsel the patient that colchicine overdose is dangerous (multi-organ failure) and that several drugs interact with colchicine (clarithromycin, statins, ciclosporin), requiring dose adjustment ^[2]."

Examiner: What about the family? ^[1]

"FMF is autosomal recessive, so each sibling has a one-in-four chance of being affected (though penetrance is variable). I would arrange genetic counselling and offer cascade testing of siblings with a careful attack history, urinalysis for proteinuria, serum amyloid A, and MEFV genetic testing where the history is suggestive. This is important because a sibling with subclinical inflammation is at risk of AA amyloidosis and could benefit from prophylactic colchicine. For family planning, I would offer carrier testing to the patient's partner, given the high carrier frequency in Mediterranean populations." ^[1]