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 MEV 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]

Short Case Viva — A chronic urticarial rash

Examination instruction

"Examine this patient's skin, then present your findings and discuss the differential of a chronic urticarial rash." [1]

Systematic examination routine

1. Inspect the skin — describe the rash: chronic urticarial lesions, distribution (trunk and limbs), whether they leave bruising, whether they are cold-induced, and whether there is scarring or pigmentation. Note whether the rash is present continuously or intermittently.
2. Examine for syndrome-specific signs — hearing aids or cochlear implants (Muckle-Wells syndrome), joint deformity and bony overgrowth (NOMID/CINCA), hepatosplenomegaly and lymphadenopathy (AOSD, MAS), periorbital oedema (TRAPS), oral and genital ulceration (Behcet).
3. Examine for complications — pitting oedema and hypertension (AA amyloid nephropathy), digital clubbing and papilloedema on fundoscopy (NOMID with chronic raised intracranial pressure).
4. Take a targeted history — age of onset (infancy suggests CAPS), family history (autosomal dominant in CAPS and TRAPS), cold triggering (FCAS), hearing loss (Muckle-Wells), a prior monoclonal paraprotein (Schnitzler), fever pattern (AOSD). [1]

Presentation template

"This patient has a chronic urticarial rash present since childhood, with bilateral hearing aids indicating sensorineural hearing loss. The combination of chronic urticaria and progressive sensorineural hearing loss, with an autosomal dominant family history, is characteristic of Muckle-Wells syndrome, a cryopyrin-associated periodic syndrome caused by a gain-of-function mutation in NLRP3. [1]

I would confirm with NLRP3 genetic testing, a skin biopsy to demonstrate neutrophilic urticarial dermatosis (distinguishing it from ordinary mast-cell-driven urticaria), and baseline urinalysis and serum amyloid A to screen for AA amyloidosis. The treatment is canakinumab 150 mg subcutaneously every 8 weeks, an interleukin-1 beta blocker that halts further hearing loss and prevents amyloidosis." [1]

Discussion questions

Examiner: How do you distinguish autoinflammatory from autoimmune disease at the bedside? [1]

"The distinction is innate versus adaptive immunity. Autoinflammatory disease is driven by excessive activation of innate immune pathways — inflammasomes and the cytokines they release, chiefly interleukin-1 beta — without high-titre autoantibodies or antigen-specific lymphocyte responses. The autoantibody screen is typically negative, the inflammation is often episodic (in the periodic fever syndromes) or continuous (in the CAPS spectrum), and the treatment targets cytokines rather than lymphocytes. [1]

Autoimmune disease, in contrast, arises from loss of adaptive immune tolerance — autoreactive T cells and high-titre autoantibodies such as anti-dsDNA in lupus, anti-CCP in rheumatoid arthritis, or ANCA in the ANCA-associated vasculitides. A patient with recurrent fever and a relentlessly negative autoimmune screen is the classic autoinflammatory presentation. Two diseases sit at the interface: adult-onset Still disease, which is autoinflammatory in mechanism but acquired, and Behcet disease, which is partly autoinflammatory and partly vasculitic." [1]

Examiner: What is the role of interleukin-1 blockade, and when do you reach for it? [1]

"Interleukin-1 blockade is transformative for a defined group of autoinflammatory diseases in which interleukin-1 beta is the dominant driver. The IL-1-dependent syndromes are the cryopyrin-associated periodic syndromes (CAPS, where the mutant NLRP3 inflammasome is constitutively active), mevalonate kinase deficiency (HIDS), colchicine-resistant familial Mediterranean fever, TNF receptor-associated periodic syndrome (TRAPS), adult-onset Still disease, and Schnitzler syndrome. [1]

Three agents are available: canakinumab, a monoclonal antibody against interleukin-1 beta given every 8 weeks; anakinra, a recombinant interleukin-1 receptor antagonist given daily; and rilonacept, an interleukin-1 trap given weekly. Canakinumab is the preferred long-term agent for CAPS and the hereditary recurrent fevers, with the CLUSTER trial underpinning approval in colchicine-resistant FMF, HIDS and TRAPS [3][5]. Anakinra is the preferred first IL-1 blocker in AOSD and Schnitzler, where its rapid onset makes it useful as a diagnostic-therapeutic probe. I reach for IL-1 blockade early in any confirmed IL-1-driven syndrome, because it reduces cumulative steroid exposure and, in CAPS, prevents irreversible hearing loss."

Examiner: How reliable is genetic testing, and what do you do when the panel is negative? [1]

"Genetic testing is confirmatory but not perfect, and I treat the patient, not the genotype. Two cautions apply. First, a variant of uncertain significance is a common result and must be interpreted in the clinical context — a pathogenic-looking variant in a gene consistent with the phenotype supports the diagnosis, but a variant of uncertain significance does not confirm or exclude it. Second, a negative panel does not exclude a hereditary recurrent fever, because novel genes, incomplete penetrance and somatic mosaicism (especially in NLRP3 in CAPS, where up to a third of patients are somatic mosaic and negative on standard blood testing) occur. [1]

When the panel is negative but the clinical phenotype is compelling, I manage on the clinical pattern — attack duration, organ involvement, ancestry and family history — and treat with the appropriate cytokine blocker. A therapeutic trial of anakinra, with a brisk response supporting an IL-1-driven process, is a legitimate diagnostic-therapeutic manoeuvre. I would re-test or use more comprehensive sequencing (including somatic mosaic testing on multiple tissues) if the clinical phenotype strongly suggests a specific syndrome." [1]