Question
A 52-year-old man attends the acute medical unit with episodic severe abdominal discomfort, fever, painful swollen joints, and pleuritic central chest pain. He reports that similar attacks have occurred several times over the past few years, each episode lasting about 2–4 days and resolving spontaneously. He was born and raised in southeastern Turkey.
On assessment:
- Pulse: 88 beats/min
- Blood pressure: 126/80 mmHg
- Temperature: 38.6°C
Clinical examination reveals diffuse abdominal tenderness without guarding, an effusion in the right knee and left ankle, and sharp chest pain that improves when he sits forward. Blood tests show raised inflammatory markers. He is started on colchicine with rapid resolution of symptoms.
What is the most likely diagnosis?
A. Systemic vasculitis with mucocutaneous involvement
B. Post-myocardial infarction inflammatory syndrome
C. Hereditary periodic fever syndrome
D. Crystal-induced inflammatory arthritis
E. Post-infectious spondyloarthropathy
Answer
C. Hereditary periodic fever syndrome (Familial Mediterranean Fever)
Detailed Discussion
This presentation is classic for Familial Mediterranean Fever (FMF), an inherited autoinflammatory condition characterised by recurrent, self-limiting attacks of fever and serosal inflammation. The key diagnostic clues in this case are the ethnic background (Turkish), recurrent short-lived episodes (2–4 days), involvement of multiple serosal surfaces (peritonitis causing abdominal pain, synovitis causing arthritis, and pericarditis/pleuritis causing chest pain), and the dramatic response to colchicine.
FMF is caused by mutations in the MEFV gene, which encodes pyrin, a protein involved in regulation of the innate immune response. Mutations lead to inappropriate activation of the inflammasome and excessive production of interleukin-1β, resulting in episodic inflammation. It is classically autosomal recessive, though heterozygotes may sometimes be symptomatic.
Attacks usually begin in childhood or adolescence, but delayed diagnosis into adulthood is common, particularly in milder phenotypes. Episodes typically last 1–3 days, resolve completely, and recur at variable intervals. Between attacks, patients are usually asymptomatic.
A crucial exam and clinical point is that untreated FMF can lead to AA amyloidosis, particularly affecting the kidneys, resulting in proteinuria and progressive renal failure. Lifelong colchicine therapy is therefore not only symptomatic treatment but also prevents amyloid deposition, making early recognition essential.
Differentials such as Behçet disease are important in patients from Turkey, but Behçet is defined by recurrent oral and genital ulcers, uveitis, and vasculitis, which are absent here. Reactive arthritis typically follows a gastrointestinal or genitourinary infection and is associated with urethritis and conjunctivitis, not peritonitis or pericarditis. Dressler syndrome occurs weeks after myocardial infarction and does not explain recurrent abdominal or joint symptoms. Gout may respond to colchicine but does not cause serositis or fever of this pattern.
Diagnosis is largely clinical, supported by criteria such as the Tel-Hashomer criteria, genetic testing, and response to colchicine. In colchicine-resistant cases, IL-1 inhibitors (e.g., anakinra, canakinumab) are effective and increasingly used.
For MRCP candidates, FMF is a high-yield diagnosis whenever short, recurrent inflammatory attacks with serositis occur in patients of Mediterranean or Middle Eastern origin.
Exam Cheat Sheet – Familial Mediterranean Fever
- Inheritance: Autosomal recessive
- Gene: MEFV (pyrin)
- Ethnic groups: Turkish, Armenian, Arab, Jewish
- Attack duration: 1–3 days
- Key features:
- Fever
- Peritonitis → abdominal pain
- Pleuritis / pericarditis → chest pain
- Mono- or oligo-arthritis (ankle, knee)
- Erysipelas-like rash on legs
- Between attacks: Normal health
- Major complication: AA amyloidosis → renal failure
- Treatment: Lifelong colchicine
- Colchicine-resistant: IL-1 inhibitors
- Diagnostic pearl: Dramatic response to colchicine
Flash Cards
Q: What gene is mutated in FMF?
A: MEFV gene encoding pyrin
Q: Typical duration of FMF attacks?
A: 1–3 days
Q: Most feared long-term complication of FMF?
A: AA amyloidosis
Q: First-line treatment for FMF?
A: Colchicine
Q: Which cytokine drives inflammation in FMF?
A: Interleukin-1β
Q: Most common joints involved?
A: Ankle and knee
Q: Is FMF autoimmune or autoinflammatory?
A: Autoinflammatory
Q: Can FMF patients be asymptomatic between attacks?
A: Yes
Q: Typical ethnic association of FMF?
A: Mediterranean / Middle Eastern
Q: What rash may be seen in FMF?
A: Erysipelas-like erythema
MCQs (Exam-Oriented)
- FMF is best classified as:
A. Autoimmune disease
B. Immune complex vasculitis
C. Autoinflammatory disorder
D. Paraneoplastic syndrome
E. Post-infectious arthritis
Answer: C - The protein affected in FMF is involved in regulation of:
A. Adaptive immunity
B. Complement cascade
C. Inflammasome activation
D. Antibody production
E. T-cell tolerance
Answer: C - Which feature most strongly supports FMF over Behçet disease?
A. Ethnic origin
B. Fever
C. Recurrent short attacks
D. Response to steroids
E. Absence of oral ulcers
Answer: E - Which complication is prevented by colchicine in FMF?
A. Vasculitis
B. Uveitis
C. Amyloidosis
D. Thrombosis
E. Osteoporosis
Answer: C - Typical age of onset of FMF is:
A. Neonatal period
B. Childhood/adolescence
C. Late adulthood
D. After menopause
E. Only after infections
Answer: B - FMF attacks most commonly involve which system?
A. Central nervous system
B. Respiratory parenchyma
C. Serosal surfaces
D. Endocrine glands
E. Skin only
Answer: C - Which drug targets IL-1 and may be used in colchicine-resistant FMF?
A. Etanercept
B. Tocilizumab
C. Anakinra
D. Rituximab
E. Methotrexate
Answer: C - FMF inheritance pattern is usually:
A. Autosomal dominant
B. X-linked recessive
C. Mitochondrial
D. Autosomal recessive
E. Polygenic
Answer: D - Which laboratory abnormality is typical during an attack?
A. Low ESR
B. Neutropenia
C. Raised CRP
D. Low ferritin
E. Hypocomplementemia
Answer: C - A patient with FMF is asymptomatic between attacks because:
A. Immune suppression persists
B. Disease is degenerative
C. Inflammation is episodic
D. Autoantibodies disappear
E. Pyrin is overexpressed
Answer: C
- Which clinical feature most strongly differentiates Familial Mediterranean Fever (FMF) from reactive arthritis?
A. Asymmetric oligoarthritis
B. Preceding diarrhoeal illness
C. Recurrent peritonitis
D. Conjunctivitis
E. Sacroiliac pain
Answer: C - The inflammatory pathway primarily dysregulated in FMF involves:
A. TNF-α overexpression
B. Autoantibody-mediated immune complexes
C. Excess IL-1β production
D. Reduced IL-10 activity
E. Interferon-γ deficiency
Answer: C - Which joint pattern is most typical of FMF-related arthritis?
A. Symmetrical small joint polyarthritis
B. Chronic erosive arthritis
C. Monoarthritis of ankle or knee
D. Axial inflammatory arthritis
E. Distal interphalangeal arthritis
Answer: C - Which statement regarding FMF attacks is most accurate?
A. They usually last several weeks
B. They progress inexorably with each episode
C. They resolve completely between episodes
D. They are always triggered by infection
E. They respond best to NSAIDs alone
Answer: C - In untreated FMF, amyloid deposition most commonly affects which organ first?
A. Liver
B. Heart
C. Brain
D. Kidney
E. Spleen
Answer: D - Which laboratory finding is most likely during an acute FMF flare?
A. Reduced ESR and CRP
B. Raised serum amyloid A
C. Low white cell count
D. Hypocomplementemia
E. Positive ANA
Answer: B - A patient with suspected FMF has normal genetic testing. What is the most appropriate next step?
A. Exclude FMF definitively
B. Start high-dose steroids
C. Trial colchicine therapy
D. Perform renal biopsy
E. Start IL-6 inhibitor
Answer: C - Which of the following best explains why colchicine is used lifelong in FMF?
A. It cures the genetic defect
B. It prevents future arthritis
C. It reduces cardiovascular risk
D. It prevents secondary amyloidosis
E. It suppresses adaptive immunity
Answer: D - Which ethnic group has the highest prevalence of FMF?
A. Northern European
B. East Asian
C. Turkish
D. Sub-Saharan African
E. South American
Answer: C - A patient with FMF continues to have frequent attacks despite maximum tolerated colchicine. Which therapy is most appropriate?
A. Azathioprine
B. Methotrexate
C. Anti-TNF therapy
D. IL-1 receptor antagonist
E. Cyclophosphamide
Answer: D
Summary for Quick Exam Revision
Familial Mediterranean Fever is an autosomal recessive autoinflammatory disorder caused by mutations in the MEFV gene, leading to inappropriate inflammasome activation and excess IL-1β production. It predominantly affects individuals of Turkish, Armenian, Arab, or Jewish descent and presents with recurrent, short-lived episodes of fever and serositis. Typical manifestations include abdominal pain from peritonitis, pleuritic or pericardial chest pain, and acute mono- or oligo-arthritis affecting large joints such as the ankle or knee. Attacks last 1–3 days and patients are completely well between episodes. Diagnosis is primarily clinical, supported by Tel-Hashomer criteria, genetic testing, and response to colchicine. Lifelong colchicine is the cornerstone of treatment and crucially prevents AA amyloidosis, the most serious long-term complication, particularly affecting the kidneys. In colchicine-resistant cases, IL-1 inhibitors are effective. FMF should always be considered in recurrent inflammatory syndromes with serositis in patients from Mediterranean or Middle Eastern backgrounds, making it a high-yield diagnosis for MRCP examinations.