Familial Mediterranean Fever and Other Hereditary Autoinflammatory Diseases¶
Chapter 381 | Part 11: Immune-Mediated, Inflammatory, and Rheumatologic Disorders
KEY CLINICAL POINTS¶
- FMF is a hereditary autoinflammatory disorder characterized by recurrent fever, serositis, and amyloidosis risk.
- Colchicine is the first-line treatment, reducing attack frequency and preventing amyloidosis.
- Genetic mutations in the MEFV gene (pyrin) drive inflammasome activation, leading to IL-1 β /IL-18 release.
- Amyloidosis is most common in M694V homozygotes and requires early colchicine prophylaxis.
- Differential diagnosis includes TRAPS, HIDS/MKD, and other hereditary fever syndromes.
1. DEFINITION & OVERVIEW¶
Familial Mediterranean fever (FMF) is a prototypical hereditary autoinflammatory disease characterized by recurrent episodes of fever, serositis (peritonitis, pleuritis), and cutaneous manifestations. Amyloidosis is a major complication. Other hereditary autoinflammatory diseases include TRAPS, HIDS/MKD, MWS, FCAS, and NOMID, all involving innate immune dysregulation.
Table 381-1 The Hereditary Recurrent Fever Syndromes¶
| Feature | FMF | TRAPS | HIDS/MKD | MWS | FCAS | NOMID |
|---|---|---|---|---|---|---|
| Ethnicity | Jewish, Arab, Turkish, Armenian, Italian | Any ethnic group | Predominantl y Dutch, northern European | Any ethnic group | Any ethnic group | Any ethnic group |
| Inheritance | Recessive or dominant | Dominant | Recessive | Dominant | Dominant | Dominant |
| Gene/chromo some | MEFV/16p13. 3 | TNFRSF1A/1 2p13 | MVK/12q24 | NLRP3/1q44 | NLRP3/1q44 | NLRP3/1q44 |
| Attack length | 1–3 days | Often >7 days | 3–7 days | 1–2 days | Minutes–3 days | Continuous, with flares |
| Serosa | Pleurisy, peritonitis; asymptomatic pericardial effusions | Pleurisy, peritonitis, pericarditis | Abdominal pain, seldom peritonitis; pleurisy, pericarditis | Abdominal pain; pleurisy, pericarditis rare | Rare | Rare |
| Feature | FMF | TRAPS | HIDS/MKD | MWS | FCAS | NOMID |
|---|---|---|---|---|---|---|
| Skin | Erysipeloid erythema | Centrifugally migrating erythema | Diffuse macul opapular rash; oral ulcers | Diffuse urticaria-like rash | Cold-induced urticaria-like rash | Diffuse urticaria-like rash |
| Joints | Acute monoarthritis; chronic hip arthritis (rare) | Acute monoarthritis, arthralgia | Arthralgia, oligoarthritis | Arthralgia, large joint oligoarthritis | Polyarthralgia | Epiphyseal, patellar overgrowth, clubbing |
| Muscle | Exercise-indu ced myalgia common; protracted febrile myalgia rare | Migratory myalgia | Uncommon | Myalgia common | Sometimes myalgia | Sometimes myalgia |
| CNS | Aseptic meningitis rare | Headache | Headache | Headache | Headache | Aseptic meningitis, seizures |
| Amyloidosis | Most common in M694V homozygotes | ~15% of cases, cysteine mutations, T50M | Sometimes associated with V377I/I268T MVK genotype | ~25% of cases | Uncommon | Late complication |
| Treatment | Oral colchicine, IL-1 inhibitors | Glucocorticoi ds, IL-1 inhibitors, etanercept | NSAIDs for fever; IL-1 inhibitors | Canakinumab , rilonacept, anakinra | Canakinumab , rilonacept, anakinra | Anakinra |
1.1 Genetic Basis¶
FMF is caused by mutations in the MEFV gene encoding pyrin, a protein regulating inflammasome activation. Other syndromes involve mutations in TNFRSF1A (TRAPS), MVK (HIDS/MKD), NLRP3 (MWS, FCAS, NOMID), and other genes.
1.2 Clinical Spectrum¶
FMF presents with fever, abdominal pain, arthritis, erysipelas-like erythema, and myalgia. Amyloidosis is a late complication. Other syndromes exhibit distinct patterns (e.g., TRAPS with migratory myalgia, HIDS with periodic fever and rash).
2. EPIDEMIOLOGY¶
FMF is most common in Mediterranean and Middle Eastern populations (Jews, Armenians, Arabs, Turks). Prevalence is 1:10 among affected populations. Risk factors include M694V homozygosity, male gender, noncompliance with colchicine, and certain ethnic backgrounds. TRAPS and HIDS/MKD have distinct demographic distributions.
2.1 Demographics¶
FMF: Jewish, Arab, Turkish, Armenian, Italian populations. TRAPS: Global, with dominant inheritance. HIDS/MKD: Northern European, recessive. MWS/FCAS/NOMID: Global, with NLRP3 mutations.
2.2 Genetic Factors¶
FMF: M694V homozygosity is a major risk factor. TRAPS: R92Q/P46L variants in TNFRSF1A. HIDS/MKD: MVK mutations (V377I/I268T). NLRP3 mutations in MWS/FCAS/NOMID.
3. ETIOLOGY & PATHOPHYSIOLOGY¶
FMF is caused by pyrin mutations (MEFV gene) leading to hyperactivation of the NLRP3 inflammasome. This results in caspase-1 activation, IL-1 β /IL-18 release, and pyroptosis. Other syndromes involve mutations in TNFRSF1A (TRAPS), MVK (HIDS/MKD), and NLRP3 (MWS, FCAS, NOMID).
3.1 Molecular Mechanisms¶
Pyrin's PYRIN domain mediates inflammasome assembly. M694V mutations reduce pyrin threshold for activation. NLRP3 mutations in cryopyrinopathies cause inflammasome hyperactivation. TRAPS mutations cause TNFR1 misfolding and kinase activation.
3.2 Inflammatory Pathways¶
IL-1 β /IL-18 release drives systemic inflammation. Amyloidosis results from serum amyloid A (SAA) deposition. Inflammasome dysregulation is central to all hereditary autoinflammatory diseases.
4. CLINICAL FEATURES¶
FMF attacks typically last 24–72 hours with fever, abdominal pain, arthritis, and erysipelas-like rash. TRAPS presents with prolonged attacks, migratory myalgia, and ocular inflammation. HIDS/MKD features periodic fever, rash, and arthritis. NOMID has chronic meningitis and arthropathy.
4.1 Attack Patterns¶
FMF: 1–3 days, often with abdominal pain. TRAPS: 1–2 days to weeks, with migratory myalgia. HIDS/MKD: 3–7 days with rash and arthritis. NOMID: Continuous flares with meningitis.
4.2 Complications¶
Amyloidosis (FMF), chronic arthritis (TRAPS), sensorineural hearing loss (MWS), and chronic meningitis (NOMID).
5. DIFFERENTIAL DIAGNOSIS¶
Other hereditary fever syndromes (TRAPS, HIDS/MKD, MWS, FCAS, NOMID), PFAPA syndrome, Still’s disease, porphyria, inflammatory bowel disease, and gynecologic disorders in women.
5.1 Key Differentiators¶
FMF vs TRAPS: Attack duration, myalgia pattern. FMF vs HIDS: Rash type, fever frequency. FMF vs NOMID: Meningitis presence, chronicity.
6. INVESTIGATIONS & DIAGNOSIS¶
Clinical criteria (e.g., fever, serositis), genetic testing for MEFV/TNFRSF1A/MVK/NLRP3 mutations, and lab findings (elevated CRP, ESR, SAA). Amyloidosis confirmed by renal biopsy.
6.1 Diagnostic Criteria¶
Clinical criteria: ≥ 3 attacks with fever, serositis, or rash. Genetic testing: MEFV mutations for FMF, TNFRSF1A for TRAPS, etc. Amyloidosis: Proteinuria, renal biopsy.
6.2 Laboratory Findings¶
Elevated CRP, ESR, fibrinogen, haptoglobin, and immunoglobulins. Transient albuminuria/hematuria. Urinary mevalonate elevation in HIDS/MKD.
7. MANAGEMENT & TREATMENT¶
Colchicine prophylaxis (1.2–1.8 mg/day) is first-line. IL-1 inhibitors (canakinumab, rilonacept, anakinra) for refractory cases. Avoid TNF inhibitors in TRAPS. Bone marrow transplant for refractory FMF.
7.1 Pharmacologic Therapy¶
Colchicine: 1.2–1.8 mg/day. IL-1 inhibitors: Monthly canakinumab, weekly rilonacept, daily anakinra. NSAIDs for fever. Glucocorticoids for acute attacks.
7.2 Non-Pharmacologic¶
Genetic counseling, regular follow-up, and monitoring for amyloidosis. Avoid triggers (stress, menses).
8. PROGNOSIS & COMPLICATIONS¶
FMF: Amyloidosis risk reduced with colchicine. TRAPS: 15% risk of amyloidosis. HIDS/MKD: No amyloidosis. NOMID: Severe complications (meningitis, arthritis).
8.1 Long-Term Outcomes¶
Colchicine prevents amyloidosis. Untreated FMF: 5% chronic arthritis. TRAPS: 15% amyloidosis. NOMID: Chronic meningitis and arthropathy.
9. SPECIAL CONSIDERATIONS¶
Pregnancy: Continue colchicine due to higher miscarriage risk from FMF attacks. Pediatrics: Lower colchicine doses. Elderly: Monitor renal function. Genetic testing for family screening.
9.1 Pregnancy¶
Colchicine is safe in pregnancy. Avoid TNF inhibitors. Monitor for amyloidosis risk.
9.2 Pediatric Considerations¶
Lower colchicine doses (0.05–0.1 mg/kg/day). Monitor for myelopathy in renal insufficiency.
10. KEY POINTS & CLINICAL PEARLS¶
- Colchicine is the cornerstone of FMF management. 2. Genetic testing confirms diagnosis and guides treatment. 3. IL-1 inhibitors are effective for refractory cases. 4. Amyloidosis is preventable with early colchicine. 5. Differential diagnosis includes other hereditary fever syndromes.