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Familial Mediterranean Fever and Other Hereditary Autoinflammatory Diseases

Chapter 381 | Part 11: Immune-Mediated, Inflammatory, and Rheumatologic Disorders · Part 11 – Rheumatology & Immunology · Chapter 381

Key Clinical Points

  1. FMF is the prototype of inherited autoinflammatory diseases (not autoimmune), characterized by recurrent fever with serosal, synovial, or cutaneous inflammation.
  2. The FMF gene encodes pyrin; mutations are gain-of-function, lowering the threshold for pyrin inflammasome activation.
  3. Oral colchicine is the first-line treatment for FMF, reducing attack frequency and preventing systemic AA amyloidosis.
  4. M694V homozygotes in FMF have an earlier age of onset, higher frequency of arthritis/rash, and increased risk of amyloidosis.
  5. TRAPS patients respond better to glucocorticoids than prophylactic colchicine; anti-TNF antibodies should be avoided as they may exacerbate attacks.
  6. IL-1 inhibitors (canakinumab, rilonacept, anakinra) are used for refractory FMF, TRAPS, HIDS/MKD, and CAPS.
  7. Amyloidosis is caused by deposition of serum amyloid A (SAA) in kidneys, adrenals, intestine, spleen, lung, and testes.
  8. PFAPA is the most common periodic fever syndrome in children, characterized by nearly regular intervals between episodes.
  9. VEXAS syndrome results from myeloid-restricted somatic mutations in an essential ubiquitylation enzyme, presenting as relapsing polychondritis or vasculitis.
  10. DADA2 (ADA2 deficiency) causes a vasculopathy with livedoid rash, early-onset lacunar strokes, and/or polyarteritis nodosa.

DEFINITION & CLASSIFICATION

• Definition (Harrison's 21e): Familial Mediterranean fever (FMF) is the prototype of a group of inherited diseases (Table 381-1) that are characterized by recurrent episodes of fever with serosal, synovial, or cutaneous inflammation and, in some individuals, the eventual development of systemic AA amyloidosis. • Autoinflammatory vs. Autoimmune: ◦ Autoinflammatory: Characterized by a lack of high-titer autoantibodies or antigen-specific T cells; driven primarily by the innate immune system (myeloid effector cells and germline receptors for PAMPs/DAMPs). ◦ Hereditary recurrent fevers: A major category of autoinflammatory diseases. • Molecular Basis: ◦ FMF gene encodes pyrin (~95-kDa protein) in granulocytes, monocytes, and fibroblasts. ◦ PYRIN domain (N-terminal 92 amino acids): Mediates homotypic protein-protein interactions; mutations are gain-of-function → reduced threshold for inflammasome activation. • Table 381-1: The Hereditary Recurrent Fever Syndromes ◦ Key distinctions include: → FMF (MEFV/pyrin): Mediterranean/Middle Eastern ancestry; recurrence of serositis/peritonitis; treatment with colchicine. → TRAPS (TNFRSF1A/p55): Any ethnicity; longer attacks (>7 days); treated with glucocorticoids and IL-1 inhibitors. → HIDS/MKD (MVK): Northern European; shorter attacks (3–7 days); includes rash and aphthous ulcers. → CAPS (NLRP3/cryopyrin): Includes MWS, FCAS, NOMID; various presentations including hearing loss or cold-induced urticaria.

EPIDEMIOLOGY

• FMF Distribution: ◦ Primarily Mediterranean and Middle Eastern (Armenian, Arab, Turkish, North African/Iraqi Jewish). ◦ Increasing frequency in Ashkenazi Jews, Italians, and others. ◦ Occasional cases without known Mediterranean ancestry. • Inheritance Patterns: ◦ Generally recessive; however, some mutations show clear-of-cut dominant inheritance. ◦ High carrier frequencies (up to 1:10) suggest a possible selective advantage. • Other Syndromes: ◦ HIDS: Predominantly Northern European (especially Dutch). ◦ TRAPS/CAPS: Any ethnic group. ◦ DADA2: Common in the Middle East; associated with polyarteritis nodosa.

ETIOLOGY & PATHOPHYSIOLOGY

• Inflammasome Activation: ◦ Triggered by bacterial toxins blocking RhoA GTPase → pyrin inflammasome activation. ◦ Mechanism: Caspase-1 activation → IL-1β and IL-18 release → pyroptosis (Gasdermin D-mediated). • Specific Pathologies: ◦ FMF: Gain-of-function mutations in the pyrin gene. ◦ TRAPS: Mutations in TNFRSF1A (p55) → intracellular receptor misfolding/aggregation → ligand-independent kinase activation and pro-inflammatory cytokine release. ◦ HIDS: Mutations in MVK → impaired synthesis of geranylgeranyl pyrophosphate → RhoA mislocalization → pyrin inflammasome activation. ◦ CAPS: Mutations in NLRP3 (cryopyrin) → formation of NLRP3 inflammasome → IL-1β/IL-18 release. ◦ VEXAS: Myeloid-restricted somatic mutations in an essential ubiquitylation enzyme. ◦ DADA2: Recessive loss-of-function in ADA2 gene → vasculopathy.

CLINICAL FEATURES

• General FMF Presentation: ◦ Onset: Often in early infancy; 90% of patients have first attack by age 20. ◦ Duration: Typically 24–72 hours (arthritic attacks may last longer). ◦ Triggers: Physical exertion, emotional stress, menses; pregnancy may lead to remission. • Abdominal Attacks: ◦ Frequency: >90% of patients experience these at some point. ◦ Severity: Ranges from dull/aching pain to severe generalized pain with rigidity and absent bowel sounds. ◦ Findings: CT may show small amount of fluid; laparotomy shows sterile, neutrophil-rich exudate. • Musculoskeletal & Cutaneous: ◦ Arthritis: Most common in M694V homozygotes; usually monoarticular (knee, ankle, hip) with large sterile effusions.  Chronic sacroiliitis can occur regardless of HLA-B27 status. ◦ Erysipeloid erythema: Characteristic rash on the dorsum of foot/ankle; seen most often in M694V homozygotes. ◦ Myalgia: Exercise-induced (nonfebrile) is common; protracted febrile myalgia can last weeks. • Other Organ Involvement: ◦ Pleurisy: Unilateral, sharp pain; exudative fluid rich in neutrophils. ◦ Pericarditis: Rare; small effusions may be seen on echocardiography. ◦ Scrotal: Acute unilateral inflammation in prepubertal boys. ◦ Vasculitis: IgA vasculitis and polyarteritis nodosa occur more frequently in FMF. • Other Syndromes: ◦ HIDS: Cervical adenopathy, maculopapular rash (palms/soles), aphthous ulcers. ◦ NOMID: Severe; chronic aseptic meningitis, arthropathy, and rash. ◦ FCAS: Cold-induced urticaria-like rash, chills, fever. ◦ MWS: Abdominal pain, limb pain, conjunctivitis, sensorineural hearing loss. ◦ PFAPA: Clock-like regularity of episodes; resolves by early adulthood.

DIFFERENTIAL DIAGNOSIS

• Hereditary Recurrent Fevers: → FMF, TRAPS, HIDS/MKD, CAPS (MWS, FCAS, NOMID), PFAPA. • Non-Hereditary Mimics: → Systemic-onset juvenile rheumatoid arthritis; Adult Still's disease. → Porphyria; Hereditary angioedema. → Inflammatory bowel disease; Gynecologic disorders (in women).

DIAGNOSTIC APPROACH

  1. Laboratory Evaluation: → Assess for acute inflammation: Elevated ESR, Leukocytosis, Thrombocytosis (children), elevated CRP, Fibrinogen, Haptoglobin, and serum immunoglobulins. → Check for renal involvement: Transient albuminuria or hematuria.
  2. Clinical Correlation: → Diagnosis of FMF often made on clinical grounds alone in experienced clinicians. → Use clinical criteria sets (high sensitivity/specificity) in high-prevalence areas.
  3. Genetic Testing: → Used as an adjunct in ambiguous cases or to determine prognosis. → Identify mutations in MEFV (FMF), TNFRSF1A (TRAPS), MVK (HIDS), or NLRP3 (CAPS).
  4. Amyloidosis Confirmation: → Renal or rectal biopsy used to confirm diagnosis of systemic AA amyloidosis.

MANAGEMENT & TREATMENT

  1. FMF Treatment: → First-line: Daily oral colchicine (1.2–1.8 mg/d). → Goal: Reduce frequency/intensity of attacks; prevent amyloidosis. → Refractory cases: IL-1 inhibitors (Canakinumab, Rilonacept, Anakinra).
  2. TRAPS Treatment: → Primary: Glucocorticoids. → Secondary: IL-1 inhibitors or Etanercept. → Warning: Avoid anti-TNF antibodies alone as they may exacerbate attacks.
  3. HIDS/MKD Treatment: → NSAIDs for fever; IL-1 inhibitors (Canakinumab) for management.
  4. CAPS Treatment: → Canakinumab, Rilonacept, or Anakinra (depending on specific syndrome: MWS, FCAS, NOMID).
  5. PFAPA Treatment: → Options: Intermittent glucocorticoids; daily oral colchicine, cimetidine, or apremilast; tonsillectomy/adenoidectomy.
  6. VEXAS Treatment: → TNF inhibitors are highly effective in preventing strokes.

COMPLICATIONS & PROGNOSIS

• Systemic AA Amyloidosis: → Cause: Deposition of serum amyloid A (SAA) fragments. → Sites: Kidneys, adrenals, intestine, spleen, lung, and testes. → Clinical suspicion: Presence of proteinuria between attacks. → Risk Factors for Amyloidosis: ◦ M694V homozygous genotype. ◦ Positive family history. ◦ SAA1 genotype. ◦ Male gender. ◦ Noncompliance with colchicine or IL-1 inhibitory therapy. → Syndrome-specific risks: ◦ TRAPS: ~15% develop amyloidosis (mostly cysteine mutations). ◦ HIDS: Associated with V377I/I268T MVK genotype. ◦ NOMID: ~25% of cases. ◦ FCAS: Amyloidosis is a late complication.

SPECIAL POPULATIONS

• Pregnancy: → Continue colchicine; risk of miscarriage from FMF attacks outweighs risks of colchicine on fetal development. • Elderly/Renal Impairment: → Colchicine may cause myoneuropathy (proximal muscle weakness, elevated CK). • Drug Interactions: → Cyclosporine inhibits hepatic excretion of colchicine → risk of toxicity in renal transplant patients. → Avoid IV colchicine if patient is already taking oral colchicine (risk of fatal toxicity).

KEY PEARLS & HIGH-YIELD POINTS

• FMF vs. TRAPS: FMF responds to colchicine; TRAPS responds better to glucocorticoids and IL-1 inhibitors. • M694V Mutation: High risk for amyloidosis, earlier onset, and higher frequency of arthritis/rash. • IL-1 Inhibitors: Effective across multiple autoinflammatory syndromes (FMF, TRAPS, HIDS, CAPS). • Amyloidosis Detection: Look for proteinuria between attacks as a primary indicator of SAA deposition.

Reference Tables

TABLE 381-1 The Hereditary Recurrent Fever Syndromes Ethnicity Inheritance

Harrison's 22e, p.2935

FMF TRAPS HIDS/MKD MWS FCAS NOMID
Ethnicity Jewish, Arab, Turkish,
Armenian, Italian		 Any ethnic group Predominantly Dutch,
northern European		 Any ethnic group Any ethnic group Any ethnic group
Recessive or dominanta Dominant Recessive Dominant Dominant
Gene/chromosome MEFV/16p13.3 TNFRSF1A/12p13 MVK/12q24 NLRP3/1q44 NLRP3/1q44 NLRP3/1q44
Pyrin p55 TNF receptor Mevalonate kinase NLRP3 (cryopyrin) NLRP3 (cryopyrin)
Attack length 1–3 days Often >7 days 3–7 days 1–2 days Minutes–3 days Continuous, with
flares
Pleurisy, peritonitis;
asymptomatic
pericardial effusions		 Pleurisy, peritonitis,
pericarditis		 Abdominal pain, but
seldom peritonitis;
pleurisy, pericarditis
uncommon		 Abdominal pain;
pleurisy, pericarditis
rare		 Rare
Skin Erysipeloid erythema Centrifugally
migrating erythema		 Diffuse maculopapular
rash; oral ulcers		 Diffuse urticaria-like
rash		 Cold-induced
urticaria-like rash		 Diffuse urticaria-like
rash
Acute monoarthritis;
chronic hip arthritis
(rare)		 Acute monoarthritis,
arthralgia		 Arthralgia,
oligoarthritis		 Arthralgia, large joint
oligoarthritis		 Polyarthralgia
Muscle Exercise-induced
myalgia common;
protracted febrile
myalgia rare		 Migratory myalgia Uncommon Myalgia common Sometimes myalgia Sometimes myalgia
Uncommon Periorbital edema,
conjunctivitis		 Uncommon Conjunctivitis,
episcleritis, optic disc
edema; sensorineural
hearing loss		 Conjunctivitis
CNS Aseptic meningitis rare Headache Headache Headache Headache Aseptic meningitis,
seizures
Most common in M694V
homozygotes		 ~15% of cases,
most often cysteine
mutations, T50M		 Sometimes associated
with V377I/I268T MVK
genotype		 ~25% of cases Uncommon
Treatment Oral colchicine
prophylaxis, IL-1
inhibitors for refractory
cases		 Glucocorticoids, IL-1
inhibitors, etanercept		 NSAIDs for fever; IL-1
inhibitors		 Canakinumab,
rilonacept, anakinra		 Canakinumab,
rilonacept, anakinra		 Anakinra