Autoinflammatory diseases
Autoinflammatory diseases are monogenic disorders of enhanced inflammasome function that cause recurrent, stereotyped fever and multiorgan inflammation without autoantibodies or autoreactive T cells. The cryopyrin-associated periodic syndromes, tumor necrosis factor receptor-associated periodic syndrome, and familial Mediterranean fever are the core named entities; diagnosis rests on the attack pattern plus genetic confirmation, and treatment is built around interleukin-1 blockade with anakinra or canakinumab, or colchicine for familial Mediterranean fever.
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What this article covers
- Overview
Definition: autoinflammatory diseases are monogenic conditions in which innate immune pathways are activated independently of any specific known antigen, producing periodic or chronic fever and multiorgan inflammation.
- Epidemiology
FMF is the most common autoinflammatory disease, concentrated in Mediterranean, Jewish, Arab, and Turkish populations, autosomal recessive.
- Risk factors
A known pathogenic variant in the familial Mediterranean fever gene (MEFV), NLRP3, or TNFRSF1A: the causal mutation for FMF, CAPS, and TRAPS, respectively.
- Pathophysiology
Innate activation without an antigen trigger: the defining mechanism here is innate immune activation independent of any known antigen, unlike autoimmune disease, which requires an antigen-specific adaptive response.
- Clinical features
FMF (comparator): fever, abdominal pain from sterile peritonitis, arthritis, pleuritis, and an erysipeloid rash on the lower legs, each attack lasting 12 to 72 hours; MEFV-driven, autosomal recessive (familial Mediterranean fever).
- Differential diagnosis
Occult or recurrent bacterial infection: fever with elevated inflammatory markers, but cultures identify an organism and fever resolves with targeted antibiotics, unlike the stereotyped attacks here.
- Diagnosis
What establishes the diagnosis: matching a documented pattern of recurrent, stereotyped attacks to a known syndrome, after excluding infection and malignancy, then confirming with genetic testing for the causative gene.
- Management
FMF, first-line: colchicine 0.6 mg orally once daily, titrated to a maintenance range of 1.2 to 1.8 mg/day, up to a maximum of 2.4 mg/day, taken lifelong even between attacks, since it is the only therapy proven to prevent renal amyloidosis.
- Complications
Secondary (AA) amyloidosis: the most feared complication, from sustained subclinical inflammation depositing serum amyloid A-derived amyloid in the kidney; risk is highest in FMF and MWS.
- Prognosis
FMF on adherent colchicine: attacks are prevented or reduced in most patients and renal amyloidosis is effectively prevented, making adherence the strongest prognostic factor.
- Prevention
Lifelong, continuous colchicine adherence in FMF, taken even during symptom-free intervals, is the specific intervention proven to avert renal amyloidosis.
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Related articles
- Familial Mediterranean fever
Familial Mediterranean fever is an autosomal recessive autoinflammatory disease of pyrin, most common in Jewish, Arab, and Turkish populations, causing recurrent short attacks of fever with sterile peritonitis, pleuritis, monoarthritis, or an erysipelas-like leg rash. First-line treatment is lifelong daily colchicine, which both suppresses attacks and prevents secondary (AA) amyloidosis; colchicine-resistant disease escalates to interleukin-1 blockade.
- Adult-onset Still disease
Adult-onset Still disease is a rare systemic autoinflammatory disorder marked by quotidian spiking fevers, an evanescent salmon-colored rash, arthritis, sore throat, and a markedly elevated ferritin. It is a diagnosis of exclusion confirmed by the Yamaguchi criteria, and treatment begins with NSAIDs, escalates to glucocorticoids, then to interleukin-1 blockade (anakinra or canakinumab) or interleukin-6 blockade (tocilizumab) for refractory disease.
- Juvenile idiopathic arthritis
Juvenile idiopathic arthritis is arthritis beginning before age 16 and persisting at least 6 weeks with no other identifiable cause, spanning oligoarticular, polyarticular, systemic, enthesitis-related, and psoriatic subtypes. Diagnosis is clinical and antibody-subtyped; treatment starts with an NSAID and escalates through methotrexate to a biologic, while antinuclear-antibody-positive oligoarticular disease requires routine slit-lamp screening for silent chronic anterior uveitis.
- Amyloidosis
Amyloidosis is extracellular deposition of misfolded protein fibrils that stain apple-green with Congo red under polarized light, most often AL (clonal light chains, linked to plasma cell dyscrasias), AA (chronic inflammation), or ATTR (transthyretin, hereditary or wild-type). Diagnosis requires tissue biopsy for Congo red birefringence plus typing of the amyloid protein, and treatment targets the underlying source, plasma-cell-directed therapy for AL, inflammatory disease control for AA, and transthyretin stabilizers or silencers for ATTR.
- Behcet disease
Behcet disease is a variable-vessel vasculitis, the only vasculitis that can involve arteries and veins of any size, marked by recurrent oral and genital ulceration, uveitis, skin lesions, and pathergy. There is no confirmatory laboratory test; diagnosis is clinical. Treatment is organized by organ severity, from colchicine for mucocutaneous disease to urgent immunosuppression and tumor necrosis factor inhibitors for sight-, organ-, or life-threatening involvement.