Phys · rheumatological
Systemic Autoinflammatory Syndromes
Also known as autoinflammatory disease · periodic fever syndrome · hereditary recurrent fever · familial Mediterranean fever · FMF · TNF receptor-associated periodic syndrome · TRAPS · hyper-IgD syndrome · HIDS · mevalonate kinase deficiency · MKD · cryopyrin-associated periodic syndrome · CAPS · familial cold autoinflammatory syndrome · FCAS · Muckle-Wells syndrome · NOMID · CINCA · adult-onset Still disease · AOSD · Schnitzler syndrome · Behcet disease
Consultant-physician-depth guide to the systemic autoinflammatory syndromes for FRACP DWE and DCE — the innate-versus-adaptive immune framework, the hereditary recurrent fevers (familial Mediterranean fever with MEFV and colchicine prophylaxis and AA amyloidosis, TNF receptor-associated periodic syndrome with TNFRSF1A and prolonged fever, hyper-IgD syndrome with mevalonate kinase deficiency), the cryopyrin-associated periodic syndromes (CAPS spectrum of FCAS, Muckle-Wells and NOMID), adult-onset Still disease with the Yamaguchi criteria and elevated ferritin, Schnitzler syndrome with chronic urticaria and monoclonal IgM gammopathy, Behcet disease cross-referenced with the vasculitis topic, the diagnostic approach of pattern recognition plus a targeted genetic panel, and the treatment principle that IL-1 blockade is transformative for NLRP3-driven disease, HIDS, colchicine-resistant FMF, TRAPS, AOSD and Schnitzler syndrome.
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Red flags
- A patient with recurrent self-limiting attacks of fever and serositis since childhood, of Mediterranean ancestry, with a previous negative laparotomy or appendicectomy — familial Mediterranean fever until proven otherwise; a single serum amyloid A and urinalysis for proteinuria screens for AA amyloidosis
- Progressive sensorineural hearing loss with a chronic urticarial rash from infancy — Muckle-Wells syndrome; the hearing loss is irreversible once established, so canakinumab must not be delayed
- A young adult with spiking quotidian fever, an evanescent salmon-pink rash on the trunk with the fever, and a ferritin above 1000 micrograms per litre with negative ANA and rheumatoid factor — adult-onset Still disease; exclude infection and malignancy, then start IL-1 blockade early to spare steroids
- An older adult with chronic urticarial rash, recurrent fever and a monoclonal IgM on serum electrophoresis — Schnitzler syndrome; IL-1 blockade with anakinra is transformative, and haematology surveillance for Waldenstrom macroglobulinaemia is required
- Ferritin above 10,000 micrograms per litre with pancytopenia, hepatosplenomegaly and high fever in a patient with adult-onset Still disease — macrophage activation syndrome, a life-threatening complication requiring urgent steroids and anakinra
- Recurrent oral and genital ulceration with uveitis and a positive pathergy test — Behcet disease; pulmonary artery aneurysm causes massive haemoptysis and is life-threatening
Systemic Autoinflammatory Syndromes
The answer first
Autoinflammatory diseases are defined by innate immune system dysregulation — recurrent, often unprovoked attacks of systemic inflammation driven by excess cytokine signalling (chiefly interleukin-1), without high-titre autoantibodies or antigen-specific lymphocyte responses. That single idea is the lens for the whole topic: where autoimmune disease (SLE, rheumatoid arthritis) is adaptive, antibody-driven and acquired, autoinflammatory disease is innate, cytokine-driven and often hereditary. [1]
Three rules that change outcome: [1]
- Interleukin-1 blockade is transformative for a defined group of these diseases. CAPS, HIDS, colchicine-resistant FMF, TRAPS, AOSD and Schnitzler syndrome respond dramatically to canakinumab or anakinra. Recognising an IL-1-responsive syndrome changes a patient's life.
- Colchicine prevents AA amyloidosis in familial Mediterranean fever. The goal of FMF treatment is complete attack prevention and amyloidosis prevention, not just fewer attacks. Adherence to lifelong colchicine is the single biggest determinant of long-term renal outcome.
- Attack duration is the best discriminator between the hereditary recurrent fevers. FMF attacks last 1 to 3 days; HIDS attacks last 3 to 7 days; TRAPS attacks last 1 to 3 weeks. When the genetic panel is pending or ambiguous, this single feature points to the diagnosis. [1]
The clinical reasoning moves in three steps at the bedside. First, exclude infection, malignancy and autoimmune disease — these are far more common than autoinflammatory disease and must never be missed. Second, characterise the attack pattern — duration, interval, family history, ancestry and accompanying organ features. Third, confirm with a targeted genetic panel and syndrome-specific tests, then treat by the dominant cytokine (colchicine for FMF; IL-1 for CAPS, HIDS, TRAPS, AOSD, Schnitzler; IL-6 for articular AOSD). [1]
References8ShowHide
- [1]Livneh A, Langevitz P, Zemer D, et al. Criteria for the diagnosis of familial Mediterranean fever Arthritis Rheum, 1997.PMID 9336425
- [2]Ozen S, Demirkaya E, Erer B, et al. EULAR recommendations for the management of familial Mediterranean fever Ann Rheum Dis, 2016.PMID 26802180
- [3]Ozen S, Ben-Cherit E, Foeldvari I, et al. Long-term efficacy and safety of canakinumab in patients with colchicine-resistant familial Mediterranean fever: results from the randomised phase III CLUSTER trial Ann Rheum Dis, 2020.PMID 32571870
- [4]Lachmann HJ, Lowe P, Felix SD, et al. In vivo regulation of interleukin 1beta in patients with cryopyrin-associated periodic syndromes J Exp Med, 2009.PMID 19364880
- [5]Yamaguchi M, Ohta A, Tsunematsu T, et al. Preliminary criteria for classification of adult Still's disease J Rheumatol, 1992.PMID 1578458
- [6]Simon A, Asli B, Braun-Falco M, et al. Schnitzler's syndrome: diagnosis, treatment, and follow-up Allergy, 2013.PMID 23480774
- [7]de Koning HD, Bodar EJ, Simon A, et al. Schnitzler syndrome: beyond the case reports: review and follow-up of 94 patients with an emphasis on prognosis and treatment Semin Arthritis Rheum, 2007.PMID 17586002
- [8]Hatemi G, Christensen R, Bang D, et al. 2018 update of the EULAR recommendations for the management of Behçet's syndrome Ann Rheum Dis, 2018.PMID 29625968