Rheumatologists are likely to be asked to evaluate patients with recurrent febrile syndromes, so it is important that they are familiar with the clinical and diagnostic features, pathophysiology and therapeutic options for these rare autoinflammatory disorders. These syndromes are all characterized by recurrent episodes of fever and systemic inflammation; however, some syndromes have unique historical and physical features that can help with making a diagnosis. The primary associated morbidity is systemic amyloidosis, usually with renal involvement. Diagnostic testing is mostly limited to genetic testing. NSAIDs, colchicine and corticosteroids have roles in the treatment of some of these disorders, but biologic drugs that target interleukin-1β are emerging as consistently effective therapies.
The autoinflammatory disorders are diseases of innate immune dysregulation
The recurrent febrile syndromes are characterized by episodes of systemic and tissue inflammation
The recurrent febrile syndromes present a diagnostic challenge
The primary long-term morbidity of the inherited recurrent febrile syndromes is systemic amyloidosis
Advances in the understanding of the genetics and pathogenesis of these disorders have led to improved diagnostic ability and therapy, including the development of biologic therapies that target interleukin-1β
This is a preview of subscription content
Subscribe to Journal
Get full journal access for 1 year
only $4.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Get time limited or full article access on ReadCube.
All prices are NET prices.
McDermott, M. F. et al. Germline mutations in the extracellular domains of the 55 kDa TNF receptor, TNFR1, define a family of dominantly inherited autoinflammatory syndromes. Cell 97, 133–144 (1999).
Samuels, J. et al. Familial Mediterranean fever at the millennium. Clinical spectrum, ancient mutations, and a survey of 100 American referrals to the National Institutes of Health. Medicine (Baltimore) 77, 268–297 (1998).
Livneh, A. et al. The changing face of familial Mediterranean fever. Semin. Arthritis. Rheum. 26, 612–627 (1996).
Drenth, J. P. H. & van der Meer, J. W. M. Hereditary periodic fever. N. Engl. J. Med. 345, 1748–1757 (2001).
International FMF Consortium. Ancient missense mutations in a new member of the RoRet gene family are likely to cause familial Mediterranean fever. Cell 90, 797–807 (1997).
The French FMF Consortium. A candidate gene for familial Mediterranean fever. Nat. Genet. 17, 25–31 (1997).
Lidar, M. & Livneh, A. Familial Mediterranean fever: clinical, molecular and management advancements. Neth. J. Med. 65, 318–324 (2007).
van der Hilst, J. C. et al. Long-term follow-up, clinical features, and quality of life in a series of 103 patients with hyperimmunoglobulinemia D syndrome. Medicine (Baltimore) 87, 301–310 (2008).
Houten, S. M. et al. Mutations in MVK, encoding mevalonate kinase, cause hyperimmunoglobulinaemia D and periodic fever syndrome. Nat. Genet. 22, 175–177 (1999).
Drenth, J. P. H. et al. Mutations in the gene encoding mevalonate kinase cause hyper-IgD and periodic fever syndrome. International Hyper-IgD Study Group. Nat. Genet. 22, 178–181 (1999).
Houten, S. M., Frenkel, J., & Waterham, H. R. Isoprenoid biosynthesis in hereditary periodic fever syndromes and inflammation. Cell. Mol. Life Sci. 60, 1118–1134 (2003).
Hoffmann, G. et al. Mevalonic aciduria—an inborn error of cholesterol and nonsterol isoprene biosynthesis. N. Engl. J. Med. 314, 1610–1614 (1986).
Feldmann, J. et al. Chronic infantile neurological cutaneous and articular syndrome is caused by mutations in CIAS1, a gene highly expressed in polymorphonuclear cells and chondrocytes. Am. J. Hum. Genet. 71, 198–203 (2002).
Hoffman, H. M. et al. Mutation of a new gene encoding a putative pyrin-like protein causes familial cold autoinflammatory syndrome and Muckle–Wells syndrome. Nat. Genet. 29, 301–305 (2001).
Hawkins, P. N. et al. Spectrum of clinical features in Muckle–Wells syndrome and response to anakinra. Arthritis Rheum. 50, 607–612 (2004).
Hoffman, H. M., Wanderer, A. A. & Broide, D. H. Familial cold autoinflammatory syndrome: phenotype and genotype of an autosomal dominant periodic fever. J. Allergy Clin. Immunol. 108, 615–620 (2001).
Prieur, A. M. A recently recognised chronic inflammatory disease of early onset characterised by the triad of rash, central nervous system involvement and arthropathy. Clin. Exp. Rheumatol. 19, 103–106 (2001).
Hoffman, H. M. et al. Prevention of cold-associated acute inflammation in familial cold autoinflammatory syndrome by interleukin-1 receptor antagonist. Lancet 364, 1779–1785 (2004).
Feder, H. M., Jr Periodic fever, aphthous stomatitis, pharyngitis, adenitis: a clinical review of a new syndrome. Curr. Opin. Pediatr. 12, 253–256 (2000).
Lindor, N. M. et al. A new autosomal dominant disorder of pyogenic sterile arthritis, pyoderma gangrenosum, and acne: PAPA syndrome. Mayo Clin. Proc. 72, 611–615 (1997).
Punzi, L. et al. Clinical and genetic aspects of Blau syndrome: a 25-year follow-up of one family and a literature review. Autoimmun. Rev. 8, 228–232 (2008).
de Koning, H. D. 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. 37, 137–148 (2007).
Majeed, H. A. et al. The syndrome of chronic recurrent multifocal osteomyelitis and congenital dyserythropoietic anaemia. Report of a new family and a review. Eur. J. Pediatr. 160, 705–710 (2001).
Gershoni-Baruch, R. et al. Familial Mediterranean fever: prevalence, penetrance and genetic drift. Eur. J. Hum. Genet. 9, 634–637 (2001).
Simon, A. et al. A founder effect in the hyperimmunoglobulinemia D and periodic fever syndrome. Am. J. Med. 114, 148–152 (2003).
Martinon, F. & Tschopp, J. NLRs join TLRs as innate sensors of pathogens. Trends Immunol. 26, 447–454 (2005).
Martinon, F., Burns, K. & Tschopp, J. The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-β. Mol. Cell 10, 417–426 (2002).
Agostini, L. et al. NALP3 forms an IL-1β-processing inflammasome with increased activity in Muckle–Wells autoinflammatory disorder. Immunity 20, 319–325 (2004).
Chae, J. J. et al. The B30.2 domain of pyrin, the familial Mediterranean fever protein, interacts directly with caspase-1 to modulate IL-1β production. Proc. Natl Acad. Sci. USA 103, 9982–9987 (2006).
Kimberley, F. C. et al. Falling into TRAPS—receptor misfolding in the TNF receptor 1-associated periodic fever syndrome. Arthritis Res. Ther. 9, 217 (2007).
Simon, A. & van der Meer, J. W. Pathogenesis of familial periodic fever syndromes or hereditary autoinflammatory syndromes. Am. J. Physiol. Regul. Integr. Comp. Physiol. 292, R86–R98 (2007).
Kuijk, L. M. et al. HMG-CoA reductase inhibition induces IL-1β release through Rac1/PI3K/PKB-dependent caspase-1 activation. Blood 112, 3563–3573 (2008).
Simon, A. et al. Effect of inflammatory attacks in the classical type hyper-IgD syndrome on immunoglobulin D, cholesterol and parameters of the acute phase response. J. Intern. Med. 256, 247–253 (2004).
Ozen, S. Familial Mediterranean fever: revisiting an ancient disease. Eur. J. Pediatr. 162, 449–454 (2003).
Aksentijevich, I. et al. The clinical continuum of cryopyrinopathies: novel CIAS1 mutations in North American patients and a new cryopyrin model. Arthritis Rheum. 56, 1273–1285 (2007).
Simon, A. et al. Approach to genetic analysis in the diagnosis of hereditary autoinflammatory syndromes. Rheumatology (Oxford) 45, 269–273 (2006).
van der Hilst, J. C., Simon, A. & Drenth, J. P. Hereditary periodic fever and reactive amyloidosis. Clin. Exp. Med. 5, 87–98 (2005).
Cazeneuve, C. et al. Identification of MEFV-independent modifying genetic factors for familial Mediterranean fever. Am. J. Hum. Genet. 67, 1136–1143 (2000).
Akdogan, A. et al. Are familial Mediterranean fever (FMF) patients at increased risk for atherosclerosis? Impaired endothelial function and increased intima–media thickness are found in FMF. J. Am. Coll. Cardiol. 48, 2351–2353 (2006).
Langevitz, P. et al. Prevalence of ischemic heart disease in patients with familial Mediterranean fever. Isr. Med. Assoc. J. 3, 9–12 (2001).
Stojanov, S. et al. Clinical and functional characterisation of a novel TNFRSF1A c.605T>A/V173D cleavage site mutation associated with tumour necrosis factor receptor-associated periodic fever syndrome (TRAPS), cardiovascular complications and excellent response to etanercept treatment. Ann. Rheum. Dis. 67, 1292–1298 (2008).
Renko, M. et al. A randomized, controlled trial of tonsillectomy in periodic fever, aphthous stomatitis, pharyngitis, and adenitis syndrome. J. Pediatr. 151, 289–292 (2007).
Zemer, D. et al. Colchicine in the prevention and treatment of the amyloidosis of familial Mediterranean fever. N. Engl. J. Med. 314, 1001–1005 (1986).
Zemer, D. et al. A controlled trial of colchicine in preventing attacks of familial Mediterranean fever. N. Engl. J. Med. 291, 932–934 (1974).
Tasher, D., Stein, M. & Dalal Eli Somekh, I. Colchicine prophylaxis for frequent periodic fever, aphthous stomatitis, pharyngitis and adenitis episodes. Acta Paediatr. 97, 1090–1092 (2008).
Hull, K. M. et al. The TNF receptor-associated periodic syndrome (TRAPS): emerging concepts of an autoinflammatory disorder. Medicine (Baltimore) 81, 349–368 (2002).
Drewe, E. et al. Prospective study of anti-tumour necrosis factor receptor superfamily 1B fusion protein, and case study of anti-tumour necrosis factor receptor superfamily 1A fusion protein, in tumour necrosis factor receptor associated periodic syndrome (TRAPS): clinical and laboratory findings in a series of seven patients. Rheumatology (Oxf.) 42, 235–239 (2003).
Hawkins, P. N., Lachmann, H. J. & McDermott, M. F. Interleukin-1-receptor antagonist in the Muckle–Wells syndrome. N. Engl. J. Med. 348, 2583–2584 (2003).
Goldbach-Mansky, R. et al. Neonatal-onset multisystem inflammatory disease responsive to interleukin-1β inhibition. N. Engl. J. Med. 355, 581–592 (2006).
Leslie, K. S. et al. Phenotype, genotype, and sustained response to anakinra in 22 patients with autoinflammatory disease associated with CIAS-1/NALP3 mutations. Arch. Dermatol. 142, 1591–1597 (2006).
Ross, J. B. et al. Use of anakinra (Kineret) in the treatment of familial cold autoinflammatory syndrome with a 16-month follow-up. J. Cutan. Med. Surg. 12, 8–16 (2008).
Hoffman, H. M. et al. Efficacy and safety of rilonacept (interleukin-1 Trap) in patients with cryopyrin-associated periodic syndromes: results from two sequential placebo-controlled studies. Arthritis Rheum. 58, 2443–2452 (2008).
Calligaris, L. et al. The efficacy of anakinra in an adolescent with colchicine-resistant familial Mediterranean fever. Eur. J. Pediatr. 167, 695–696 (2008).
Bodar, E. J. et al. Effect of etanercept and anakinra on inflammatory attacks in the hyper-IgD syndrome: introducing a vaccination provocation model. Neth. J. Med. 63, 260–264 (2005).
Gattorno, M. et al. Persistent efficacy of anakinra in patients with tumor necrosis factor receptor-associated periodic syndrome. Arthritis Rheum. 58, 1516–1520 (2008).
Simon, A., van der Meer, J. W. M. & Drenth, J. P. H. Familial Autoinflammatory Syndromes. In Kelley's Textbook of Rheumatology, 8th edn, Ch. 113 (Eds Firestein, G. S. et al.) 1863–1882 (Saunders, Philadelphia, 2008).
H. M. Hoffman is supported by the National Institute of Allergy and Infectious Diseases and the Ludwig Institute of Cancer Research. A. Simon is supported by a ZonMW VENI grant.
Hal Hoffman is a consultant for Regeneron pharmaceuticals and Novartis pharmaceuticals, who make rilonacept and canakinumab, respectively.
A. Simon has declared no competing interests.
About this article
Cite this article
Hoffman, H., Simon, A. Recurrent febrile syndromes—what a rheumatologist needs to know. Nat Rev Rheumatol 5, 249–256 (2009). https://doi.org/10.1038/nrrheum.2009.40
Clinical and Genetic Characterization of Japanese Sporadic Cases of Periodic Fever, Aphthous Stomatitis, Pharyngitis and Adenitis Syndrome from a Single Medical Center in Japan
Journal of Clinical Immunology (2014)
In Vitro Analysis of the Functional Effects of an NLRP3 G809S Variant with the co-Existence of MEFV Haplotype Variants in Atypical Autoinflammatory Syndrome
Journal of Clinical Immunology (2013)
Monatsschrift Kinderheilkunde (2012)
Journal of Clinical Immunology (2012)