Periodic fever syndromes and other autoinflammatory diseases: An overview
- Peter A Nigrovic, MD
Peter A Nigrovic, MD
- Associate Professor of Medicine
- Harvard Medical School
- Section Editors
- Jordan S Orange, MD, PhD
Jordan S Orange, MD, PhD
- Section Editor — Immunology and Immunodeficiency
- Professor of Pediatrics
- Chief of Immunology, Allergy, and Rheumatology
- Baylor College of Medicine
- Texas Children's Hospital
- Sheldon L Kaplan, MD
Sheldon L Kaplan, MD
- Editor-in-Chief — Pediatrics
- Section Editor — Pediatric Infectious Diseases
- Professor and Vice Chairman for Clinical Affairs
- Baylor College of Medicine
In the autoinflammatory diseases, pathogenic inflammation arises through aberrant, antigen-independent activation of the immune system. Many of these diseases present with recurrent fevers and are termed the periodic fever syndromes, although other features may sometimes dominate the clinical picture. The best characterized autoinflammatory diseases arise from mutations in single genes, but related mechanisms participate in many diseases in which inflammation contributes to tissue injury.
An overview of autoinflammatory diseases is presented here, with a focus on shared pathogenic and pathophysiologic mechanisms. While the most salient features of the individual disorders are discussed in this topic review, more detailed descriptions of the clinical manifestations, diagnosis, and treatment of the major autoinflammatory diseases are presented elsewhere. (See appropriate topic reviews.)
OVERVIEW OF PATHOGENESIS
Immune defense requires both antigen-specific and antigen-independent mechanisms. The antigen-specific arm of the immune response, referred to as adaptive immunity, is based upon learned self/nonself discrimination mediated by selective expansion of T and B cell clones in which genetic recombination has generated antigen-specific receptors. (See "The adaptive cellular immune response".)
However, these "learned" responses are not the only mechanism of immune defense. Innate immunity refers to a network of cells and proteins that respond to infection or tissue injury through genetically "hard-wired" recognition of foreign molecules (eg, bacterial cell wall components) or host molecules produced or released by damaged cells (eg, interleukin-1 [IL-1] and uric acid crystals). Neutrophils, macrophages, mast cells, and natural killer cells are among the principal cellular effectors of innate immunity. Complement, a set of proteins that recognize and bind nonself targets, exemplifies noncellular innate immunity. (See "An overview of the innate immune system" and "Complement pathways" and "Toll-like receptors: Roles in disease and therapy".)
Innate and adaptive immune mechanisms work closely together. Recognition of danger signals by innate immune mechanisms directs the development of adaptive immune responses, while lack of such recognition favors tolerance. Established adaptive immune responses recruit innate immunity to assist with the effector response. As examples, T cells can recruit neutrophils, and B cell-derived antibodies can target bacteria for lysis by complement.
- McDermott MF, Aksentijevich I, Galon J, et al. Germline mutations in the extracellular domains of the 55 kDa TNF receptor, TNFR1, define a family of dominantly inherited autoinflammatory syndromes. Cell 1999; 97:133.
- Stojanov S, Kastner DL. Familial autoinflammatory diseases: genetics, pathogenesis and treatment. Curr Opin Rheumatol 2005; 17:586.
- Kalyoncu M, Acar BC, Cakar N, et al. Are carriers for MEFV mutations "healthy"? Clin Exp Rheumatol 2006; 24:S120.
- Koc B, Oktenli C, Bulucu F, et al. The rate of pyrin mutations in critically ill patients with systemic inflammatory response syndrome and sepsis: a pilot study. J Rheumatol 2007; 34:2070.
- Comak E, Dogan CS, Akman S, et al. MEFV gene mutations in Turkish children with juvenile idiopathic arthritis. Eur J Pediatr 2013; 172:1061.
- Tunca M, Akar S, Onen F, et al. Familial Mediterranean fever (FMF) in Turkey: results of a nationwide multicenter study. Medicine (Baltimore) 2005; 84:1.
- Akkoc N, Sari I, Akar S, et al. Increased prevalence of M694V in patients with ankylosing spondylitis: additional evidence for a link with familial mediterranean fever. Arthritis Rheum 2010; 62:3059.
- Rabinovich E, Livneh A, Langevitz P, et al. Severe disease in patients with rheumatoid arthritis carrying a mutation in the Mediterranean fever gene. Ann Rheum Dis 2005; 64:1009.
- McGonagle D, McDermott MF. A proposed classification of the immunological diseases. PLoS Med 2006; 3:e297.
- Martinon F, Pétrilli V, Mayor A, et al. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature 2006; 440:237.
- Duewell P, Kono H, Rayner KJ, et al. NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature 2010; 464:1357.
- Tunca M, Ozdogan H. Molecular and genetic characteristics of hereditary autoinflammatory diseases. Curr Drug Targets Inflamm Allergy 2005; 4:77.
- Federici S, Sormani MP, Ozen S, et al. Evidence-based provisional clinical classification criteria for autoinflammatory periodic fevers. Ann Rheum Dis 2015; 74:799.
- Gattorno M, Sormani MP, D'Osualdo A, et al. A diagnostic score for molecular analysis of hereditary autoinflammatory syndromes with periodic fever in children. Arthritis Rheum 2008; 58:1823.
- Cuisset L, Jeru I, Dumont B, et al. Mutations in the autoinflammatory cryopyrin-associated periodic syndrome gene: epidemiological study and lessons from eight years of genetic analysis in France. Ann Rheum Dis 2011; 70:495.
- van der Hilst JC, Simon A, Drenth JP. Hereditary periodic fever and reactive amyloidosis. Clin Exp Med 2005; 5:87.
- Shinar Y, Obici L, Aksentijevich I, et al. Guidelines for the genetic diagnosis of hereditary recurrent fevers. Ann Rheum Dis 2012; 71:1599.
- Simon A, van der Meer JW, Vesely R, et al. Approach to genetic analysis in the diagnosis of hereditary autoinflammatory syndromes. Rheumatology (Oxford) 2006; 45:269.
- Nigrovic PA. Reply: To PMID 24623686. Arthritis Rheumatol 2014; 66:2645.
- Nigrovic PA. Autoinflammation and autoimmunity in systemic juvenile idiopathic arthritis. Proc Natl Acad Sci U S A 2015; 112:15785.
- Jéru I, Duquesnoy P, Fernandes-Alnemri T, et al. Mutations in NALP12 cause hereditary periodic fever syndromes. Proc Natl Acad Sci U S A 2008; 105:1614.
- Gandhi C, Healy C, Wanderer AA, Hoffman HM. Familial atypical cold urticaria: description of a new hereditary disease. J Allergy Clin Immunol 2009; 124:1245.
- Lindor NM, Arsenault TM, Solomon H, et al. A new autosomal dominant disorder of pyogenic sterile arthritis, pyoderma gangrenosum, and acne: PAPA syndrome. Mayo Clin Proc 1997; 72:611.
- Wise CA, Gillum JD, Seidman CE, et al. Mutations in CD2BP1 disrupt binding to PTP PEST and are responsible for PAPA syndrome, an autoinflammatory disorder. Hum Mol Genet 2002; 11:961.
- Shoham NG, Centola M, Mansfield E, et al. Pyrin binds the PSTPIP1/CD2BP1 protein, defining familial Mediterranean fever and PAPA syndrome as disorders in the same pathway. Proc Natl Acad Sci U S A 2003; 100:13501.
- Cortis E, De Benedetti F, Insalaco A, et al. Abnormal production of tumor necrosis factor (TNF) -- alpha and clinical efficacy of the TNF inhibitor etanercept in a patient with PAPA syndrome [corrected]. J Pediatr 2004; 145:851.
- Stichweh DS, Punaro M, Pascual V. Dramatic improvement of pyoderma gangrenosum with infliximab in a patient with PAPA syndrome. Pediatr Dermatol 2005; 22:262.
- Dierselhuis MP, Frenkel J, Wulffraat NM, Boelens JJ. Anakinra for flares of pyogenic arthritis in PAPA syndrome. Rheumatology (Oxford) 2005; 44:406.
- Blau EB. Familial granulomatous arthritis, iritis, and rash. J Pediatr 1985; 107:689.
- Manouvrier-Hanu S, Puech B, Piette F, et al. Blau syndrome of granulomatous arthritis, iritis, and skin rash: a new family and review of the literature. Am J Med Genet 1998; 76:217.
- Rosé CD, Aróstegui JI, Martin TM, et al. NOD2-associated pediatric granulomatous arthritis, an expanding phenotype: study of an international registry and a national cohort in Spain. Arthritis Rheum 2009; 60:1797.
- Miceli-Richard C, Lesage S, Rybojad M, et al. CARD15 mutations in Blau syndrome. Nat Genet 2001; 29:19.
- Maekawa S, Ohto U, Shibata T, et al. Crystal structure of NOD2 and its implications in human disease. Nat Commun 2016; 7:11813.
- Aróstegui JI, Arnal C, Merino R, et al. NOD2 gene-associated pediatric granulomatous arthritis: clinical diversity, novel and recurrent mutations, and evidence of clinical improvement with interleukin-1 blockade in a Spanish cohort. Arthritis Rheum 2007; 56:3805.
- Martin TM, Zhang Z, Kurz P, et al. The NOD2 defect in Blau syndrome does not result in excess interleukin-1 activity. Arthritis Rheum 2009; 60:611.
- Kanazawa N, Okafuji I, Kambe N, et al. Early-onset sarcoidosis and CARD15 mutations with constitutive nuclear factor-kappaB activation: common genetic etiology with Blau syndrome. Blood 2005; 105:1195.
- Rosé CD, Doyle TM, McIlvain-Simpson G, et al. Blau syndrome mutation of CARD15/NOD2 in sporadic early onset granulomatous arthritis. J Rheumatol 2005; 32:373.
- Saulsbury FT, Wouters CH, Martin TM, et al. Incomplete penetrance of the NOD2 E383K substitution among members of a pediatric granulomatous arthritis pedigree. Arthritis Rheum 2009; 60:1804.
- Rosé CD, Wouters CH, Meiorin S, et al. Pediatric granulomatous arthritis: an international registry. Arthritis Rheum 2006; 54:3337.
- Xirotagaros G, Hernández-Ostiz S, Aróstegui JI, Torrelo A. Newly Described Autoinflammatory Diseases in Pediatric Dermatology. Pediatr Dermatol 2016; 33:602.
- Goldbach-Mansky R. Immunology in clinic review series; focus on autoinflammatory diseases: update on monogenic autoinflammatory diseases: the role of interleukin (IL)-1 and an emerging role for cytokines beyond IL-1. Clin Exp Immunol 2012; 167:391.
- Park H, Bourla AB, Kastner DL, et al. Lighting the fires within: the cell biology of autoinflammatory diseases. Nat Rev Immunol 2012; 12:570.
- Rodero MP, Crow YJ. Type I interferon-mediated monogenic autoinflammation: The type I interferonopathies, a conceptual overview. J Exp Med 2016; 213:2527.
- Lee-Kirsch MA. The Type I Interferonopathies. Annu Rev Med 2017; 68:297.
- Marrakchi S, Guigue P, Renshaw BR, et al. Interleukin-36-receptor antagonist deficiency and generalized pustular psoriasis. N Engl J Med 2011; 365:620.
- Liu Y, Jesus AA, Marrero B, et al. Activated STING in a vascular and pulmonary syndrome. N Engl J Med 2014; 371:507.
- Omoyinmi E, Melo Gomes S, Nanthapisal S, et al. Stimulator of interferon genes-associated vasculitis of infancy. Arthritis Rheumatol 2015; 67:808.
- Romberg N, Al Moussawi K, Nelson-Williams C, et al. Mutation of NLRC4 causes a syndrome of enterocolitis and autoinflammation. Nat Genet 2014; 46:1135.
- Canna SW, de Jesus AA, Gouni S, et al. An activating NLRC4 inflammasome mutation causes autoinflammation with recurrent macrophage activation syndrome. Nat Genet 2014; 46:1140.
- Boisson B, Laplantine E, Prando C, et al. Immunodeficiency, autoinflammation and amylopectinosis in humans with inherited HOIL-1 and LUBAC deficiency. Nat Immunol 2012; 13:1178.
- Ombrello MJ, Remmers EF, Sun G, et al. Cold urticaria, immunodeficiency, and autoimmunity related to PLCG2 deletions. N Engl J Med 2012; 366:330.
- Zhou Q, Lee GS, Brady J, et al. A hypermorphic missense mutation in PLCG2, encoding phospholipase Cγ2, causes a dominantly inherited autoinflammatory disease with immunodeficiency. Am J Hum Genet 2012; 91:713.
- Aderibigbe OM, Priel DL, Lee CC, et al. Distinct Cutaneous Manifestations and Cold-Induced Leukocyte Activation Associated With PLCG2 Mutations. JAMA Dermatol 2015; 151:627.
- Hoffman HM, Broderick L. Editorial: It Just Takes One: Somatic Mosaicism in Autoinflammatory Disease. Arthritis Rheumatol 2017; 69:253.
- Kawasaki Y, Oda H, Ito J, et al. Identification of a High-Frequency Somatic NLRC4 Mutation as a Cause of Autoinflammation by Pluripotent Cell-Based Phenotype Dissection. Arthritis Rheumatol 2017; 69:447.
- Zhou Q, Aksentijevich I, Wood GM, et al. Brief Report: Cryopyrin-Associated Periodic Syndrome Caused by a Myeloid-Restricted Somatic NLRP3 Mutation. Arthritis Rheumatol 2015; 67:2482.
- Rowczenio DM, Trojer H, Omoyinmi E, et al. Brief Report: Association of Tumor Necrosis Factor Receptor-Associated Periodic Syndrome With Gonosomal Mosaicism of a Novel 24-Nucleotide TNFRSF1A Deletion. Arthritis Rheumatol 2016; 68:2044.
- Mensa-Vilaro A, Cham WT, Tang SP, et al. Brief Report: First Identification of Intrafamilial Recurrence of Blau Syndrome due to Gonosomal NOD2 Mosaicism. Arthritis Rheumatol 2016; 68:1039.
- OVERVIEW OF PATHOGENESIS
- HALLMARKS OF THE AUTOINFLAMMATORY DISEASES
- DIFFERENTIAL DIAGNOSIS
- SCHNITZLER SYNDROME
- MAJOR PERIODIC FEVER SYNDROMES
- Familial Mediterranean fever
- TNF receptor-1 associated periodic syndrome
- Hyperimmunoglobulin D syndrome
- Cryopyrin-associated periodic syndromes
- PFAPA syndrome
- OTHER AUTOINFLAMMATORY DISORDERS
- Deficiency of the interleukin-1 receptor antagonist
- PAPA syndrome
- Blau syndrome
- Chronic atypical neutrophilic dermatitis with lipodystrophy and elevated temperature
- Deficiency of the interleukin-36 receptor antagonist
- Chronic recurrent multifocal osteomyelitis
- STING-associated vasculopathy with onset in infancy
- NLRC4-activating mutations
- LUBAC deficiency