Purpose of Review
One purpose of this review was to raise awareness for the new autoinflammatory syndromes. These diseases are increasingly recognized and are in the differential diagnosis of many disease states. We also aimed to review the latest recommendations for the diagnosis, management, and treatment of these patients.
Familial Mediterranean fever (FMF), cryopyrin-associated periodic syndrome (CAPS), tumor necrosis factor receptor-associated periodic fever syndrome (TRAPS), and hyperimmunoglobulinemia D and periodic fever syndrome/mevalonate kinase deficiency (HIDS/MVKD) are the more common autoinflammatory diseases that are characterized by periodic fevers and attacks of inflammation. Recently much collaborative work has been done to understand the characteristics of these patients and to develop recommendations to guide the physicians in the care of these patients. These recent recommendations will be summarized for all four diseases.
FMF is the most common periodic fever disease. We need to further understand the pathogenesis and the role of single mutations in the disease. Recently, the management and treatment of the disease have been nicely reviewed. CAPS is another interesting disease associated with severe complications. Anti-interleukin-1 (anti-IL-1) treatment provides cure for these patients. TRAPS is characterized by the longest delay in diagnosis; thus, both pediatricians and internists should be aware of the characteristic features and the follow-up of these patients. HIDS/MVKD is another autoinflammatory diseases characterized with fever attacks. The spectrum of disease manifestation is rather large in this disease, and we need further research on biomarkers for the optimal management of these patients.
This is a preview of subscription content, access via your institution.
Buy single article
Instant access to the full article PDF.
Price excludes VAT (USA)
Tax calculation will be finalised during checkout.
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
Hull KM, Shoham N, Chae JJ, Aksentijevich I, Kastner DL. The expanding spectrum of systemic autoinflammatory disorders and their rheumatic manifestations. Curr Opin Rheumatol. 2003;15(1):61–9.
Kastner DL, Aksentijevich I, Goldbach-Mansky R. Autoinflammatory disease reloaded: a clinical perspective. Cell. 2010;140(6):784–90.
• Ozen S, Bilginer Y. A clinical guide to autoinflammatory diseases: familial Mediterranean fever and next-of-kin. Nat Rev Rheumatol. 2014;10(3):135–47. This is an outstanding review for autoinflammatory disease.
Marshall GS, Edwards KM, Butler J, Lawton AR. Syndrome of periodic fever, pharyngitis, and aphthous stomatitis. J Pediatr. 1987;110(1):43–6.
•• Hofer M, Pillet P, Cochard MM, et al. International periodic fever, aphthous stomatitis, pharyngitis, cervical adenitis syndrome cohort: description of distinct phenotypes in 301 patients. Rheumatology. 2014;53(6):1125–9. This study revealed the clinical features of the largest cohort of PFAPA patients.
Batu ED, Eroglu FK, Tsoukas P, et al. Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome: analysis of patients from two geographic areas. Arthritis Care Res. 2016;68:1859.
Berkun Y, Levy R, Hurwitz A, et al. The familial Mediterranean fever gene as a modifier of periodic fever, aphthous stomatitis, pharyngitis, and adenopathy syndrome. Semin Arthritis Rheum. 2011;40(5):467–72.
•• ter Haar NM, Oswald M, Jeyaratnam J, et al. Recommendations for the management of autoinflammatory diseases. Ann Rheum Dis. 2015;74(9):1636–44. This study proposed the most recent recommendations of the SHARE initiative for autoinflammatory diseases.
Vanoni F, Theodoropoulou K, Hofer M. PFAPA syndrome: a review on treatment and outcome. Pediatric Rheumatol Online J. 2016;14(1):38.
Licameli G, Lawton M, Kenna M, Dedeoglu F. Long-term surgical outcomes of adenotonsillectomy for PFAPA syndrome. Arch Otolaryngol Head Neck Surg. 2012;138(10):902–6.
Chae JJ, Cho YH, Lee GS, et al. Gain-of-function pyrin mutations induce NLRP3 protein-independent interleukin-1beta activation and severe autoinflammation in mice. Immunity. 2011;34(5):755–68.
Xu H, Yang J, Gao W, et al. Innate immune sensing of bacterial modifications of rho GTPases by the pyrin inflammasome. Nature. 2014;513(7517):237–41.
Park YH, Wood G, Kastner DL, Chae JJ. Pyrin inflammasome activation and RhoA signaling in the autoinflammatory diseases FMF and HIDS. Nat Immunol. 2016;17(8):914–21.
Livneh A, Langevitz P, Zemer D, et al. Criteria for the diagnosis of familial Mediterranean fever. Arthritis Rheum. 1997;40(10):1879–85.
Yalcinkaya F, Ozen S, Ozcakar ZB, et al. A new set of criteria for the diagnosis of familial Mediterranean fever in childhood. Rheumatology. 2009;48(4):395–8.
Demirkaya E, Saglam C, Turker T, et al. Performance of different diagnostic criteria for familial Mediterranean fever in children with periodic fevers: results from a multicenter international registry. J Rheumatol. 2016;43(1):154–60.
Shinar Y, Obici L, Aksentijevich I, et al. Guidelines for the genetic diagnosis of hereditary recurrent fevers. Ann Rheum Dis. 2012;71(10):1599–605.
•• Giancane G, Ter Haar NM, Wulffraat N, et al. Evidence-based recommendations for genetic diagnosis of familial Mediterranean fever. Ann Rheum Dis. 2015;74(4):635–41. This study proposed the most recent recommendations for the genetic diagnosis of FMF.
Demirkaya E, Erer B, Ozen S, Ben-Chetrit E. Efficacy and safety of treatments in familial Mediterranean fever: a systematic review. Rheumatol Int. 2016;36(3):325–31.
Livneh A, Zemer D, Langevitz P, Shemer J, Sohar E, Pras M. Colchicine in the treatment of AA and AL amyloidosis. Semin Arthritis Rheum. 1993;23(3):206–14.
Polat A, Acikel C, Sozeri B, et al. Comparison of the efficacy of once- and twice-daily colchicine dosage in pediatric patients with familial Mediterranean fever—a randomized controlled noninferiority trial. Arthritis Res Ther. 2015;18:85.
•• Ozen S, Demirkaya E, Erer B, et al. EULAR recommendations for the management of familial Mediterranean fever. Ann Rheum Dis. 2016;75(4):644–51. This is the most recent recommendations for the management of FMF.
Kallinich T, Haffner D, Niehues T, et al. Colchicine use in children and adolescents with familial Mediterranean fever: literature review and consensus statement. Pediatrics. 2007;119(2):e474–83.
Hentgen V, Grateau G, Kone-Paut I, et al. Evidence-based recommendations for the practical management of familial Mediterranean fever. Semin Arthritis Rheum. 2013;43(3):387–91.
• Demirkaya E, Acikel C, Hashkes P, et al. Development and initial validation of international severity scoring system for familial Mediterranean fever (ISSF). Ann Rheum Dis. 2016;75(6):1051–6. This study proposed an International Severity Score for FMF and validated for both pediatric and adult FMF patients.
Williamson LM, Hull D, Mehta R, Reeves WG, Robinson BH, Toghill PJ. Familial Hibernian fever. Q J Med. 1982;51(204):469–80.
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(1):133–44.
•• Lachmann HJ, Papa R, Gerhold K, et al. The phenotype of TNF receptor-associated autoinflammatory syndrome (TRAPS) at presentation: a series of 158 cases from the Eurofever/EUROTRAPS international registry. Ann Rheum Dis. 2014;73(12):2160–7. This study revealed the clinical features of one of largest cohorts of TRAPS patients.
Ravet N, Rouaghe S, Dode C, et al. Clinical significance of P46L and R92Q substitutions in the tumour necrosis factor superfamily 1A gene. Ann Rheum Dis. 2006;65(9):1158–62.
Ter Haar N, Lachmann H, Ozen S, et al. Treatment of autoinflammatory diseases: results from the Eurofever Registry and a literature review. Ann Rheum Dis. 2013;72(5):678–85.
Park H, Bourla AB, Kastner DL, Colbert RA, Siegel RM. Lighting the fires within: the cell biology of autoinflammatory diseases. Nat Rev Immunol. 2012;12(8):570–80.
Dickie LJ, Aziz AM, Savic S, et al. Involvement of X-box binding protein 1 and reactive oxygen species pathways in the pathogenesis of tumour necrosis factor receptor-associated periodic syndrome. Ann Rheum Dis. 2012;71(12):2035–43.
Bachetti T, Chiesa S, Castagnola P, et al. Autophagy contributes to inflammation in patients with TNFR-associated periodic syndrome (TRAPS). Ann Rheum Dis. 2013;72(6):1044–52.
•• Federici S, Sormani MP, Ozen S, et al. Evidence-based provisional clinical classification criteria for autoinflammatory periodic fevers. Ann Rheum Dis. 2015;74(5):799–805. This study proposed a provisional clinical classification criteria for autoinflammatory periodic fevers.
Bulua AC, Mogul DB, Aksentijevich I, et al. Efficacy of etanercept in the tumor necrosis factor receptor-associated periodic syndrome: a prospective, open-label, dose-escalation study. Arthritis Rheum. 2012;64(3):908–13.
Gattorno M, Pelagatti MA, Meini A, et al. Persistent efficacy of anakinra in patients with tumor necrosis factor receptor-associated periodic syndrome. Arthritis Rheum. 2008;58(5):1516–20.
Gattorno M, Obici L, Cattalini M, et al. Canakinumab treatment for patients with active recurrent or chronic TNF receptor-associated periodic syndrome (TRAPS): an open-label, phase II study. Ann Rheum Dis. 2016;76:173.
Aksentijevich I, Nowak M, Mallah M, et al. De novo CIAS1 mutations, cytokine activation, and evidence for genetic heterogeneity in patients with neonatal-onset multisystem inflammatory disease (NOMID): a new member of the expanding family of pyrin-associated autoinflammatory diseases. Arthritis Rheum. 2002;46(12):3340–8.
Feldmann J, Prieur AM, Quartier P, 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. 2002;71(1):198–203.
Hoffman HM, Mueller JL, Broide DH, Wanderer AA, Kolodner RD. Mutation of a new gene encoding a putative pyrin-like protein causes familial cold autoinflammatory syndrome and Muckle-Wells syndrome. Nat Genet. 2001;29(3):301–5.
Walker UA, Hoffman HM, Williams R, Kuemmerle-Deschner J, Hawkins PN. Brief report: severe inflammation following vaccination against Streptococcus pneumoniae in patients with cryopyrin-associated periodic syndromes. Arthritis Rheumatol. 2016;68(2):516–20.
Drenth JP, Haagsma CJ, van der Meer JW. Hyperimmunoglobulinemia D and periodic fever syndrome. The clinical spectrum in a series of 50 patients. International Hyper-IgD Study Group. Medicine. 1994;73(3):133–44.
van der Meer JWVJ, Radl J, van Nieuwkoop JA, Meyer CJ, Lobatto S, et al. Hyperimmunoglobulinaemia D and periodic fever: a new syndrome. Lancet. 1984;1(8386):1087–90.
Mandey SH, Kuijk LM, Frenkel J, Waterham HR. A role for geranylgeranylation in interleukin-1beta secretion. Arthritis Rheum. 2006;54(11):3690–5.
van der Burgh R, Ter Haar NM, Boes ML, Frenkel J. Mevalonate kinase deficiency, a metabolic autoinflammatory disease. Clin Immunol. 2013;147(3):197–206.
•• Ter Haar NM, Jeyaratnam J, Lachmann HJ, et al. The phenotype and genotype of mevalonate kinase deficiency: a series of 114 cases from the Eurofever Registry. Arthritis Rheumatol. 2016;68:2795. This study revealed the clinical features of one of largest cohorts of HIDS patients.
Ammouri W, Cuisset L, Rouaghe S, et al. Diagnostic value of serum immunoglobulinaemia D level in patients with a clinical suspicion of hyper IgD syndrome. Rheumatology. 2007;46(10):1597–600.
Arkwright PD, Abinun M, Cant AJ. Mevalonic aciduria cured by bone marrow transplantation. N Engl J Med. 2007;357(13):1350.
Chaudhury S, Hormaza L, Mohammad S, et al. Liver transplantation followed by allogeneic hematopoietic stem cell transplantation for atypical mevalonic aciduria. Am J Transplant. 2012;12(6):1627–31.
Neven B, Valayannopoulos V, Quartier P, et al. Allogeneic bone marrow transplantation in mevalonic aciduria. N Engl J Med. 2007;356(26):2700–3.
Conflict of Interest
Dr. Ozen reports personal fees NOVARTIS, SOBI, and R-PHARM, outside the submitted work.
Erdal Sag and Yelda Bilginer declare that they have no conflict of interest.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
There is no external funding for this manuscript.
This article is part of the Topical Collection on Pediatric Rheumatology
Rights and permissions
About this article
Cite this article
Sag, E., Bilginer, Y. & Ozen, S. Autoinflammatory Diseases with Periodic Fevers. Curr Rheumatol Rep 19, 41 (2017). https://doi.org/10.1007/s11926-017-0670-8
- Autoinflammatory syndromes
- Periodic fever diseases