Abstract
Autoinflammatory diseases are disorders of the innate immune system characterized by uncontrolled inflammation. The most commonly encountered autoinflammatory diseases are the hereditary periodic fever syndromes, which present with fever and other features of the skin, serosal membranes, and musculoskeletal system. The main inherited (monogenic) periodic fever syndromes are familial Mediterranean fever (FMF), cryopyrin-associated periodic syndrome (CAPS), tumor necrosis factor receptor-associated periodic syndrome (TRAPS), and hyperimmunoglobulin D syndrome (HIDS)/mevalonate kinase deficiency (MKD). Recent advances in our understanding of the molecular and pathophysiological basis of autoinflammatory diseases have provided new treatment strategies. Patients with periodic fever syndromes have clearly benefited from anti-interleukin (IL)-1 treatment. Colchicine is still the mainstay of FMF therapy, but IL-1 blockade is also effective if colchicine fails. Early diagnosis and effective treatment can prevent irreversible organ damage. The scope of pathogenic mutations and more targeted therapy for better management of these rare diseases remains to be defined.
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Masters SL, Simon A, Aksentijevich I, Kastner DL. Horror autoinflammaticus: the molecular pathophysiology of autoinflammatory disease (*). Annu Rev Immunol. 2009;27:621–68.
French FMFC. A candidate gene for familial Mediterranean fever. Nat Genet. 1997;17(1):25–31.
Ancient missense mutations in a new member of the RoRet gene family are likely to cause familial Mediterranean fever. The International FMF Consortium. Cell. 1997;90(4):797–807.
Berkun Y, Padeh S, Reichman B, Zaks N, Rabinovich E, Lidar M, et al. A single testing of serum amyloid a levels as a tool for diagnosis and treatment dilemmas in familial Mediterranean fever. Semin Arthritis Rheum. 2007;37(3):182–8.
Heller H, Sohar E, Gafni J, Heller J. Amyloidosis in familial Mediterranean fever. An independent genetically determined character. Arch Intern Med. 1961;107:539–50.
Meinzer U, Quartier P, Alexandra JF, Hentgen V, Retornaz F, Kone-Paut I. Interleukin-1 targeting drugs in familial Mediterranean fever: a case series and a review of the literature. Semin Arthritis Rheum. 2011;41(2):265–71.
Ozen S, Bilginer Y, Aktay Ayaz N, Calguneri M. Anti-interleukin 1 treatment for patients with familial Mediterranean fever resistant to colchicine. J Rheumatol. 2011;38(3):516–8.
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.
Aksentijevich I, Putnam CD, Remmers EF, Mueller JL, Le J, Kolodner RD, et al. The clinical continuum of cryopyrinopathies: novel CIAS1 mutations in North American patients and a new cryopyrin model. Arthritis Rheum. 2007;56(4):1273–85.
Kuemmerle-Deschner JB, Ozen S, Kone-Paut I, Goldbach-Mansky R, Lachmann H, Blank N, et al. Diagnostic criteria for cryopyrin-associated periodic syndrome (CAPS). Ann Rheum Dis. 2016. doi:10.1136/annrheumdis-2016-209686.
McDermott MF, Aksentijevich I, Galon J, McDermott EM, Ogunkolade BW, Centola M, 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.
Aksentijevich I, Galon J, Soares M, Mansfield E, Hull K, Oh HH, et al. The tumor-necrosis-factor receptor-associated periodic syndrome: new mutations in TNFRSF1A, ancestral origins, genotype-phenotype studies, and evidence for further genetic heterogeneity of periodic fevers. Am J Hum Genet. 2001;69(2):301–14.
Feldmann J, Prieur AM, Quartier P, Berquin P, Certain S, Cortis E, 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.
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.
van der Hilst JC, Bodar EJ, Barron KS, Frenkel J, Drenth JP, van der Meer JW, et al. Long-term follow-up, clinical features, and quality of life in a series of 103 patients with hyperimmunoglobulinemia D syndrome. Medicine (Baltimore). 2008;87(6):301–10.
ter Haar NM, Oswald M, Jeyaratnam J, Anton J, Barron KS, Brogan PA, et al. Recommendations for the management of autoinflammatory diseases. Ann Rheum Dis. 2015;74(9):1636–44.
Ozen S, Demirkaya E, Erer B, Livneh A, Ben-Chetrit E, Giancane G, et al. EULAR recommendations for the management of familial Mediterranean fever. Ann Rheum Dis. 2016;75(4):644–51.
Jesus AA, Goldbach-Mansky R. IL-1 blockade in autoinflammatory syndromes. Annu Rev Med. 2014;65:223–44.
Goldfinger SE. Colchicine for familial Mediterranean fever. N Engl J Med. 1972;287(25):1302.
Padeh S, Gerstein M, Berkun Y. Colchicine is a safe drug in children with familial Mediterranean fever. J Pediatr. 2012;161(6):1142–6.
Livneh A, Langevitz P. Diagnostic and treatment concerns in familial Mediterranean fever. Baillieres Best Pract Res Clin Rheumatol. 2000;14(3):477–98.
Majeed HA, Rawashdeh M, El-Shanti H, Qubain H, Khuri-Bulos N, Shahin HM. Familial Mediterranean fever in children: the expanded clinical profile. QJM. 1999;92(6):309–18.
Zemer D, Livneh A, Danon YL, Pras M, Sohar E. Long-term colchicine treatment in children with familial Mediterranean fever. Arthritis Rheum. 1991;34(8):973–7.
Zemer D, Pras M, Sohar E, Modan M, Cabili S, Gafni J. Colchicine in the prevention and treatment of the amyloidosis of familial Mediterranean fever. N Engl J Med. 1986;314(16):1001–5.
Shinar Y, Obici L, Aksentijevich I, Bennetts B, Austrup F, Ceccherini I, et al. Guidelines for the genetic diagnosis of hereditary recurrent fevers. Ann Rheum Dis. 2012;71(10):1599–605.
Ben-Chetrit E, Backenroth R. Amyloidosis induced, end stage renal disease in patients with familial Mediterranean fever is highly associated with point mutations in the MEFV gene. Ann Rheum Dis. 2001;60(2):146–9.
Cerquaglia C, Diaco M, Nucera G, La Regina M, Montalto M, Manna R. Pharmacological and clinical basis of treatment of Familial Mediterranean Fever (FMF) with colchicine or analogues: an update. Curr Drug Targets Inflamm Allergy. 2005;4(1):117–24.
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.
Grattagliano I, Bonfrate L, Ruggiero V, Scaccianoce G, Palasciano G, Portincasa P. Novel therapeutics for the treatment of familial Mediterranean fever: from colchicine to biologics. Clin Pharmacol Ther. 2014;95(1):89–97.
van der Hilst J, Moutschen M, Messiaen PE, Lauwerys BR, Vanderschueren S. Efficacy of anti-IL-1 treatment in familial Mediterranean fever: a systematic review of the literature. Biologics. 2016;10:75–80.
Hashkes PJ, Spalding SJ, Giannini EH, Huang B, Johnson A, Park G, et al. Rilonacept for colchicine-resistant or -intolerant familial Mediterranean fever: a randomized trial. Ann Intern Med. 2012;157(8):533–41.
Topaloglu R, Batu ED, Orhan D, Ozen S, Besbas N. Anti-interleukin 1 treatment in secondary amyloidosis associated with autoinflammatory diseases. Pediatr Nephrol. 2016;31(4):633–40.
Benedetti FD, Anton J, Gattorno M, Lachmann H, Kone-Paut I, Ozen S. A phase III pivotal umbrella trial of canakinumab in patients with autoinflammatory periodic fever syndromes (colchicine resistant FMF, HIDS/MKD and TRAPS). Ann Rheum Dis. 2016;75(suppl 2):615–6.
Seyahi E, Ozdogan H, Celik S, Ugurlu S, Yazici H. Treatment options in colchicine resistant familial Mediterranean fever patients: thalidomide and etanercept as adjunctive agents. Clin Exp Rheumatol. 2006;24(5 Suppl 42):S99–103.
Bilgen SA, Kilic L, Akdogan A, Kiraz S, Kalyoncu U, Karadag O, et al. Effects of anti-tumor necrosis factor agents for familial mediterranean fever patients with chronic arthritis and/or sacroiliitis who were resistant to colchicine treatment. J Clin Rheumatol. 2011;17(7):358–62.
Ter Haar N, Lachmann H, Ozen S, Woo P, Uziel Y, Modesto C, et al. Treatment of autoinflammatory diseases: results from the Eurofever Registry and a literature review. Ann Rheum Dis. 2013;72(5):678–85.
Koitschev A, Gramlich K, Hansmann S, Benseler S, Plontke SK, Koitschev C, et al. Progressive familial hearing loss in Muckle–Wells syndrome. Acta Otolaryngol. 2012;132(7):756–62.
Kuemmerle-Deschner JB, Koitschev A, Ummenhofer K, Hansmann S, Plontke SK, Koitschev C, et al. Hearing loss in Muckle–Wells syndrome. Arthritis Rheum. 2013;65(3):824–31.
Neven B, Marvillet I, Terrada C, Ferster A, Boddaert N, Couloignier V, et al. Long-term efficacy of the interleukin-1 receptor antagonist anakinra in ten patients with neonatal-onset multisystem inflammatory disease/chronic infantile neurologic, cutaneous, articular syndrome. Arthritis Rheum. 2010;62(1):258–67.
Sibley CH, Plass N, Snow J, Wiggs EA, Brewer CC, King KA, et al. Sustained response and prevention of damage progression in patients with neonatal-onset multisystem inflammatory disease treated with anakinra: a cohort study to determine three- and five-year outcomes. Arthritis Rheum. 2012;64(7):2375–86.
Goldbach-Mansky R, Dailey NJ, Canna SW, Gelabert A, Jones J, Rubin BI, et al. Neonatal-onset multisystem inflammatory disease responsive to interleukin-1beta inhibition. N Engl J Med. 2006;355(6):581–92.
Ross JB, Finlayson LA, Klotz PJ, Langley RG, Gaudet R, Thompson K, et al. Use of anakinra (Kineret) in the treatment of familial cold autoinflammatory syndrome with a 16-month follow-up. J Cutan Med Surg. 2008;12(1):8–16.
Sibley CH, Chioato A, Felix S, Colin L, Chakraborty A, Plass N, et al. A 24-month open-label study of canakinumab in neonatal-onset multisystem inflammatory disease. Ann Rheum Dis. 2015;74(9):1714–9.
Rodriguez-Smith J, Lin YC, Li Tsai W, Kim H, Montealegre-Sanchez G, Chapelle D, et al. CSF cytokines correlate with aseptic meningitis and blood brain barrier function in neonatal-onset multisystem inflammatory disease (NOMID). Arthritis Rheumatol. 2017. doi:10.1002/art.40055.
Kone-Paut I, Lachmann HJ, Kuemmerle-Deschner JB, Hachulla E, Leslie KS, Mouy R, et al. Sustained remission of symptoms and improved health-related quality of life in patients with cryopyrin-associated periodic syndrome treated with canakinumab: results of a double-blind placebo-controlled randomized withdrawal study. Arthritis Res Ther. 2011;13(6):R202.
Lachmann HJ, Kone-Paut I, Kuemmerle-Deschner JB, Leslie KS, Hachulla E, Quartier P, et al. Use of canakinumab in the cryopyrin-associated periodic syndrome. N Engl J Med. 2009;360(23):2416–25.
Kuemmerle-Deschner JB, Hachulla E, Cartwright R, Hawkins PN, Tran TA, Bader-Meunier B, et al. Two-year results from an open-label, multicentre, phase III study evaluating the safety and efficacy of canakinumab in patients with cryopyrin-associated periodic syndrome across different severity phenotypes. Ann Rheum Dis. 2011;70(12):2095–102.
Kuemmerle-Deschner JB, Ramos E, Blank N, Roesler J, Felix SD, Jung T, et al. Canakinumab (ACZ885, a fully human IgG1 anti-IL-1beta mAb) induces sustained remission in pediatric patients with cryopyrin-associated periodic syndrome (CAPS). Arthritis Res Ther. 2011;13(1):R34.
Kuemmerle-Deschner JB, Hofer F, Endres T, Kortus-Goetze B, Blank N, Weissbarth-Riedel E, et al. Real-life effectiveness of canakinumab in cryopyrin-associated periodic syndrome. Rheumatology (Oxford). 2016;55(4):689–96.
Yokota S, Imagawa T, Nishikomori R, Takada H, Abrams K, Lheritier K, et al. Long-term safety and efficacy of canakinumab in cryopyrin-associated periodic syndrome: results from an open-label, phase III pivotal study in Japanese patients. Clin Exp Rheumatol. 2016 [Epub ahead of print, PMID 27974104].
Hoffman HM, Throne ML, Amar NJ, Sebai M, Kivitz AJ, Kavanaugh A, 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. 2008;58(8):2443–52.
Hoffman HM, Throne ML, Amar NJ, Cartwright RC, Kivitz AJ, Soo Y, et al. Long-term efficacy and safety profile of rilonacept in the treatment of cryopryin-associated periodic syndromes: results of a 72-week open-label extension study. Clin Ther. 2012;34(10):2091–103.
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.
Bulua AC, Mogul DB, Aksentijevich I, Singh H, He DY, Muenz LR, 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.
Nedjai B, Hitman GA, Quillinan N, Coughlan RJ, Church L, McDermott MF, et al. Proinflammatory action of the antiinflammatory drug infliximab in tumor necrosis factor receptor-associated periodic syndrome. Arthritis Rheum. 2009;60(2):619–25.
Gattorno M, Pelagatti MA, Meini A, Obici L, Barcellona R, Federici S, 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, Tormey V, Abrams K, Davis N, 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. 2017;76(1):173–8.
Quillinan N, Mannion G, Mohammad A, Coughlan R, Dickie LJ, McDermott MF, et al. Failure of sustained response to etanercept and refractoriness to anakinra in patients with T50M TNF-receptor-associated periodic syndrome. Ann Rheum Dis. 2011;70(9):1692–3.
Torene R, Nirmala N, Obici L, Cattalini M, Tormey V, Caorsi R, et al. Canakinumab reverses overexpression of inflammatory response genes in tumour necrosis factor receptor-associated periodic syndrome. Ann Rheum Dis. 2017;76(1):303–9.
Vaitla PM, Radford PM, Tighe PJ, Powell RJ, McDermott EM, Todd I, et al. Role of interleukin-6 in a patient with tumor necrosis factor receptor-associated periodic syndrome: assessment of outcomes following treatment with the anti-interleukin-6 receptor monoclonal antibody tocilizumab. Arthritis Rheum. 2011;63(4):1151–5.
Akasbi N, Soyfoo MS. Successful treatment of tumor necrosis factor receptor-associated periodic syndrome (TRAPS) with tocilizumab: a case report. Eur J Rheumatol. 2015;2(1):35–6.
Hosoya T, Mizoguchi F, Hasegawa H, Miura K, Koike R, Kubota T, et al. A case presenting with the clinical characteristics of tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS) without TNFRSF1A mutations successfully treated with tocilizumab. Intern Med. 2015;54(16):2069–72.
Simon A, Drewe E, van der Meer JW, Powell RJ, Kelley RI, Stalenhoef AF, et al. Simvastatin treatment for inflammatory attacks of the hyperimmunoglobulinemia D and periodic fever syndrome. Clin Pharmacol Ther. 2004;75(5):476–83.
Vitale A, Rigante D, Lucherini OM, Caso F, Muscari I, Magnotti F, et al. Biological treatments: new weapons in the management of monogenic autoinflammatory disorders. Mediators Inflamm. 2013;2013:939847.
Bodar EJ, van der Hilst JC, Drenth JP, van der Meer JW, Simon A. Effect of etanercept and anakinra on inflammatory attacks in the hyper-IgD syndrome: introducing a vaccination provocation model. Neth J Med. 2005;63(7):260–4.
Kostjukovits S, Kalliokoski L, Antila K, Korppi M. Treatment of hyperimmunoglobulinemia D syndrome with biologics in children: review of the literature and Finnish experience. Eur J Pediatr. 2015;174(6):707–14.
Galeotti C, Meinzer U, Quartier P, Rossi-Semerano L, Bader-Meunier B, Pillet P, et al. Efficacy of interleukin-1-targeting drugs in mevalonate kinase deficiency. Rheumatology (Oxford). 2012;51(10):1855–9.
Shendi HM, Devlin LA, Edgar JD. Interleukin 6 blockade for hyperimmunoglobulin D and periodic fever syndrome. J Clin Rheumatol. 2014;20(2):103–5.
Arkwright PD, Abinun M, Cant AJ. Mevalonic aciduria cured by bone marrow transplantation. N Engl J Med. 2007;357(13):1350.
Neven B, Valayannopoulos V, Quartier P, Blanche S, Prieur AM, Debre M, et al. Allogeneic bone marrow transplantation in mevalonic aciduria. N Engl J Med. 2007;356(26):2700–3.
Chaudhury S, Hormaza L, Mohammad S, Lokar J, Ekong U, Alonso EM, et al. Liver transplantation followed by allogeneic hematopoietic stem cell transplantation for atypical mevalonic aciduria. Am J Transplant. 2012;12(6):1627–31.
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Seza Ozen has previously received consultancy and speaker fees from Novartis, Sobi, and R-Pharma. Selcan Demir has no conflicts of interest.
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Ozen, S., Demir, S. Monogenic Periodic Fever Syndromes: Treatment Options for the Pediatric Patient. Pediatr Drugs 19, 303–311 (2017). https://doi.org/10.1007/s40272-017-0232-6
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DOI: https://doi.org/10.1007/s40272-017-0232-6