[en] BACKGROUND: Familial Mediterranean fever, mevalonate kinase deficiency (also known as the hyperimmunoglobulinemia D syndrome), and the tumor necrosis factor receptor-associated periodic syndrome (TRAPS) are monogenic autoinflammatory diseases characterized by recurrent fever flares. METHODS: We randomly assigned patients with genetically confirmed colchicine-resistant familial Mediterranean fever, mevalonate kinase deficiency, or TRAPS at the time of a flare to receive 150 mg of canakinumab subcutaneously or placebo every 4 weeks. Patients who did not have a resolution of their flare received an add-on injection of 150 mg of canakinumab. The primary outcome was complete response (resolution of flare and no flare until week 16). In the subsequent phase up to week 40, patients who had a complete response underwent a second randomization to receive canakinumab or placebo every 8 weeks. Patients who underwent a second randomization and had a subsequent flare and all other patients received open-label canakinumab. RESULTS: At week 16, significantly more patients receiving canakinumab had a complete response than those receiving placebo: 61% vs. 6% of patients with colchicine-resistant familial Mediterranean fever (P<0.001), 35% versus 6% of those with mevalonate kinase deficiency (P=0.003), and 45% versus 8% of those with TRAPS (P=0.006). The inclusion of patients whose dose was increased to 300 mg every 4 weeks yielded a complete response in 71% of those with colchicine-resistant familial Mediterranean fever, 57% of those with mevalonate kinase deficiency, and 73% of those with TRAPS. After week 16, an extended dosing regimen (every 8 weeks) maintained disease control in 46% of patients with colchicine-resistant familial Mediterranean fever, 23% of those with mevalonate kinase deficiency, and 53% of those with TRAPS. Among patients who received canakinumab, the most frequently reported adverse events were infections (173.3, 313.5, and 148.0 per 100 patient-years among patients with colchicine-resistant familial Mediterranean fever, those with mevalonate kinase deficiency, and those with TRAPS, respectively), with a few being serious infections (6.6, 13.7, and 0.0 per 100 patient-years). CONCLUSIONS: In this trial, canakinumab was effective in controlling and preventing flares in patients with colchicine-resistant familial Mediterranean fever, mevalonate kinase deficiency, and TRAPS. (Funded by Novartis; CLUSTER ClinicalTrials.gov number, NCT02059291 .).
Disciplines :
General & internal medicine
Author, co-author :
De Benedetti, Fabrizio
Gattorno, Marco
Anton, Jordi
Ben-Chetrit, Eldad
Frenkel, Joost
Hoffman, Hal M.
Kone-Paut, Isabelle
Lachmann, Helen J.
Ozen, Seza
Simon, Anna
Zeft, Andrew
Calvo Penades, Inmaculada
Moutschen, Michel ; Université de Liège - ULiège > Département des sciences cliniques > Immunopath. - Maladies infect. et médec. interne gén.
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: 2795-805.
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;73:2160-7.
Özen S, Batu ED, Demir S. Familial Mediterranean fever: recent developments in pathogenesis and new recommendations for management. Front Immunol 2017;8:253.
Sahin S, Yalcin I, Senel S, et al. Assessment life quality of familial Mediterranean fever patients by Short Form-36 and its relationship with disease parameters. Eur Rev Med Pharmacol Sci 2013;17: 958-63.
van der Hilst JC, Bodar EJ, Barron KS, 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; 87:301-10.
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 2017;76:173-8.
Papa R, Doglio M, Lachmann HJ, et al. A Web-based collection of genotype-phenotype associations in hereditary recurrent fevers from the Eurofever registry. Orphanet J Rare Dis 2017;12:167.
Ozen S, Demirkaya E, Erer B, et al. EULAR recommendations for the management of familial Mediterranean fever. Ann Rheum Dis 2016;75:644-51.
Park YH, Wood G, Kastner DL, Chae JJ. Pyrin inflammasome activation and RhoA signaling in the autoinflammatory diseases FMF and HIDS. Nat Immunol 2016;17:914-21.
Omenetti A, Carta S, Delfino L, Martini A, Gattorno M, Rubartelli A. Increased NLRP3-dependent interleukin 1β secretion in patients with familial Mediterranean fever: correlation with MEFV genotype. Ann Rheum Dis 2014;73:462-9.
Akula MK, Shi M, Jiang Z, et al. Control of the innate immune response by the mevalonate pathway. Nat Immunol 2016; 17:922-9.
Drenth JP, Göertz J, Daha MR, van der Meer JW. Immunoglobulin D enhances the release of tumor necrosis factor-alpha, and interleukin-1 beta as well as interleukin-1 receptor antagonist from human mononu-clear cells. Immunology 1996;88:355-62.
Frenkel J, Rijkers GT, Mandey SH, et al. Lack of isoprenoid products raises ex vivo interleukin-1beta secretion in hyperimmunoglobulinemia D and periodic fever syndrome. Arthritis Rheum 2002;46: 2794-803.
Bachetti T, Chiesa S, Castagnola P, et al. Autophagy contributes to inflammation in patients with TNFR-associated periodic syndrome (TRAPS). Ann Rheum Dis 2013;72:1044-52.
Lobito AA, Kimberley FC, Muppidi JR, et al. Abnormal disulfide-linked oligo-merization results in ER retention and altered signaling by TNFR1 mutants in TNFR1-associated periodic fever syndrome (TRAPS). Blood 2006;108:1320-7.
Bulua AC, Simon A, Maddipati R, et al. Mitochondrial reactive oxygen species promote production of proinflammatory cytokines and are elevated in TNFR1-associated periodic syndrome (TRAPS). J Exp Med 2011;208:519-33.
Simon A, Park H, Maddipati R, et al. Concerted action of wild-type and mutant TNF receptors enhances inflammation in TNF receptor 1-associated periodic fever syndrome. Proc Natl Acad Sci U S A 2010; 107:9801-6.
Gül A, Ozdogan H, Erer B, et al. Efficacy and safety of canakinumab in adolescents and adults with colchicine-resistant familial Mediterranean fever. Arthritis Res Ther 2015;17:243.
Brik R, Butbul-Aviel Y, Lubin S, et al. Canakinumab for the treatment of children with colchicine-resistant familial Mediterranean fever: a 6-month open-label, single-arm pilot study. Arthritis Rheumatol 2014;66:3241-3.
Alpay N, Sumnu A, Calışkan Y, Yazıcı H, Türkmen A, Gül A. Efficacy of anakinra treatment in a patient with colchicine-resistant familial Mediterranean fever. Rheumatol Int 2012;32:3277-9.
Ozen S, Bilginer Y, Aktay Ayaz N, Cal-guneri M. Anti-interleukin 1 treatment for patients with familial Mediterranean fever resistant to colchicine. J Rheumatol 2011;38:516-8.
Stankovic Stojanovic K, Delmas Y, Torres PU, et al. Dramatic beneficial effect of interleukin-1 inhibitor treatment in patients with familial Mediterranean fever complicated with amyloidosis and renal failure. Nephrol Dial Transplant 2012;27:1898-901.
Arostegui JI, Anton J, Calvo I, et al. Open-label, phase II study to assess the efficacy and safety of canakinumab treatment in active hyperimmunoglobulinemia D with periodic fever syndrome. Arthritis Rheumatol 2017;69:1679-88.
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;58:1516-20.
Obici L, Meini A, Cattalini M, et al. Favourable and sustained response to anakinra in tumour necrosis factor receptor-associated periodic syndrome (TRAPS) with or without AA amyloidosis. Ann Rheum Dis 2011;70:1511-2.
Livneh A, Langevitz P, Zemer D, et al. Criteria for the diagnosis of familial Mediterranean fever. Arthritis Rheum 1997; 40:1879-85.
Shinar Y, Obici L, Aksentijevich I, et al. Guidelines for the genetic diagnosis of hereditary recurrent fevers. Ann Rheum Dis 2012;71:1599-605.
Hashkes PJ, Spalding SJ, Giannini EH, et al. Rilonacept for colchicine-resistant or -intolerant familial Mediterranean fever: a randomized trial. Ann Intern Med 2012;157:533-41.
Ben-Zvi I, Kukuy O, Giat E, et al. Anakinra for colchicine-resistant familial Mediterranean fever: a randomized, double-blind, placebo-controlled trial. Arthritis Rheumatol 2017;69:854-62.
Lachmann HJ, Kone-Paut I, Kuem-merle-Deschner JB, et al. Use of canakinumab in the cryopyrin-associated periodic syndrome. N Engl J Med 2009;360:2416-25.
Lachmann HJ, Brogan PA. Autoin-flammation: when is familial Mediterranean fever ‘severe’? Nat Rev Rheumatol 2016;12:256-8.
Piram M, Koné-Paut I, Lachmann HJ, et al. Validation of the Auto-Inflammatory Diseases Activity Index (AIDAI) for hereditary recurrent fever syndromes. Ann Rheum Dis 2014;73:2168-73.
Lachmann HJ, Goodman HJB, Gil-bertson JA, et al. Natural history and outcome in systemic AA amyloidosis. N Engl J Med 2007;356:2361-71.
Kuemmerle-Deschner JB, Hoffman H, Hawkins PN, et al. Long-term safety and efficacy of canakinumab in patients with CAPS: final results from the Beta-Confident Registry. Pediatr Rheumatol Online J 2015;13(Suppl 1):P3.
Brogan P, Hofer M, Kuemmerle-Deschner J, et al. FRI0503 efficacy and safety of canakinumab in patients with cryopyrin associated periodic syndromes: an open-label, phase-III, extension study. Ann Rheum Dis 2016;75:Suppl 2:620-1.
