Rheumatology key message Canakinumab is effective in controlling relapsing pericardial inflammation in patients with systemic disease-associated pericarditis. Sir, Canakinumab is an anti-IL-1β mAb approved for refractory gout, cryopyrin-associated periodic syndromes, adult-onset Still’s disease (AOSD) and systemic JIA. We report our experience with canakinumab in recurrent rheumatic disease-associated pericarditis, recalcitrant to multiple immunosuppressive therapies. A 32-year-old male presented with fever, pericarditis, leucocytosis, increased ESR and CRP. NSAIDs failed to control the disease. Comprehensive work-up excluded infections and malignancies, and immunology tests were negative (RF, ACPAs, ANAs). Incomplete AOSD was diagnosed (three major, one minor Yamaguchi criteria) . He responded to high-dose CSs and MTX was added. During steroid tapering (prednisolone <10 mg/day), pericarditis relapsed necessitating increased CS doses (three flares on CS tapering). Colchicine was added but proved ineffective. After 4 years on continuous CS therapy, he developed osteoporosis and anakinra was administered but was discontinued due to severe injection-site reaction. Ultimately, canakinumab 150 mg/month was initiated; 2 months later, CSs were discontinued without serositis relapse. During the following 2 years on canakinumab monotherapy, he was in remission. A 37-year-old male developed fever, arthralgia, pericarditis, pleurisy and evanescent rash. He had leucocytosis and increased ESR/CRP, while RF, ACPAs and ANA were negative. AOSD was diagnosed (four major, one minor Yamaguchi criteria). The patient received high-dose CS and MTX (20 mg/week), but pericarditis relapsed at prednisolone tapering (7.5 mg/day). After 14 months on MTX, combined with oral and intravenous CS due to six disease flares, he developed arterial hypertension and cushingoid appearance. Anakinra administration was effective and he discontinued CS. However, 1 year later, he relapsed and developed injection-site reaction. Adalimumab and, next, tocilizumab were given (together with CS and MTX), but pericarditis relapsed during CS tapering. Four years after diagnosis, canakinumab was started (150 mg bimonthly) with prompt resolution of symptoms and tapering of CS. Two weeks before the third dose, the patient experienced mild relapse and canakinumab dosage was up-titrated to 150 mg/month, resulting in CS discontinuation and lack of relapse for 3.5 years. The third patient (a 58-year-old woman) manifested large pericardial effusion, small joint polyarthritis and elevated ESR/CRP, with negative RF, ACPAs and ANA. Seronegative RA was diagnosed  and the patient received MTX and CS, but effusion relapsed on CS tapering (<15 mg/day). Certolizumab failed to prevent pericarditis relapses. Anakinra was effective and CS tapered to 5 mg/day. Soon, however, she developed injection-site reaction, necessitating drug discontinuation. During the ensuing 12 months, she received sequentially tocilizumab, rituximab and abatacept, which were all ineffective (pericarditis relapsed while on a combination of MTX and prednisolone >15 mg/day) or induced allergic reaction (rituximab). The patient experienced >10 disease flares and multiple hospitalizations. Canakinumab (150 mg/month) was started and the patient lowered prednisolone dose to 7.5 mg/day. Due to a relapse, the dose was increased to 300 mg/month; however, the patient experienced two more relapses, albeit milder, at prednisolone dose 10 mg/day. A decision to discontinue canakinumab was made based on the patient’s preference and high cost of treatment. Recurrent pericarditis, idiopathic or associated with an underlying systemic autoimmune/autoinflammatory disease, often poses treatment challenges. Besides steroids, therapeutic choices are usually guided by the underlying diagnosis. We here reported cases of recurrent pericarditis in patients with different systemic diseases who received canakinumab after failure/intolerance to synthetic and biologic agents, including anakinra. Two patients (definitive and possible AOSD, respectively) attained rapid and long-standing remission (Fig. 1). AOSD is an autoinflammatory disease , wherein uncontrolled IL-1β production is considered the main underlying pathogenic mechanism. Accordingly, the clinical effectiveness of anakinra corroborates experimental findings . Interestingly, myocarditis, a rare (7%) but severe manifestation of AOSD, seems to be controlled by anakinra, while there are cases of severe viral myocarditis successfully treated by IL-1 receptor antagonist . The third patient (seronegative RA) had partial response, with disease relapses albeit at low CS doses, which ultimately led to canakinumab discontinuation. Although autoimmunity is the pathogenetic basis for RA, distinct genetic and immune pathways may operate in seropositive and seronegative subgroups. IL-1β has been implicated in RA pathogenesis . Notwithstanding blocking IL-1β by anakinra has been shown less effective in RA patients as compared with TNFα inhibition, patients with an inflammatory phenotype, such as our case, might benefit from it. While data support efficacy of anakinra in recurrent idiopathic pericarditis, similar effectiveness for canakinumab has not been reported. Although our patients did not have isolated idiopathic pericarditis, recurrent pericardial inflammation was the major determinant of treatment. The efficacy of anakinra was also evident in our case series, but development of injection-site reactions or failure mandated its discontinuation. Reasons for anakinra failure could be the drug’s short half-life time (6 h), associated suboptimal IL-1 receptor blockade or its immunogenicity (up to 14.3%) [7, 8]. Therefore, canakinumab could be an alternative in selected cases of recurrent pericarditis resistant to other immunosuppressive and anti-IL1β treatments. Fig. 1 View largeDownload slide A parallel reduction in CRP and daily prednisolone dose is clearly shown in the three patients following canakinumab associationPatients 1 and 2 discontinued prednisolone by 3–5 months and remained in remission for more than 3 years. Patient 3 had to discontinue canakinumab after 10 months, despite decreases in CRP and corticosteroid dose. Fig. 1 View largeDownload slide A parallel reduction in CRP and daily prednisolone dose is clearly shown in the three patients following canakinumab associationPatients 1 and 2 discontinued prednisolone by 3–5 months and remained in remission for more than 3 years. Patient 3 had to discontinue canakinumab after 10 months, despite decreases in CRP and corticosteroid dose. Funding: No specific funding was received from any funding bodies in the public, commercial or not-for-profit sectors to carry out the work described in this manuscript. Disclosure statement: The authors have declared no conflicts of interest. References 1 Yamaguchi M, Ohta A, Tsunematsu et al. Preliminary criteria for classification of adult Still's disease. J Rheumatol 1992; 19: 424– 30. Google Scholar PubMed 2 Aletaha D, Neogi T, Silman AJ et al. 2010 Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum 2010; 62: 2569– 81. Google Scholar CrossRef Search ADS PubMed 3 Kastner DL, Aksentijevich I, Goldbach-Mansky R. Autoinflammatory disease reloaded: a clinical perspective. Cell 2010; 140: 784– 90. Google Scholar CrossRef Search ADS PubMed 4 Lequerré T, Quartier P, Rosellini D. Interleukin-1 receptor antagonist (anakinra) treatment in patients with systemic-onset juvenile idiopathic arthritis or adult onset Still disease: preliminary experience in France. Ann Rheum Dis 2008; 67: 302– 8. Google Scholar CrossRef Search ADS PubMed 5 Cavalli G, Pappalardo F, Mangieri A et al. Treating life-threatening myocarditis by blocking interleukin-1. Crit Care Med 2016; 44: e751– 4. Google Scholar CrossRef Search ADS PubMed 6 Horai R, Saijo S, Tanioka H et al. Development of chronic inflammatory arthropathy resembling rheumatoid arthritis in interleukin 1 receptor antagonist-deficient mice. J Exp Med 2000; 191: 313– 20. Google Scholar CrossRef Search ADS PubMed 7 Dinarello CA, van der Meer JW. Treating inflammation by blocking interleukin-1 in humans. Semin Immunol 2013; 25: 469– 84. Google Scholar CrossRef Search ADS PubMed 8 Bao J, Yue T, Liu W et al. Secondary failure to treatment with recombinant human IL-1 receptor antagonist in Chinese patients with rheumatoid arthritis. Clin Rheumatol 2011; 30: 697– 701. Google Scholar CrossRef Search ADS PubMed © The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: firstname.lastname@example.org This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)
Rheumatology – Oxford University Press
Published: Mar 21, 2018
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