In order to bring you the best possible user experience, this site uses Javascript. If you are seeing this message, it is likely that the Javascript option in your browser is disabled. For optimal viewing of this site, please ensure that Javascript is enabled for your browser.
Did you know that your browser is out of date? To get the best experience using our website we recommend that you upgrade to a newer version. Learn more.

We use cookies to optimise the design of this website and make continuous improvement. By continuing your visit, you consent to the use of cookies. Learn more

Effect of Anakinra on Recurrent Pericarditis Among Patients With Colchicine Resistance and Corticosteroid Dependence: The AIRTRIP Randomized Clinical Trial

Paper commented by the Working Group on Myocardial and Pericardial Diseases

Topic(s): Pericardial Disease

Authors: Antonio Brucato, Massimo Imazio,Marco Gattorno, George Lazaros,Silvia Maestroni,Mara Carraro, Martina Finetti, Davide Cumetti, Alessandra Carobbio, Nicolino Ruperto, Renzo Marcolongo, Monia Lorini, Alessandro Rimini, Anna Valenti, Gian Luca Erre, Maria Pia Sormani, Riccardo Belli, Fiorenzo Gaita, Alberto Martini.

Commented by: Ivana Burazor, Cardiology, Institute for rehabilitation, Belgrade, Serbia



Background

Recurrent pericarditis is a difficult clinical problem1,2 that affects up to 30% of patients after a first episode of acute pericarditis, and up to 50% of those with a first recurrence, if not treated with colchicine.3-5 The optimal regimen for avoiding recurrences has not been clearly established. Treatment modalities in recurrent pericarditis include non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids, colchicine, immunosuppressive agents, and pericardiectomy. Quality of life may be severely affected in frequently relapsing cases, and patients with frequent recurrences can develop corticosteroid-dependence.

Anakinra is an interleukin (IL)-1 beta recombinant receptor antagonist that has been proposed as a potential treatment for recurrent pericarditis. Anakinra was used first in pediatric patients and then evaluated in adults.6,7 Anakinra administered daily subcutaneously for several months showed in both children and adults a rapid response with corticosteroid withdrawal.7,8 Current evidence with anakinra is based entirely on case reports and retrospective series,9 and to our knowledge, no randomized controlled trials have been conducted.

Aim of the Randomised Clinical Trial

To evaluate the efficacy and tolerability of anakinra in adults and children with recurrent idiopathic pericarditis that was corticosteroid-dependent and colchicine-resistant.

Study design

The study was an investigator initiated, 8-month, multicenter, randomized, double-blind, placebo-controlled, medication-withdrawal study to evaluate the efficacy and tolerability of anakinra in adults and children with idiopathic recurrent pericarditis. This study was investigator-initiated. SOBI provided anakinra and placebo as part of unrestricted institutional grant and had no role in the design and conduct of the study and in preparation of the
manuscript. SOBI is currently evaluating the outcomes of this study and potential next steps.

It consisted of two parts: (1) an open-label treatment period in which anakinra was administered daily for 60 days followed by (2) a double-blind withdrawal period in which patients who had a sustained complete response in part 1 were randomized to anakinra or to placebo daily for up to 6 months. The end of the study was the end of part 2 (8 months after enrollment) or the time of relapse, whichever occurred first. Patients who had another pericarditis recurrence could have the option to be re-treated with anakinra. All the patients were then followed for other 4 months to assess safety.

Summary

  • Out of 25 patients screened for entry in the study from 3 centers in Italy, 21 were enrolled. One patient was in the pediatric age-range (15 years old), and the remaining 20 patients were adults (age >18 years).
  • Mean number of recurrences before the study was 6.8, with a clinical history of recurrent pericarditis lasting 27.8 months on average. Median duration of follow up was 14 months.

Open-Label Phase (Part 1)

At the time of study enrollment, all 21 patients were experiencing a recurrence of pericarditis with a mean VAS of pain of 7.7; mean CRP level was 4.2 mg/dL . Eighteen patients displayed a pericardial effusion, mild in all cases (<10mm).

All patients had a complete response to open-label anakinra treatment at day 8, according to the protocol definition, that was maintained until randomization (day 60).

CRP was normalized in all the patients at day 8, and remained normal at day 60. Pain VAS quickly dropped, and was 0.4 on average at day 60. Also patient/parent's global assessment of overall well-being on a 21 circle VAS greatly improved over time, being 5.8 at day 0 and 1.6 at day 60 (where 10 is the worst quality).

All patients successfully discontinued corticosteroids within 6 weeks and proceeded to part 2. At randomization (day 60) CRP was normal in all the 21 patients, mean pain VAS was 0.4, and all the 21 patients were without corticostertoids and NSAIDs

Double-Blind Withdrawal Phase (Part 2)

During the double-blind treatment, recurrence of pericarditis occurred in 9 of the 10 (90%) patients randomized to placebo and in 2 of the 11 (18.2%) patients randomized to anakinra (33 and 120 days after randomization). Median flare-free survival (time to flare) was 72 days (IQR 64-150) from randomization in the placebo group and it could not be calculated in the anakinra group (p=0.0002). Half the patients assigned to placebo were free of flare after 72 days from randomization, while more than half of patients assigned to anakinra were still free of recurrence at the end of the study. In patients with recurrences, the mean time to flare was 28.4 days versus 76.5 days in the placebo and the anakinra group, respectively.

Nine patients (4 randomized to placebo and 5 randomized to anakinra) discontinued colchicine and 12 (6 randomized to placebo and 6 randomized to anakinra) were maintained on colchicine (according to physician and patient decision). During the double-blind treatment, concurrent treatment with colchicine did not significantly affect recurrence rate: 7/12 (58,3%) in colchicine and 4/9 (44,4%) without colchicine, and time to flare (median flare-free survival 90 days in colchicine while it could not be calculated in the not-colchicine group), but the study did not have the power to compare monotherapy with anakinra vs. combined therapy with anakinra plus colchicine. In patients with recurrences, the mean time to flare was 52.7 days in the colchicine group versus 10 days in the non-colchicine group, respectively resulting in an absolute mean difference of -42.7 (95% CI: -97.1; 11.7).

Adverse Events

The most common side effect in anakinra-treated patients was a local reaction at the injection site, observed in 20 out of 21 patients (95%) during the initial open-label phase (first phase, part 1); generally they disappeared over one month; 3 patients temporarily discontinued anakinra in the first open-label phase, but resumed it after topical treatment and systemic antihistamines, and no patient discontinued the study for this side effect. Herpes Zoster occurred in one patient treated with anakinra during the first open-label phase of the study with temporary discontinuation of anakinra.

Three patients (14.3%) showed an elevation of transaminases (<x2 normal values) in the first open-label phase, reversible after temporary discontinuation or dose reduction of anakinra.

Conclusions

In this preliminary study of patients with recurrent pericarditis with colchicine resistance and corticosteroid dependence, the use of anakinra compared with placebo reduced the risk of recurrence over a median of 14 months. Larger studies are needed to replicate these findings, as well as to assess safety and longer-term efficacy.

Comment

Refractory recurrent pericarditis is a major management issue since it is corticosteroid-dependent and does not respond to colchicine, thus patients are unable to withdraw corticosteroids without a relapse. Corticosteroids impair the growth in children, and Picco described the first 3 patients, all children, successfully treated with anakinra.6 At present 10 reports describing 46 patients (adults and children) have been published 6-8,10-16. In the recent 2015 guidelines of the European Society of Cardiology17 it was stated that anakinra, azathioprine and high dose intravenous immunoglobulins may be considered in corticosteroid-dependent recurrent pericarditis that is resistant or intolerant to colchicine, but the level of evidence was low: C (case series and experts opinion).

This study is the first randomized placebo controlled trial of anakinra for idiopathic recurrent pericarditis, showing that anakinra is a potential option for this subset of patients. These findings also provide evidence that IL1 plays an important role in the pathogenesis of idiopathic recurrent pericarditis 6,18.

Anakinra use is associated with an increased risk of side effects especially related to injection site reactions. These generally occurred early after drug delivery and were relatively transient (generally few weeks) and can be managed by the use of oral antihistamines and topical corticosteroids.19 Warming the syringe to room temperature before use is advisable along with application of cold pack to the injection site approximately 2-3 minutes before and immediately after the injection. Patients should be informed in advance about the potentiality of such reactions, to prevent unjustified drug discontinuation. Additional potential side effects include transaminase elevation that was observed in 3/21 (14.3%) of patients, and was limited and transient. The most important potential side effect is an increased risk of infections: one patient (4.7%) developed Herpes zoster and required temporary discontinuation of the study drug.

First usage of anakinra dates 1996 20; serious infections are rare and in a review of 5 clinical trials, they appeared in 1.7% of patients in the active arm as compared to 0.7% observed in the placebo group.21 Finally, neutropenia has been reported in approximately 5% of cases without, however, evidence of association with clinical events 21-23.

Anakinra has both advantages and disadvantages to consider in treating patients similar to those in this study. The main advantages of the drug are a rapid onset of effect and the capability to allow a quick withdrawal of corticosteroids. The potential disadvantages include a long duration of therapy as well as its high costs. Strict selection of the patients is important: only patients with a clear inflammatory pattern are candidates for this therapy. Such patients usually have a history of high fever, strikingly elevated levels of CRP, pleural effusions, particularly in the pediatric age: these clinical signs are likely associated to a pivotal pathogenic role of IL-1. Conversely, patients with mild or doubtful symptoms, and/or normal or near normal levels of CRP are not good candidates for anti-IL1 therapy 24.

Study limitations

The main limitation of this study is its small sample size. However, given the large treatment effect, the current study had the statistical power to verify the initial study hypothesis.

References


1. Imazio M, Gaita F, LeWinter M. Evaluation and Treatment of Pericarditis: A Systematic Review. JAMA. 2015;314:1498-506.

2. LeWinter MM. Clinical practice. Acute pericarditis. N Engl J Med. 2014;371:2410-6.

3. Imazio M, Brucato A, Cemin R, Ferrua S, Maggiolini S, Beqaraj F, Demarie D,Forno D, Ferro S, Maestroni S, Belli R, Trinchero R, Spodick DH, Adler Y; ICAP Investigators. A randomized trial of colchicine for acute pericarditis. N Engl J Med 2013;369:1522–1528.

4. Imazio M, Belli R, Brucato A, Cemin R, Ferrua S, Beqaraj F, et al. Efficacy and safety of colchicine for treatment of multiple recurrences of pericarditis (CORP-2): a multicentre, double-blind, placebo-controlled, randomised trial. Lancet 2014;383:2232-7.

5. Imazio M, Brucato A, Cemin R, Ferrua S, Belli R, Maestroni S, et al. Colchicine for recurrent pericarditis (CORP): a randomized trial. Ann Int Med 2011;155:409-14.

6. Picco P, Brisca G, Traverso F, Loy A, Gattorno M, Martini A. Successful treatment of idiopathic recurrent pericarditis in children with interleukin-1beta receptor antagonist (anakinra): an unrecognized autoinflammatory disease? Arth rheum 2009;60:264-8.

7. Lazaros G, Vasileiou P, Koutsianas C, Antonatou K, Stefanadis C, Pectasides D, et al. Anakinra for the management of resistant idiopathic recurrent pericarditis. Initial experience in 10 adult cases. Ann Rheum Dis. 2014; 73:2215-7.

8. Finetti M, Insalaco A, Cantarini L, Meini A, Breda L, Alessio M, et al. Long-term efficacy of interleukin-1 receptor antagonist (Anakinra) in corticosteroid-dependent and colchicine-resistant recurrent pericarditis. J Pediatrics 2014;164:1425-31.e1.

9. Lazaros G, Imazio M, Brucato A, Picardi E, Vassilopoulos D, Vasileiou P, Tousouis D, Gaita F. Anakinra: an emerging option for refractory idiopathic recurrent pericarditis. A systematic review of published evidence. J Cardiovasc Med 2016;17:256-62.

10. Jain S, Thongprayoon C, Espinosa RE, Hayes SN, Klarich KW, Cooper LT, et al. Effectiveness and Safety of Anakinra for Management of Refractory Pericarditis. American Journal of Cardiology. 2015; 116:1277-9

11. Massardier C, Dauphin C, Eschalier R, Lusson JR, Soubrier M. Resistant or recurrent acute pericarditis: A new therapeutic opportunity? Int J Cardiol 2014;177:e75-e7.

12. Scardapane A, Brucato A, Chiarelli F, Breda L. Efficacy of an interleukin-1β receptor antagonist (Anakinra) in idiopathic recurrent pericarditis. Pediatr Cardiol 2013;34:1989-91.

13. Scott IC, Hajela V, Hawkins PN, Lachmann HJ. A case series and systematic literature review of anakinra and immunosuppression in idiopathic recurrent pericarditis. J Cardiol Cases 2011;4:e93-e7.

14. Emmi G, Barnini T, Silvestri E, Milco D'Elios M, Emmi L, Prisco D. A new case of idiopathic recurrent acute pericarditis due to R104Q mutation in TNFRSF1A successfully treated with anakinra: expanding the questions. Clin Exp Rheumatol 2014; 32:297.

15. Cantarini L, Lucherini OM, Cimaz R, Galeazzi M. Recurrent pericarditis caused by a rare mutation in the TNFRSF1A gene and with excellent response to anakinra treatment. Clin Exp Rheumatol 2010;28:802.

16. D'Elia E, Brucato A, Pedrotti P, Valenti A, De Amici M, Fiocca L, et al. Successful treatment of subacute constrictive pericarditis with interleukin-1beta receptor antagonist (anakinra). Clin Exp Rheumatol 2015;33:294-5.

17. Adler Y, Charron P, Imazio M, Badano L, Baron-Esquivias G, Bogaert J, et al. 2015 ESC Guidelines for the diagnosis and management of pericardial diseases: The Task Force for the Diagnosis and Management of Pericardial Diseases of the European Society of Cardiology (ESC)Endorsed by: The European Association for Cardio-Thoracic Surgery (EACTS). European heart journal. 2015;36:2921-64.

18. Cantarini L, Imazio M, Brizi MG, Lucherini OM, Brucato A, Cimaz R, et al. Role of autoimmunity and autoinflammation in the pathogenesis of idiopathic recurrent pericarditis. Clin Rev Allergy Immunol. 2013;44:6-13.

19. Kaiser C, Knight A, Nordström D, et al. Injection-site reactions upon Kineret (anakinra) administration: experiences and explanations. Rheumatol Int 2012; 32:295-299.

20. Campion GV, Lebsack ME, Lookabaugh J, Gordon G, Catalano M. Dose-range and dose-frequency study of recombinant human interleukin-1 receptor antagonist in patients with rheumatoid arthritis. The IL-1Ra Arthritis Study Group. Arthritis Rheum. 1996;39:1092-101.

21. Salliot C, Dougados M, Gossec L. Risk of serious infections during rituximab, abatacept and anakinra treatments for rheumatoid arthritis: meta-analyses of randomized placebo controlled trials. Ann Rheum Dis 2009; 68:25–32.

22. Fleischmann RM. Addressing the safety of anakinra in patients with rheumatoid arthritis. Rheumatology (Oxford) 2003; 42 (Suppl. 2):ii29–ii35.

23. Woodrick R, Ruderman E. Safety of biologic therapy in rheumatoid arthritis. Robert S. and Eric M. Nat Rev Rheumatol 2011; 7:639–652.

24. Brucato A, D’Elia E, Pedrotti P, Valenti A, De Amici M, Fiocca L, Duino V, Senni M, Imazio M, Martini A. Reply to: "Effusive-constrictive pericarditis successfully treated with anakinra" G. Lazaros et al. Interleukin-1β receptor antagonist and pericardial constriction.Clin Exp Rheumatol. 2015;33:946

The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.

Contact us

Working Group on Myocardial & Pericardial Diseases

European Society of Cardiology

European Heart House
Les Templiers
2035 Route des Colles
CS 80179 Biot

06903Sophia Antipolis, FR