Anakinra: A Promising Therapy For Refractory Idiopathic Recurrent Pericarditis
Idiopathic recurrent acute pericarditis (IRAP) is considered to be an auto-inflammatory condition based on a phenotypic presentation of seemingly unprovoked inflammatory episodes affecting the pericardium in the absence of significant involvement of adaptive immunity.1 Hence, blockade of interleukin 1 (IL-1) pathway has been touted to be a promising therapeutic approach especially in patients who are refractory to the conventional regimens which include colchicine , non-steroid anti-inflammatory agents and prednisone. NSAIDs and colchicine have been the mainstay agents to be used in IRAP with good efficacy for the majority of patients.2 Prednisone is reserved for those with recurrent attacks but it is associated with a prolonged course and further recurrences, especially if used at high doses.2
Although extensive and well-designed pathogenetic studies are lacking, there is emerging clinical evidence that biologic medications targeting IL-1 pathway such as the recombinant IL-1 receptor antagonist anakinra is beneficial. Anakinra is currently approved for the treatment of rheumatoid arthritis and Cryopyrin-Associated Periodic Syndromes. Anakinra and other IL-1 blockers such as rilonacept and canakinumab have been increasingly used with efficacy in the field of rheumatology in conditions where there is evidence that IL-1 is involved, such as familial Mediterranean fever, adult onset Still's disease, systemic onset Juvenile Idiopathic Arthritis, gout, and pseudogout.3 The study of Finetti et al4 even though retrospective in nature, corroborates this hypothesis and justifies the need for prospective well-designed trials with larger number of patients. An advantage of the study is the long-term follow up of 39 months especially given the patient variability in their attack-remission intervals.
Anakinra was shown to be impressively effective in reducing flares by 95% compared to the preatreatment period with no relapses during treatment. Response was universal and fast (median time to clinical response 2.2 days). Additionally, prednisone use, which is a significant contributor to morbidity was tapered to nil withintwo months after anakinra administration.4 Given that use of steroids is associated with more frequent and persistent flares5 we can speculate that use of anakinra prior to steroid use in cases refractory to colchicine and NSAIDs could yield better long term outcomes without the associated comorbidities driven by chronic steroid use and decreased incidence of constrictive pericarditis. This remains to be studied.
Evidence for the use of other immunosuppressive agents such as azathioprine, methotrexate, mycophenolate and intravenous immunoglobulins remains anecdotal at best.6-8
As evidenced by this study, anakinra is well tolerated with an acceptable safety profile. Once infectious, neoplastic and other autoimmune or auto-inflammatory causes have been ruled out IL-1 blockade is a reasonable option. However, we should bebe cognizant of the increased risk of infections, especially opportunistic ones as with any other biologic agent.
What remains to be seen in prospective studies is what would be the acceptable duration of treatment with anakinra? In the study of Finetti et al. median duration of treatment with anakinra was 12 months. The study demonstrated a signal that anakinra has the potential to alter the natural course of the disease, with some patients (8/14) being able to completely discontinue the medication after a total mean duration of treatment of 25.1 months whileothers had to be restarted and remain on that but for less time than the initial administration. It is interesting to note thatpatients who relapsed were treated for shorter time period (median treatment duration 8 months). A vexing question to be addressed is whether anakinra has disease-modifying properties as evidenced by long-term remission once discontinued or by decreased prevalence of constrictive pericarditis and/or pericardiectomy.
Granted that mechanistic studies at the tissue level are not always feasible or absolutely clinically indicated and given that immunologic perturbations may not be reflected in the periphery, it is important in the future to use other research tools such as genomics and/or metabolomics in an effort to elucidate the drivers of recurrent inflammation in these patients. In this way we may be able to find biomarkers that predict flares and treatment responses to different medications and patient subgroups. Currently, C-reactive protein (CRP) and high sensitivity CRP remains the most cost effective test to detect inflammatory activity and identify patients at higher risk of recurrence.9 Incorporating cardiac magnetic resonance to tailor treatment has been gaining traction in an effort to reduce pericarditis recurrence and exposure to steroids.10
This study provides further evidence to support the use of anakinra in refractory patients with IRAP and substantiates the need for prospective well designed trials to assess its efficacy and safety in this patient population.
References
- Maestroni, S., et al., Recurrent pericarditis: autoimmune or autoinflammatory? Autoimmun Rev, 2012. 12(1): p. 60-5.
- Lilly, L.S., Treatment of acute and recurrent idiopathic pericarditis. Circulation, 2013. 127(16): p. 1723-6.
- Jesus, A.A. and R. Goldbach-Mansky, IL-1 blockade in autoinflammatory syndromes. Annu Rev Med, 2014. 65: p. 223-44.
- Finetti, M., et al., Long-term efficacy of interleukin-1 receptor antagonist (anakinra) in corticosteroid-dependent and colchicine-resistant recurrent pericarditis. J Pediatr, 2014. 164(6): p. 1425-31 e1.
- Imazio, M., et al., Corticosteroid therapy for pericarditis: a double-edged sword. Nat Clin Pract Cardiovasc Med, 2008. 5(3): p. 118-9.
- Moretti, M., et al., Usefulness of high-dose intravenous human immunoglobulins treatment for refractory recurrent pericarditis. Am J Cardiol, 2013. 112(9): p. 1493-8.
- Vianello, F., et al., Azathioprine in isolated recurrent pericarditis: a single centre experience. Int J Cardiol, 2011. 147(3): p. 477-8.
- Marcolongo, R., et al., Immunosuppressive therapy prevents recurrent pericarditis. J Am Coll Cardiol, 1995. 26(5): p. 1276-9.
- Imazio, M., et al., Prevalence of C-reactive protein elevation and time course of normalization in acute pericarditis: implications for the diagnosis, therapy, and prognosis of pericarditis. Circulation, 2011. 123(10): p. 1092-7.
- Alraies, M.C., et al., Usefulness of cardiac magnetic resonance-guided management in patients with recurrent pericarditis. Am J Cardiol, 2015. 115(4): p. 542-7.
Keywords: Adaptive Immunity, Anti-Inflammatory Agents, Non-Steroidal, Antibodies, Monoclonal, Arthritis, Juvenile, Arthritis, Rheumatoid, Azathioprine, Biological Products, Biomarkers, C-Reactive Protein, Chondrocalcinosis, Colchicine, Comorbidity, Cryopyrin-Associated Periodic Syndromes, Familial Mediterranean Fever, Genomics, Gout, Immunoglobulins, Intravenous, Immunosuppressive Agents, Incidence, Inflammation, Interleukin 1 Receptor Antagonist Protein, Interleukin-1, Magnetic Resonance Spectroscopy, Metabolomics, Methotrexate, Pericardiectomy, Pericarditis, Constrictive, Pericardium, Prednisone, Prevalence, Prospective Studies, Receptors, Interleukin-1, Recombinant Fusion Proteins, Recurrence, Retrospective Studies, Rheumatology, Still's Disease, Adult-Onset, Traction
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