Anti-interleukin-1 for recurrent pericarditis; maybe a fix (but prior studies do not really mix)

Abstract

Recurrent pericarditis, a condition associated with significant morbidity and even increased mortality, has received more recent welcome attention, mainly because of the emergence of promising, new, immunemodulating treatments. Imazio et al conduct a systematic review and metaanalysis of 2 randomised controlled trials (RCT) 3 and 5 observational studies (OS), examining the efficacy and safety of antiinterleukin-1 (IL-1) agents (all anakinra, bar 1 RCT using rilonacept in 397 pooled patients with recurrent pericarditis despite standard medical therapy (nonsteroidal antiinflammatory drugs, colchicine, corticosteroids). While this paper is not without controversy (below we will delve further into the potential for bias due to the small number of studies, small effect size and funnel plot concerns), it nonetheless merits special attention given limited data on this topic and the need for more clinical research. The authors review hypothesisgenerating, mechanistic data for the IL-1 pathway, a muchneeded additional therapeutic target for the treatment of recurrent pericarditis. IL-1 is a proinflammatory cytokine that mediates the NLR pyrin domain 3 protein (NLRP3) that is part of the inflammasome signalling pathway, which in turn stimulates the synthesis of systemic inflammatory molecules such as cyclooxygenase and prostaglandins. Through the use of IL-1 inhibitors, namely anakinra and rilonacept, the authors highlight the IL-1/NPL3 pathway as an important mediator of systemic inflammation in pericarditis. Figure 1 illustrates the pathogenic role of the IL-1 pathway in recurrent pericarditis. Patients receiving antiIL-1 agents had a statistically significant lower incidence rate ratio (IRR) (number of events divided by the persontime at risk) for recurrent pericarditis (IRR 0.06, 95% CI 0.03 to 0.14, I=95%; p<0.00001) compared with patients receiving placebo and/or standard medical therapy (figure 2) This observed efficacy was consistent across the pooled data from RCTs and OS, RCTs (IRR 0.04, 95% CI 0.01 to 0.12, I=0%) and OS (IRR 0.07, 95% CI 0.03 to 0.17, I=95%) with a median followup duration of 14 months (IQR 12–39) (figure 2). To evaluate the safety of antiIL-1 agents in this cohort, the authors conducted a pooled analysis of the risk ratio (RR) of developing adverse events (AE). AntiIL-1 agents were associated with an increased risk of any AEs compared with placebo (RR 5.38, 95% CI 2.08 to 13.92, I=0%), but all events were mild or moderate in severity according to the MedDRA System Organ Class while drug discontinuation occurred in four patients in the entire cohort, and there were no deaths on treatment. The most common AEs were injectionsiterelated reactions, which occurred in 15/41 (36.6%) vs none, RR 14.98, 95% CI 2.09 to 107.09, I=0%; infections occurred in 13/51 (25.5%) vs 3/41 (7.3%), RR 3.65, 95% CI 1.23 to 10.85, I=0%) (figure 3). The authors acknowledge the limitations of their analyses, namely the paucity of RCT data in the current literature, necessitating the derivation of end point data from the inclusion of OS. The I index is a measure of point estimate variability between studies in metaanalyses (no rule of thumb cutoff values but generally <25%=‘homogenous’,<50%=‘acceptable’); if constituent studies are relatively precise with nonwide CIs, I reflects innate differences/inconsistencies between studies (true heterogeneity). In this paper, an I=95% raises concern over the reliability of the outcome measures due to high heterogeneity within the subgroup of OS (likely accounted for by relative differences in methodological quality and/or standardisation of study design). Specifically, in the two RCTs that were included in the analysis, 3 comparisons were made between patients receiving treatment and other patients receiving placebo; however in the OS (including the International Registry of Anakinra for Pericarditis (IRAP) OS, the largest contributor to both efficacy and safety outcome measures in the metaanalysis, n=224), patients served as their own controls in that comparisons were made between the same patients on and off treatment. Undoubtedly, this heterogeneity in the study design impacts on the translatability of the pooled efficacy endpoint data. To assess the potential for publication bias, the authors performed a funnel plot analysis. It is likely that the small number of studies and the small sample size of patients within the selected studies, contributed significantly to the funnel plot asymmetry. It is described that as a rule of thumb, tests for funnel plot asymmetry should not be used when there are fewer than 10 studies in the metaanalysis, because test power is usually too low to distinguish chance from real asymmetry. In most studies included in the analysis, antiIL-1 agents were assessed in the setting of idiopathic or inflammatory recurrent pericarditis phenotype, where less common phenotypes such as infective, neoplastic or autoimmune pericarditis were excluded. This limits the generalisability of antiIL-1 agents for use in patients with a nonidiopathic or inflammatory phenotype. We have summarised the best available data of antiIL-1 agents in recurrent pericarditis, to better illustrate the paucity of available data for the use of antiIL-1 agents in recurrent pericarditis (table 1). How should readers use the data to better inform their clinical practice? First, clinicians should be reminded of the high incidence of recurrent pericarditis in their clinical practice (which complicates between 15% and 30% of patients after an index case of pericarditis despite compliance with standard medical therapy). Furthermore, if left inadequately treated or if treatment refractory, the clinical sequelae of recurrent pericariditis can be acutely lifethreatening (cardiac tamponade) and/or debilitating (constrictive pericarditis). The later, a debilitating complex diagnostic and management clinical conundrum, often requiring multiple presentations to a specialist pericardial centre for multimodality imaging diagnostic testing approach often with added complex haemodynamic catheterisation and subsequent surgical stripping of the pericardium as the final step for symptomatic relief. A lack of recognition and inertia in the management of recurrent pericarditis not infrequently results in signficant added morbidity, where patients suffer from chronic relapsing symptoms that limit functional capacity and reduce quality of life with potentially life threatening consequences. Current guidelines unfortunately reflect this inertia, as there is relative paucity of additional therapies for patients with refractory recurrent pericarditis Cardiovascular Imaging, Cleveland Clinic, Cleveland, Ohio, USA