Lessons From Genetics About the Interleukin 1 Gene and Treatment of Recurrent Pericarditis

Acute pericarditis is the most common manifestation of pericardial disease and results from inflammation of the fibroelastic lining of the heart. Complications of pericarditis include cardiac tamponade and constrictive pericarditis, both of which are associated with significant morbidity and mortality. Although acute pericarditis is often isolated to a single episode, up to 30% of pericarditis cases recur and may result in recurrent pericarditis, setting up a vicious autoinflammatory cycle in the pericardium. The combination of colchicine and nonsteroidal anti-inflammatory drugs (NSAIDs) constitutes standard first-line therapy in acute pericarditis and is frequently effective. However, the traditional treatment of recurrent pericarditis–the addition of prednisone to NSAIDs and colchicine–is frequently ineffective, leading to steroid dependence and associated glucocorticoid adverse effects.¹

Over the last decade, significant scientific advancements have come with the recognition of the role of innate immunity in pericarditis, including the NLR Family Pyrin Domain Containing 3 (NLRP3) inflammasome and downstream interleukin 1 (IL-1) activation.² This fundamental work has led to the advancement of validated therapeutic targets with the use of IL-1 blockers. Previous data supporting the role of IL-1 therapies came from use of anakinra, a competitive inhibitor of the IL-1 type 1 receptor that blocks activity of IL-1α and IL-1β, in the treatment of recurrent pericarditis (Anakinra-Treatment of Recurrent Idiopathic Pericarditis [AIRTRIP] trial).³ Subsequently, the landmark multicenter phase 3 study titled Rilonacept Inhibition of Interleukin-1 Alpha and Beta for Recurrent Pericarditis: a Pivotal Symptomatology and Outcomes Study (RHAPSODY) evaluated rilonacept (a soluble decoy receptor, or “IL-1α and IL-1β cytokine trap” binding IL-1α and IL-1β) in patients with recurrent pericarditis who were refractory to standard treatment. In RHAPSODY, rilonacept led to a 96% reduction in recurrent pericarditis compared with placebo (hazard ratio, 0.04; 95% CI, 0.01-0.18; P < .001).⁴ These striking results led to US Food and Drug Administration approval of rilonacept, making it the first biologic immunotherapy approved for the treatment of recurrent pericarditis. These results have been further confirmed with a different IL-1 trap receptor, goflikicept.⁵

The availability of biologics with efficacy against recurrent pericarditis while enabling avoidance of long-term glucocorticoid use has been transformative for affected patients. However, this rapid paradigm shift in the therapeutic landscape leaves many unanswered questions for the cardiovascular community, especially because biologics have been associated with small but significant increases in risk of sepsis and other infections. These unanswered questions include the optimal treatment of different pericarditis endophe-notypes, optimal treatment algorithm for patients who experience recurrent episodes (eg, when to reach for biologics), optimal duration of therapy before attempting withdrawal of immunosuppression, and appropriate clinical monitoring. These knowledge gaps highlight the potential utility of a deeper understanding of pericarditis pathobiology and susceptibility to guide the optimal allocation of therapies and development of additional novel therapeutic strategies. Genomewide association studies (GWAS) represent an unbiased approach, leveraging large-scale genetic datasets to identify genes and pathways linked to a particular condition or trait. However, there have been no large-scale GWAS of pericarditis published to date, and they could inform drug development for this condition.

In this issue of JAMA Cardiology, Thorolfsdottir et al⁶ report a large pericarditis GWAS meta-analysis incorporating cohorts of individuals with European genetic ancestry from 5 countries. This study included 4894 patients with pericarditis, of whom 22.6% were identified as having recurrent pericarditis, and 1 457 822 controls. The analysis identified 2 independent common intergenic genetic variants associated with pericarditis at chromosome 2q14, which includes genes for the majority of IL-1 cytokines. The strongest association was observed with rs12992780, which sits approximately 10 kilo-bases downstream of IL1B, the gene encoding IL-1β; this variant had a stronger magnitude of association with recurrent vs acute pericarditis (odds ratio, 0.76 vs 0.86; P = .03 for heterogeneity). The second association was with rs7575402, which sits close to both IL1RN (encoding the IL-1 receptor antagonist protein) and IL1F10 (encoding IL-1 family member 10). These signals did not interact with each other with respect to their associated pericarditis risk. The authors did not identify any rare variants associated with pericarditis.

The authors further performed extensive in silico analyses to prioritize the relevant causal genes linked to the identified common genetic variants, a well-recognized challenge in leveraging GWAS results to inform clinical translation.⁶ These experiments included examination of variants linked to messenger RNA expression (expression quantitative trait loci, or eQTLs) in whole blood, relevant tissues, and macrophages; variants linked to circulating plasma proteins (protein quantitative trait loci, or pQTLs); and those linked to DNA methylation, a process that helps regulate gene expression. These analyses did not identify definitive evidence for causal genes linked to these variants. However, they did provide some clues. For example, the rs7575402 variant was a methylation QTL for a regulatory element predicted to affect expression of 6 genes, 5 of which are in the IL-1 family, including IL1RN. Although this variant was not a pQTL in the datasets queried by the authors, it has been identified as a pQTL for IL1RN in other datasets with concordant direction of effect.⁶ Given the biological plausibility demonstrated in human clinical trials and proximity of these identified variants to IL-1, these results collectively lend further support to the role of IL-1 pathway in pericardial disease.

These results provide important corroboratory data supporting the use of targeted anti-IL-1 biologics in pericardial disease given that these therapies have only been recently approved after small, albeit strong, clinical trials. Insights will continue to come from larger and longer-duration clinical trials to refine optimal therapeutic approaches incorporating IL-1 inhibition in pericardial disease. The present study by Thorolfsdottir and colleagues⁶ represents an important first step toward understanding the genetic architecture of pericarditis. Future efforts at expanded genetic discovery may further inform pericarditis treatment. Future genetic studies incorporating larger numbers of cases (particularly of recurrent pericarditis, which remains the key therapeutic challenge) and multiancestry meta-analysis are expected to boost power for genetic discovery and identification of additional targets.

Clinically, the spectrum of pericarditis is vast; it cannot currently be predicted who will have recurrence vs a single episode, who will respond to standard first-line therapies and IL-1 inhibition, and who might benefit from extended therapy. Beyond genetics, how we incorporate advanced multimodality imaging in our diagnosis and longitudinal management is an active question that will require further study. In summary, while the time for targeted biologic therapy to treat a challenging cardiovascular condition has arrived, important questions remain to define precision management approaches for pericardial disease.