Emerging Therapies for Recurrent Pericarditis: Interleukin-1 inhibitors

Abstract

Recurrent pericarditis (RP) is a complex inflammatory disorder associated with adverse outcomes and poor quality of life. After the first episode of acute pericarditis, a non-negligible group of patients will fail to achieve complete remission despite treatment and will be challenged by side effects from the chronic use of medications like corticosteroids. The cause of RP remains unknown in the majority of cases, mainly due to a gap in knowledge of its complex pathophysiology. Over the past 2 decades, the interleukin-1 (IL-1) pathway has been uncovered as a key element in the inflammatory cascade, allowing the development of pharmacological targets known as IL-1 inhibitors. This group of medications has emerged as a treatment option for patients with RP colchicine-resistance and steroid dependents. Currently, anakinra and rilonacept, have demonstrated beneficial impact in clinical outcomes with a reasonable safety profile in randomized clinical trials. There is still paucity of data regarding the use of canakinumab in the treatment of patients with RP. Although further studies are needed to refine therapeutic protocols and taper of concomitant therapies, IL-1 inhibitors, continue to consolidate as part of the pharmacological armamentarium to manage this complex condition with potential use as monotherapy. The aim of this review is to highlight the role of IL-1 pathway in RP and discuss the efficacy, safety, and clinical applicability of IL-1 inhibitors in the treatment of RP based on current evidence.

Keywords: interleukin‐1 inhibitors; pericardial disease; pericarditis; recurrent pericarditis.

Figure 1. Inflammasome and activation of Interleukin‐1β.

Infectious and sterile noxious stimuli injure the pericardial cells primarily through the activation of pathogen‐associated molecular patterns and damage‐associated molecular patterns, leading to the expression/release of IL‐1α deposits. This promotes along with other triggers, the transcription of the IL‐β precursor and the assembling of the inflammasome in the cytosol of innate immune response cells (ex., tissue macrophage). The inflammasome enzymatic component Procaspase‐1 cleaves the IL‐1ß precursor into its active form. Ultimately, both IL‐1α and IL‐1ß bind to IL‐1 receptors in capillary endothelial cells promoting further pericardial inflammation by various mechanism enhancing pericardial damage which perpetuate the inflammatory cascade of events. COX indicates cyclooxygenase; CRP, C‐reactive protein; DAMPs, damage‐associated molecular patterns; IL, interleukin; NLRP3, nucleotide‐binding oligomerization domain–like receptor pyrin domain‐containing 3; PAMPs, pathogen‐associated molecular patterns; and WBC, white blood cells. Reprinted from Klein et al, with permission. ©2020, Elsevier.

Figure 2. Kaplan–Meier analysis of patients with recurrent pericarditis free of relapse in the double‐blind withdrawal phase, from day 0 to day 180 after randomization (intention‐to‐treat analysis).

Recurrent pericarditis relapse in the double‐blind withdrawal phase, from day 0 to day 180 after randomization to either anakinra (blue) or placebo (green).

Figure 3. Rilonacept mechanism of action.

Rilonacept ultrastructure with 3 main components: the ligand binding‐domain of the human IL‐1 receptor, IL‐1 receptor accessory protein, and the Fc portion of the human IgG1. Rilonacept “pocket” binds to IL‐1α and IL‐1ß acting as an IL‐1 trap blocking the interaction with their specific receptor. Fc indicates fragment crystallizable region; IL‐1RAcP, IL‐1 receptor accessory protein; IL‐1RI, IL‐1 receptor; IL, interleukin. Reprinted from Klein et al with permission. ©2020, Elsevier.

Figure 4. NRS scores (pain) and CRP levels in symptomatic patients with elevated CRP.

Numerical rating score for pain (NRS) (orange curve) and C‐reactive protein (CRP) levels (blue curve) in patients with active disease and elevated CRP during the treatment period and optional extension treatment period. Normalization of CRP levels was achieved at a median of 9 days. BL indicates baseline; CRP, c‐reactive protein; EoEP, end of extension period; EoTP, end of treatment period; NRS, numerical rating score for pain; SE, standard error; W, week. Adapted from Klein et al.

Figure 5. Rhapsody Phase III trial outcomes.

A, Time to the First Adjudicated Pericarditis Recurrence. Curves for the time to the first adjudicated pericarditis recurrence in the randomized‐withdrawal period are shown. Circles indicate the time of data censoring for reasons other than a primary efficacy end‐point event (e.g., a visit at the end of the randomized‐withdrawal period). Overall, 2 patients (7%) in the rilonacept group and 23 (74%) in the placebo group had pericarditis recurrence. The median time to recurrence could not be estimated in the rilonacept group and was 8.6 weeks (95% CI, 4.0 to 11.7) in the placebo group. CI indicates confidence interval; No, number. B, Mean Numerical Rating Scale Scores for Pain and C—reactive protein Levels over the 12‐Week Run‐In Period. Numerical rating scale scores for pain and C‐reactive protein (CRP) levels as assessed by a central laboratory were recorded during the run‐in period, during which all the patients received rilonacept. The mean pain numerical rating scale score and mean CRP level at the baseline visit differ from those recorded for the qualifying pericarditis episode; to allow for the completion of screening procedures, the investigator was permitted to treat each patient with standard‐of‐care medications temporarily during the interval between presentation with the qualifying episode and the baseline visit or trial enrollment. A 3‐day rolling mean was calculated on the basis of non‐missing values over each successive 3‐day interval. In accordance with the protocol, pain was assessed daily with the use of a numerical rating scale (with scores ranging from 0 to 10 and with higher scores indicating greater pain severity). CRP was measured at baseline, on day 4, and at weeks 1, 2, 4, 6, and 12. At week 12, a total of 81 patients had assessments of the CRP level, but 2 of these patients had discontinued treatment before week 12; therefore, only 79 patients were considered to still be participating in the run‐in period. I bars indicate the standard error. No indicates number; Wk, week. Reprinted from Klein et al. with permission. ©2020, Massachusetts Medical Society.

Figure 6. Proposed flowchart for the introduction of IL‐1 inhibitors in the management of recurrent pericarditis.

CMR indicates cardiac magnetic resonance; CRP, C‐reactive protein; CT, computed tomography; NRS, numerical rating scale; and PeFF, pericardial effusion.