Absence of Pericarditis Recurrence in Rilonacept-Treated Patients With COVID-19 and SARS-CoV-2 Vaccination: Results From the RHAPSODY Long-term Extension.

Background: Rilonacept inhibits the interleukin-1 pathway, and extended treatment in patients with recurrent pericarditis (RP) reduced recurrence risk by 98% in the phase 3 trial, RHAPSODY long-term extension (LTE). Severe acute respiratory syndrome (SARS)-CoV-2 vaccination and/or infection may trigger pericarditis recurrence, and in clinical practice, it is unknown whether to continue rilonacept during SARS-CoV-2 infection. This post-hoc analysis of the RHAPSODY LTE aimed to inform rilonacept management in RP patients vaccinated against SARS-CoV-2 or who contract COVID-19. Methods: Analysis was conducted from May 2020 to June 2022. The LTE portion of RHAPSODY LTE enabled up to 24 months of additional open-label rilonacept treatment beyond the pivotal study. Rilonacept efficacy data in preventing pericarditis recurrence were assessed, and concomitant SARS-CoV-2 vaccination and COVID-19 adverse event data were evaluated. Results: No pericarditis recurrences were temporally associated with vaccination. Sixteen COVID-19 cases were reported; 10 in 30 unvaccinated or partially vaccinated patients (33%) vs 6 of 44 fully vaccinated patients (14%; P = 0.04). Twelve of 16 patients (75%) were receiving rilonacept at the time of infection, and none experienced pericarditis recurrence. One pericarditis recurrence occurred in the peri-COVID-19 period in 1 of 4 patients who had stopped rilonacept treatment > 4.5 months prior. COVID-19 severity was mild in 13 patients, moderate in 2, and severe in 1. Conclusions: Full vaccination effectively reduced COVID-19 events in patients treated with rilonacept. Vaccination or COVID-19 during rilonacept treatment did not increase pericarditis recurrence. Continued rilonacept treatment in patients contracting COVID-19 did not worsen disease severity, whereas rilonacept interruption increased pericarditis recurrence, supporting a recommendation for continued rilonacept treatment for RP during vaccination or COVID-19. ClinicalTrialsgov identifier: NCT03737110.

Contexte: Le rilonacept inhibe la voie de l'interleukine-1 et, d'après les résultats de la période de prolongation à long terme de l'essai de phase III RHAPSODY, la poursuite du traitement par cet agent chez les patients atteints de péricardite récidivante a réduit le risque de récidive de 98 %. La vaccination contre le syndrome respiratoire aigu sévère (SRAS)-CoV-2 ou l'infection à ce virus pourrait toutefois déclencher une récidive de la péricardite, et dans la pratique clinique, on ignore s'il vaut mieux poursuivre le traitement par rilonacept pendant l'infection à SRAS-CoV-2. Cette analyse post-hoc de la période de prolongation à long terme de l'essai RHAPSODY vise à orienter la gestion du rilonacept chez les patients atteints de péricardite récidivante qui sont vaccinés contre le SRAS-CoV-2 ou qui contractent la COVID-19. Méthodologie: L'analyse a été effectuée de mai 2020 à juin 2022. La période de prolongation à long terme de l'essai RHAPSODY a permis d'accumuler des données en mode ouvert pendant une période allant jusqu'à 24 mois au-delà de l'étude pivot. Les données sur l'efficacité du rilonacept en prévention de la récidive de péricardite ont été évaluées, tout comme les données sur la vaccination concomitante contre le SRAS-CoV-2 et les cas de COVID-19. Résultats: Aucune récidive de la péricardite n'a pu être associée sur le plan temporel avec la vaccination. Au total, 16 cas de COVID-19 ont été signalés, dont 10 chez les patients non vaccinés ou partiellement vaccinés sur 30 (33 %) et 6 chez les patients complètement vaccinés sur 44 (14 %; p = 0,04). De ces 16 patients, 12 (75 %) prenaient du rilonacept au moment de l'infection et aucun n'a connu de récidive de la péricardite. Une récidive de la péricardite s'est produite dans la période suivant la COVID-19 chez 1 des 4 patients qui avaient cessé de prendre le rilonacept > 4,5 mois auparavant. La COVID-19 a été légère chez 13 patients, modérée chez 2 patients et sévère chez 1 patient. Conclusions: La vaccination complète a réduit efficacement les cas de COVID-19 chez les patients traités par le rilonacept. La vaccination ou l'infection à SRAS-CoV-2 pendant le traitement par rilonacept n'a pas augmenté le risque de récidive de la péricardite. La poursuite du traitement par rilonacept chez les patients atteints de COVID-19 n'a pas aggravé la sévérité de la maladie, tandis que l'interruption du traitement a augmenté le risque de récidive de la péricardite, ce qui plaide en faveur de la recommandation de poursuivre le traitement de la péricardite récidivante par le rilonacept pendant la vaccination ou la COVID-19. Numéro d'identification ClinicalTrialsgov: NCT03737110.

Longitudinal cardiac magnetic resonance imaging following clinical response to rilonacept and prior to recurrence upon treatment suspension: a RHAPSODY subgroup analysis.

AIMS: In the phase 3 trial, RHAPSODY, rilonacept effectively resolved active pericarditis recurrences, and long-term treatment led to sustained pericarditis recurrence risk reduction. Prior analysis suggested association between higher late gadolinium enhancement (LGE) at baseline and more rapid recurrence upon rilonacept suspension after 12 weeks of treatment. This subgroup analysis assessed the utility of longitudinal serial cardiac magnetic resonance (CMR) imaging for tracking clinical improvement and predicting post-treatment-cessation outcomes to help guide clinical decision making. METHODS AND RESULTS: At an 18-month decision milestone (18MDM) in the RHAPSODY long-term extension, investigators decided if patients would continue rilonacept, suspend rilonacept for off-treatment observation, or discontinue the study. Pericardial thickness, pericardial edema (T2-STIR), and LGE were determined at baseline and 18MDM by an imaging core lab blinded to clinical data, and pericarditis recurrence was investigator-assessed. CMR results in patients with data at both baseline and 18MDM (n=13) showed that pericardial thickness, T2-STIR, and LGE were reduced during rilonacept treatment. Among patients with CMR data who suspended rilonacept at the 18MDM (n=7), 5 (71%) had a pericarditis recurrence within 1-4 months of rilonacept suspension, despite all having had none/trace LGE (n=7) and negative T2-STIR (n=7) at the 18MDM and 2 having received prophylactic colchicine. CONCLUSIONS: Continued clinical improvement during prolonged rilonacept treatment corresponded with improvement on CMR, including reduced pericardial thickness, resolution of pericardial edema, and resolution of LGE. However, none/trace LGE at 18MDM while on treatment did not predict absence of pericarditis recurrence upon subsequent rilonacept suspension in this size-limited subgroup.

Sustained Pericarditis Recurrence Risk Reduction With Long-Term Rilonacept.

BACKGROUND: Rilonacept, a once-weekly interleukin-1 alpha and beta cytokine trap, reduced pericarditis recurrence in the phase 3 study, RHAPSODY (Rilonacept Inhibition of Interleukin-1 Alpha and Beta for Recurrent Pericarditis: A Pivotal Symptomatology and Outcomes Study). The RHAPSODY long-term extension further explored recurrent pericarditis natural history and treatment duration decision-making during 24 additional months of open-label rilonacept treatment. METHODS AND RESULTS: Seventy-four patients commenced the long-term extension, with a median (maximum) total rilonacept duration of 22 (35) months. Individually, 18 months after the most proximal pericarditis recurrence, investigators decided to continue rilonacept on study, suspend rilonacept for off-treatment observation (rescue allowed), or discontinue the study. The annualized incidence of pericarditis recurrence on rilonacept up to the 18-month decision milestone was 0.04 events/patient-year versus 4.4 events/patient-year prestudy while on oral therapies. At the 18-month decision milestone, 64% (33/52) continued rilonacept, 15% (8/52) suspended rilonacept for observation, and 21% (11/52) discontinued the study. Among the 33 patients (1/33; 3.0%) continuing rilonacept (median time to recurrence could not be estimated due to too few events), a single recurrence occurred 4 weeks after a treatment interruption. Among patients suspending rilonacept, 75% (6/8) experienced recurrence (median time to recurrence, 11.8 weeks [95% CI, 3.7 weeks to not estimable]). There was a 98% reduction in risk of pericarditis recurrence among patients continuing rilonacept treatment after the 18-month decision milestone versus those suspending treatment for observation (hazard ratio, 0.02; P<0.0001). CONCLUSIONS: In the RHAPSODY long-term extension, continued rilonacept treatment resulted in continued response; treatment suspension at the 18-month decision milestone was associated with pericarditis recurrence. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03737110.

Pericardial late gadolinium enhancement and time to recurrence: a substudy from RHAPSODY, a phase 3 clinical trial of rilonacept in recurrent pericarditis.

Aims: In this protocol-predefined substudy of the RHAPSODY trial, the primary aim was to assess whether pericardial late gadolinium enhancement (LGE) was associated with time to pericarditis recurrence. Methods and results: RHAPSODY was a Phase 3 double-blind, placebo-controlled, randomized-withdrawal trial that demonstrated the efficacy of rilonacept in recurrent pericarditis (RP). Patients with a history of multiple RP and an active recurrence were enrolled and had the option to participate in a cardiac magnetic resonance (CMR) imaging substudy. CMRs were interpreted by a blinded independent core laboratory with prespecified criteria to define pericardial LGE. Compared to patients with trace or mild pericardial LGE (n = 9), patients with moderate or severe pericardial LGE (n = 16) generally had a higher number of recurrent episodes per year (5.3 vs. 3.9) and a higher mean CRP level (3.6 vs. 1.1 mg/dL). Overall, 10/14 (71.4%) who received a placebo had a recurrence compared to 0/11 (0%) who received rilonacept. In patients randomized to placebo who had moderate or severe pericardial LGE, the median time to recurrence was 4.2 weeks compared to 10.7 weeks in patients who had trace or mild pericardial LGE. At the conclusion of the event-driven randomized-withdrawal period, among patients receiving a placebo, 5/7 (71.4%) with trace or mild pericardial LGE and 5/7 (71.4%) with moderate or severe pericardial LGE had a recurrence. Conclusions: Among patients with multiple RP, these preliminary findings support the concept of pericardial LGE as an imaging biomarker that may inform the duration of treatment and risk of recurrence with cessation of therapy and larger studies should be considered. ClinicalTrialsgov Identifier: NCT03737110.

Patients with recurrent pericarditis (RP) can suffer from debilitating pain and a poor quality of life. Rilonacept blocks interleukin 1 (IL-1), the major inflammatory driver of RP, and is highly effective at treating active episodes of RP and preventing recurrence. In pericarditis, there is the recruitment of blood vessels to the pericardium, and the extent of these new blood vessels tracks with the degree of inflammation. Cardiac magnetic resonance imaging (CMR) readily images this blood supply and can therefore assess inflammation by the magnitude of pericardial late gadolinium enhancement (LGE). In this study of RP patients with CMR, no patients who continued rilonacept had a recurrence compared to 10/14 (71.4%) patients who stopped rilonacept and received a placebo. In the patients who received a placebo, the rate of eventual recurrence was similar among patients with trace or mild pericardial LGE at baseline (5/7) compared to patients with moderate or severe pericardial LGE at baseline (5/7). However, patients who demonstrated moderate or severe pericardial LGE had a faster recurrence (∼4 weeks after stopping rilonacept) compared to patients with trace or mild pericardial LGE (∼11 weeks after stopping rilonacept). These results suggest that pericardial LGE can serve as an imaging biomarker to assess the severity of RP and raise the possibility that CMR could be studied in future clinical trials to determine appropriate therapy and treatment duration in patients with RP.