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. ClinicalTrials.gov identifier NCT03737110


R ESUM E
Contexte : Le rilonacept inhibe la voie de l'interleukine-1 et, d'après les r esultats de la p eriode de prolongation à long terme de l'essai de phase III RHAPSODY, la poursuite du traitement par cet agent chez les patients atteints de p ericardite r ecidivante a r eduit le risque de r ecidive de 98 %.La vaccination contre le syndrome respiratoire aigu s evère (SRAS)-CoV-2 ou l'infection à ce virus pourrait toutefois d eclencher une r ecidive de la p ericardite, 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 p eriode de prolongation à long terme de l'essai RHAPSODY vise à orienter la gestion du rilonacept chez les patients atteints de p ericardite 2][3] The interleukin-1 (IL-1) cytokine family dominates the inflammatory response in RP, and IL-1 pathway inhibition reduces recurrence risk in patients with RP. 4 Rilonacept reduced pericarditis recurrence risk by 96% (hazard ratio in a Cox proportional-hazards model, 0.04; 95% confidence interval, 0.01-0.18;P < 0.0001 by log-rank test) in the phase-3 study Rilonacept Inhibition of Interleukin-1 Alpha and Beta for Recurrent Pericarditis: a Pivotal Symptomatology and Outcomes Study (RHAPSODY). 5The RHAPSODY long-term extension (LTE) results showed persistent (98%) risk reduction, whereas premature rilonacept cessation increased recurrence risk. 6he RHAPSODY LTE took place during the peak of the COVID-19 pandemic.Although COVID-19 was not a primary study outcome, it provided a valuable opportunity for gaining additional on-treatment efficacy and safety insights regarding RP relating to severe acute respiratory syndrome (SARS)-CoV-2 vaccination and COVID-19 infection, refining clinical decision-making regarding rilonacept therapy under these circumstances.

Study design and patients
This was a post-hoc analysis of 74 patients between 12 and 75 years of age participating in the 24-month open-label RHAPSODY LTE (NCT03737110), 5 conducted from May 2020 to June 2022 (Fig. 1 SARS-CoV-2 vaccines became available in November 2020.The vaccine series type was recorded as concomitant medication.COVID-19 complications were recorded as adverse events and were classified by investigators as mild, moderate, or severe, according to the US Food and Drug Administration adverse-event reporting guidelines. 7COVID-19 diagnoses were not adjudicated, and the disease detection method was not reported.

Outcome measures
Outcome measures included pericarditis recurrences in the setting of SARS-CoV-2 vaccine and COVID-19 cases related to clinical management.

Statistical analysis
Due to the small sample size and the unplanned pandemic, descriptive summary statistics are provided (n, mean, standard deviation [SD]), using SAS version 9.4 (SAS Institute, Cary, NC).

COVID-19 incidence
No COVID-19 cases were reported during the randomized-withdrawal period (ended May 2020).A listing of prevalent SARS-CoV-2 variants during the conduct of the RHAPSODY LTE is found in Supplemental Table S2. 8A COVID-19 adverse event was reported in 16 of 74 patients (21.6%).COVID-19 cases were reported in 10 of 30 unvaccinated or partially vaccinated patients (33%; 13.5% of total enrollment) and in 6 of 44 fully vaccinated patients (14%; 8.1% of total enrollment).Among the 6 COVID-19 cases reported in fully vaccinated patients, 1 occurred about 11 months after, and a second case 14 months after, completion of the vaccine series (Supplemental Table S3).

Pericarditis recurrence outcomes
Among the 12 of 16 patients (75%) receiving rilonacept at the time of infection, no patients (0 of 12) experienced a pericarditis recurrence during or after the COVID-19 adverse event.Of the 2 of 16 patients (12.5%) who had previously "suspended" rilonacept for off-treatment observation at the 18month decision milestone, 1 investigator-assessed pericarditis recurrence (without C-reactive protein elevation) occurred in the peri-COVID-19 period (18 days after infection), approximately 4.5 months after rilonacept cessation.No pericarditis recurrences were reported in the 2 of 16 patients (12.5%) whose COVID-19 cases occurred after the end of rilonacept treatment visits and during the 6-week safety follow-up period (Table 1).Among the 58 of 74 patients (78%) without a COVID-19 infection, no pericarditis recurrences were temporally associated with SARS-CoV-2 vaccination.

Discussion
RP is a chronic condition, and physicians commonly must decide how to manage treatments during intercurrent events, such as infections or vaccinations, particularly when biologics agents are used.Use of an antieIL-1 agent during COVID-19 and/or other infections could be useful, and the interruption of the drug might facilitate a recurrence of pericarditis.The RHAPSODY LTE took place during the height of the COVID-19 pandemic, providing the opportunity to study rilonacept use in patients with RP who were vaccinated against SARS-CoV-2 and/or contracted COVID-19.
We observed that rilonacept did not appear to interfere with the protective effect of SARS-CoV-2 vaccination; as expected, patients who were fully vaccinated experienced a lower incidence of COVID-19, compared to patients who were unvaccinated or partially vaccinated in the setting of rilonacept treatment. 9n inappropriate and exuberant innate immune response contributes to COVID-19 morbidity, and higher levels of proinflammatory cytokines, including IL-1ß, are associated with more severe disease. 10Inhibition of IL-1 signaling reduced mortality and the need for invasive mechanical ventilation among patients hospitalized with COVID-19. 11In line with these observations, we found that rilonacept treatment did not appear to impact the safety of patients with COVID-19.Similar to other viruses, SARS-CoV-2 may retrigger autoinflammatory processes that contribute to pericarditis recurrence.Among patients participating in the RHAPSODY LTE, premature cessation of rilonacept led to pericarditis recurrences, regardless of COVID-19 or vaccination status.

Limitations
The descriptive analyses reported here were not prespecified, because of the unpredictable circumstances of the pandemic.The sample size related to vaccination and infection was small (44 patients were fully vaccinated, 30 patients were partially vaccinated or unvaccinated; 16 SARS-CoV-2 infections reported), and the cohort was not randomized.
Administration of Paxlovid and the presence of anti-SARS-CoV-2 monoclonal antibodies were not captured in this study.Recurrences were investigator-assessed and were not externally adjudicated.

Conclusions
In this size-limited analysis, rilonacept did not appear to interfere with SARS-CoV-2 vaccine protection.The results suggest that patients with RP being treated with rilonacept should receive a SARS-CoV-2 vaccination series to reduce possible complications from COVID-19.Continued rilonacept treatment during COVID-19 was well tolerated, supporting a recommendation that RP patients should continue rilonacept regardless of COVID-19 status to prevent pericarditis recurrence (Fig. 2).The data presented support the

SARS-CoV-2 Vaccine SARS-CoV-2 Infection
Findings: • No incidence of pericarditis recurrence • No impact on vaccine protection

Findings:
• No incidence of pericarditis recurrence • No impact on COVID-19 disease severity

Recommendation:
Receive vaccine* to prevent COVID-19 complications and continue rilonacept to prevent pericarditis recurrence.

Recommendation:
Continue rilonacept to prevent pericarditis recurrence.
*No live/attenuated vaccines.further study of the relationships among RP, vaccination, and infection in the setting of anti-IL-1 therapies.

aFigure 1 .
Figure 1.Rilonacept Inhibition of Interleukin-1 Alpha and Beta for Recurrent Pericarditis: a Pivotal Symptomatology and Outcomes Study (RHAPSODY) long-term extension (LTE) designda phase 3, double-blind, placebo-controlled, event-driven, randomized-withdrawal (RW) trial of rilonacept in patients with recurrent pericarditis, which also included a long-term extension phase, allowing up to 24 months of additional open-label rilonacept treatment.SC, subcutaneous.

Figure 2 .
Figure2.Summary of post-hoc analysis findings and clinical recommendations rubric.Among patients on rilonacept in the Rilonacept Inhibition of Interleukin-1 Alpha and Beta for Recurrent Pericarditis: a Pivotal Symptomatology and Outcomes Study (RHAPSODY) long-term extension (LTE) (n ¼ 74), no pericarditis recurrences were associated temporally with severe acute respiratory syndrome (SARS)-CoV-2 vaccination, and no impact on vaccine protection was observed.After SARS-CoV-2 infection, no patients had a pericarditis recurrence, and it had no impact on COVID-19 severity.It is recommended that patients with recurrent pericarditis receiving rilonacept receive a SARS-CoV-2 vaccine and continue rilonacept to prevent pericarditis recurrence.
) in 4 countries (n ¼ 45 in the US; n ¼ 29 in Italy, Israel, and Australia).A total of 69 patients completed the RHAPSODY LTE (27 [39.1%] male, 42 [60.9%]female): US sites concluded in April 2021 after approval of rilonacept for use in RP by the US Food and Drug Administration; non-US patients remained until study closure (June 2022).

Table 1 .
Severe acute respiratory syndrome (SARS)-CoV-2 infections grouped by vaccination status and whether patients were receiving rilonacept at the time of infection; pericarditis recurrences are also reported COVID-19 adverse event was reported during the safety follow-up period, 1 month after the patient had stopped rilonacept treatment.yOne pericarditis recurrence (without C-reactive protein elevation) occurred in the peri-COVID-19 period (18 days after infection), approximately 4.5 months after rilonacept cessation. *