Lin, David

Background: Recurrent pericarditis results from inflammasome activation and is associated with significant morbidity. Cannabidiol has been shown to block numerous inflammasome signaling pathways, including reducing transcription of pro-IL-1β and NLRP3, and inhibiting secretion of IL-1β and IL-6. Aim: To assess the impact of oral pharmaceutically manufactured (P-)cannabidiol in recurrent pericarditis patients (pts). Methods: Adult pts (≥18 years) with symptomatic, recurrent pericarditis (≥2 recurrences) were eligible for this open-label, multicenter study. Eligible pts had pericarditis chest pain with a numerical rating scale (NRS) pain score ≥4 within 7 days prior to enrollment, together with either elevated (≥1.0 mg/dL) C-reactive protein (CRP) within the prior 7 days or prior pericardial late gadolinium enhancement (LGE) on cardiac imaging. Pts had to be on chronic treatment with NSAIDs, colchicine or corticosteroids (any combination) with stable baseline (BL) doses. Oral P-cannabidiol was uptitrated to 10 mg/kg twice daily (BID), or maximum tolerated dose. The primary efficacy endpoint was improvement in NRS pain score at week 8 (WK8). A secondary efficacy endpoint among pts with elevated BL CRP was the percentage of pts with CRP normalization (≤0.5 mg/dL) at WK8. Results: 27 pts, mean age of 53 years (range 24-77), 18 of female sex, with a median of 3 prior pericarditis episodes were enrolled. CRP was ≥1.0 mg/dL in 10 pts (37%) at BL. Prior evidence of LGE was present in 21 pts (78%). At BL, 41% of pts were receiving corticosteroid therapy. The highest tolerated study medication dose was BID 10 mg/kg in 20 pts (74.1%), 7.5 mg/kg in 4 pts (14.8%), and 5 mg/kg in 3 pts (11.1%). All 27 pts (100%) completed the WK8 visit. Mean NRS score decreased by 3.7, from 5.8 at BL to 2.1 at WK8. In those with CRP elevation at BL, CRP normalized in 8 pts (80%) by WK8, with mean CRP decreasing from 5.71 to 0.31 mg/dL. Study medication was discontinued due to AEs in 2 pts (7.4%). 24 pts (89%) tolerated P-cannabidiol with a treatment response and proceeded into the 18-week extension period (EP) where background therapy is weaned. Conclusions: Among pts with symptomatic pericarditis recurrence, oral administration of P-cannabidiol led to a clinically relevant reduction in pericarditis chest pain (measured by NRS score) and in CRP. P-cannabidiol was shown to be safe and generally well tolerated, with the majority of pts reaching the target dose and continuing into the study EP.

Abstract 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 oedema (T2-short tau inversion recovery, 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), five (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 two having received prophylactic colchicine. Conclusion Continued clinical improvement during prolonged rilonacept treatment corresponded with improvement on CMR, including reduced pericardial thickness, resolution of pericardial oedema, 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.

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.

Introduction: Rilonacept treatment in RHAPSODY resolved active pericarditis recurrences, and long-term treatment led to sustained risk reduction. Prior analysis linked greater baseline Late Gadolinium Enhancement (LGE), with more rapid recurrence upon rilonacept suspension after 12 weeks of treatment. Serial cardiac magnetic resonance (CMR) imaging (T2-STIR, LGE) enabled longitudinal assessment for tracking clinical improvement, guiding decision-making, and predicting patient outcomes after treatment cessation. Methods: At the long-term extension (LTE) 18-month decision milestone (18MDM), investigators chose, based on clinical status, to continue rilonacept, suspend rilonacept/observe, or discontinue the LTE. An imaging core lab blinded to clinical data measured pericardial thickness and graded pericardial edema (T2-STIR) and LGE at baseline and 18MDM. Pericarditis recurrence was assessed clinically following rilonacept suspension. Results: Baseline and 18MDM CMRs were available for 13 patients. Reductions in pericardial thickness, T2-STIR, and LGE from baseline to 18MDM while on treatment are provided in Figure . CMRs were obtained in 7/8 patients suspending rilonacept at 18MDM: LGE was none/trace, and T2-STIR was negative; yet, 5/7 (71%) had pericarditis recurrence within 1-4 months of rilonacept suspension despite prophylactic colchicine (n=2). Conclusions: Continued clinical improvement during prolonged rilonacept treatment corresponded with improvement on CMR, including reduced pericardial thickness, resolution of pericardial edema on T2-STIR, and resolution of LGE. Negative/trace LGE at 18MDM while on treatment did not predict absence of pericarditis recurrence upon subsequent rilonacept suspension in this size-limited subgroup. Larger prospective studies examining CMR parameters in guiding RP treatment duration decisions and informing associated clinical outcomes are warranted.

Introduction: Rare cardiac complications of COVID-19 and COVID-19 mRNA vaccination include pericarditis and myocarditis. Patients with recurrent pericarditis may be at increased risk of triggered recurrence. The known efficacy of the interleukin (IL)-1 antagonist rilonacept in treating and preventing recurrence could inform COVID-19 disease and vaccination management. Methods: The Phase 3 trial RHAPSODY was a global, double-blind, placebo-controlled, randomized-withdrawal study. A long-term extension (LTE) enabled up to 24 months further open-label treatment from May 2020 until June 2022. Concomitant vaccination data and adverse events, including COVID-19, were collected. Results: No COVID-19 cases were reported during the run-in and randomized withdrawal periods (n=86). As of the 6 May 2022 data cutoff, a COVID-19 AE was reported in 19% (14/74) of LTE subjects, of whom 12 were on rilonacept: 5 of 44 fully-vaccinated (≥14 days beyond second serial dose) subjects (11.4%) and 9 of 30 unvaccinated or partially-vaccinated subjects (30.0%). Of the fully-vaccinated subjects, 1 case occurred ~11 months post primary vaccination cycle (no booster). COVID-19 severity was mild (n= 11), moderate (n=2), or severe (n=1). All cases resolved except the severe AE complicated by comorbidities; the subject discontinued. Of 12 subjects receiving rilonacept at the time of COVID-19 diagnosis, 10 maintained dosing with rilonacept, 1 interrupted rilonacept for ~4 weeks, and 1 discontinued rilonacept permanently; none experienced a pericarditis recurrence (PR) after the AE. The remaining 2 subjects had previously interrupted rilonacept for off-treatment observation: one had a PR >4.5 months after suspending rilonacept and 18 days after COVID-19 resolution; no PR in the other (>6 months). There were no PR AEs associated with COVID-19 vaccination (all subjects were receiving rilonacept). Conclusions: In patients on rilonacept in this study, although numbers are small, vaccination reduced COVID-19 events, pericarditis recurrence was not increased by vaccination or disease, and no pericarditis recurrences occurred during rilonacept treatment. One pericarditis recurrence occurred remotely after rilonacept suspension in the peri-COVID-19 period.

Introduction: Rilonacept reduced pericarditis recurrence in the phase 3 trial RHAPSODY. The long-term extension (LTE) enabled further insights into efficacy, safety, and clinical decision making. Methods: The RHAPSODY run-in (RI) and randomized-withdrawal periods were followed by an LTE that enabled open-label rilonacept treatment up to 24 additional months. A decision at 18 months after the most recent recurrence was based on clinical status at investigator discretion: 1) continue rilonacept on-study, 2) suspend rilonacept for observation or 3) discontinue from the LTE without observation. Endpoints included recurrence and quality of life. Results: In May 2020, 74 of 75 eligible subjects continued to LTE; US subjects (n=45) switched to commercial therapy or discontinued in April 2021 (treatment duration from RI baseline [median; maximum] 18; 27 months). Non-US subjects (n=29) completed the LTE in June 2022 (treatment duration from RI baseline [median; maximum] 27; 33 months). Concomitant oral medications during LTE: 22% NSAIDS, 20% colchicine, 0% corticosteroids, 43% none. Inflammation signs (CRP), RP symptoms (PGIPS), and recurrences were low on-treatment. Before the 18-month decision (n=74), there were 3 investigator-assessed recurrences (0.04 per patient-year). At the 18-month decision (n=52), 64% (n=33) continued rilonacept on-study, 15% (n=8) suspended rilonacept for observation, and 21% (n=11) discontinued the study without observation, of whom 7 switched to commercial rilonacept. There was a 75% recurrence rate (n=6/8) in the off-treatment observation group (median time to event 11.8 [3.7, Not-Estimable (NE)] weeks) but only 1 recurrence in subjects on rilonacept (time to event NE [too few events]) associated with a 4-week interruption; HR 0.018, p<0.0001; Fig 1. Conclusions: Continued rilonacept treatment resulted in continued treatment response, whereas treatment suspension at 18 months may be associated with pericarditis recurrence.

Abstract 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. ClinicalTrials.gov Identifier NCT03737110

AbstractRemote monitoring is beneficial for the management of patients with cardiovascular implantable electronic devices by impacting morbidity and mortality. With increasing numbers of patients using remote monitoring, keeping up with higher volume of remote monitoring transmissions creates challenges for device clinic staff. This international multidisciplinary document is intended to guide cardiac electrophysiologists, allied professionals, and hospital administrators in managing remote monitoring clinics. This includes guidance for remote monitoring clinic staffing, appropriate clinic workflows, patient education, and alert management. This expert consensus statement also addresses other topics such as communication of transmission results, use of third‐party resources, manufacturer responsibilities, and programming concerns. The goal is to provide evidence‐based recommendations impacting all aspects of remote monitoring services. Gaps in current knowledge and guidance for future research directions are also identified.

Objective Polypharmacy management of recurrent pericarditis (RP) often involves long-term therapies, often with negative effects. Slow tapering of oral therapies is often required to avoid recurrence. A post hoc analysis of the phase III trial Rilonacept inHibition of interleukin-1 Alpha and beta for recurrent Pericarditis: a pivotal Symptomatology and Outcomes Study (RHAPSODY) evaluated investigator approaches to transitioning to IL-1 blockade monotherapy with rilonacept, which was hypothesised to allow accelerated withdrawal of common multidrug pericarditis regimens. Methods RHAPSODY was a multicentre (Australia, Israel, Italy, USA), double-blind, placebo-controlled, randomised-withdrawal trial in adults and adolescents with RP. Investigators initiated rilonacept at the labelled dose level and discontinued oral pericarditis therapies during the 12-week run-in; randomised patients received study drug as monotherapy. Time to rilonacept monotherapy was quantified in patients receiving multidrug regimens at baseline who achieved rilonacept monotherapy during run-in. Results In 86 enrolled patients, mean time to rilonacept monotherapy was 7.9 weeks, with no recurrences. Of these, 64% (n=55) entered on multidrug regimens: non-steroidal anti-inflammatory drugs (NSAIDs) plus colchicine (44% (24/55)), colchicine plus glucocorticoids (24% (13/55)), or NSAIDs, colchicine, plus glucocorticoids (33% (18/55)). Investigators transitioned patients receiving colchicine and glucocorticoids at baseline to rilonacept monotherapy without recurrence regardless of taper approach: sequential (n=14; median, 7.7 weeks) or concurrent (n=17; median, 8.0 weeks). Median time to rilonacept monotherapy was similar regardless of glucocorticoid dose and duration: ≤15 mg/day (n=21): 7.3 weeks; >15 mg/day (n=18): 8.0 weeks; long-term (≥28 days): 7.6 weeks. Conclusions Rapid discontinuation of oral RP therapies while transitioning to rilonacept monotherapy was feasible without triggering pericarditis recurrence. Trial registration number NCT03737110.

Background Recurrent pericarditis is characterized by painful flares and inflammation, which negatively impact health‐related quality of life. RHAPSODY (rilonacept inhibition of interleukin‐1 alpha and beta for recurrent pericarditis: a pivotal symptomatology and outcomes study) evaluated the efficacy and safety of rilonacept (IL‐1α and ‐β cytokine trap) in recurrent pericarditis. A secondary analysis of these data evaluated the patient‐reported outcome questionnaire score change during the trial. Methods and Results Participants completed 5 patient‐reported outcome (PRO) questionnaires assessing pericarditis pain, health‐related quality of life, general health status, sleep impact, and overall symptom severity. PRO score changes during the treatment run‐in period (12 weeks) and the blinded randomized withdrawal period (up to 24 weeks) were evaluated using descriptive statistics and mixed model repeated measures analyses. Participants with PRO data from the run‐in period (n=84) and the randomized withdrawal period (n=61; 30 rilonacept, 31 placebo) were included in analyses. Run‐in baseline PRO scores indicated that pericarditis symptoms during pericarditis recurrence impacted health‐related quality of life. All PRO scores significantly improved ( P <0.001) on rilonacept treatment during the run‐in period. For the randomized withdrawal period, PRO scores were maintained for participants receiving rilonacept. For those receiving placebo and who experienced a recurrence, PRO scores deteriorated at the time of recurrence and then improved following rilonacept bailout. At randomized withdrawal Week 24/End of Study, scores of participants who received bailout rilonacept were similar to those of participants who had continued rilonacept. Conclusions These results demonstrate the burden of pericarditis recurrences and the improved physical and emotional health of patients with recurrent pericarditis while on rilonacept treatment. These findings extend prior rilonacept efficacy results, demonstrating improvements in patient‐reported health‐related quality of life, sleep, pain, and global symptom severity while on treatment. Registration URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03737110.