Brucato, Antonio

Abstract Heart involvement in eosinophilia represents a rare entity with substantial cardiac morbidity and mortality. This disorder is often overlooked and diagnosed in its advanced stages. In a subgroup of patients with eosinophilic heart disease, peripheral blood eosinophilia may not be present, and the biopsy of the affected organ or tissue is essential to establish the correct diagnosis. In this clinical consensus statement, an expert consensus group reviews the epidemiology, aetiology, diagnosis, and management of eosinophilic heart disease. The aim of the document is to increase awareness about the cardiac involvement associated with eosinophilia in order to diagnose the disease in early phases and prevent deleterious heart damage and adverse outcomes of affected individuals. The spectrum of physiological and immunological derangements requires a multidisciplinary approach for optimal management of affected individuals.

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.

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.

Abstract Cardiac amyloidosis is a serious and progressive infiltrative disease that is caused by the deposition of amyloid fibrils at the cardiac level. It can be due to rare genetic variants in the hereditary forms or as a consequence of acquired conditions. Thanks to advances in imaging techniques and the possibility of achieving a non-invasive diagnosis, we now know that cardiac amyloidosis is a more frequent disease than traditionally considered. In this position paper the Working Group on Myocardial and Pericardial Disease proposes an invasive and non-invasive definition of cardiac amyloidosis, addresses clinical scenarios and situations to suspect the condition and proposes a diagnostic algorithm to aid diagnosis. Furthermore, we also review how to monitor and treat cardiac amyloidosis, in an attempt to bridge the gap between the latest advances in the field and clinical practice.

Abstract Cardiac amyloidosis is a serious and progressive infiltrative disease that is caused by the deposition of amyloid fibrils at the cardiac level. It can be due to rare genetic variants in the hereditary forms or as a consequence of acquired conditions. Thanks to advances in imaging techniques and the possibility of achieving a non-invasive diagnosis, we now know that cardiac amyloidosis is a more frequent disease than traditionally considered. In this position paper the Working Group on Myocardial and Pericardial Disease proposes an invasive and non-invasive definition of cardiac amyloidosis, addresses clinical scenarios and situations to suspect the condition and proposes a diagnostic algorithm to aid diagnosis. Furthermore, we also review how to monitor and treat cardiac amyloidosis, in an attempt to bridge the gap between the latest advances in the field and clinical practice.

Aims Novel therapies are needed for recurrent pericarditis, particularly when corticosteroid dependent and colchicine resistant. Based on limited data, interleukin-1 blockade with anakinra may be beneficial. The aim of this multicentre registry was to evaluate the broader effectiveness and safety of anakinra in a ‘real world’ population. Methods and results This registry enrolled consecutive patients with recurrent pericarditis who were corticosteroid dependent and colchicine resistant and treated with anakinra. The primary outcome was the pericarditis recurrence rate after treatment. Secondary outcomes included emergency department visits, hospitalisations, corticosteroid use and adverse events. Among 224 patients (46 ± 14 years old, 63% women, 75% idiopathic), the median duration of disease was 17 months (interquartile range 9–33). Most patients had elevated C-reactive protein (91%) and pericardial effusion (88%). After a median treatment of 6 months (3–12), pericarditis recurrences were reduced six-fold (2.33–0.39 per patient per year), emergency department admissions were reduced 11-fold (1.08–0.10 per patient per year), hospitalisations were reduced seven-fold (0.99–0.13 per patient per year). Corticosteroid use was decreased by anakinra (respectively from 80% to 27%; P < 0.001). No serious adverse events occurred; adverse events consisted mostly of transient skin reactions (38%) at the injection site. Adverse events led to discontinuation in 3%. A full-dose treatment duration of over 3 months followed by a tapering period of over 3 months were the therapeutic schemes associated with a lower risk of recurrence. Conclusion In patients with recurrent pericarditis, anakinra appears efficacious and safe in reducing recurrences, emergency department admissions and hospitalisations.