. 2023 May 26;1(1):qyad003.

doi: 10.1093/ehjimp/qyad003. eCollection 2023 May.

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

Paul C Cremer¹, David Lin², Sushil A Luis³, John Petersen⁴, Antonio Abbate⁵, Christine L Jellis¹, Debbie Kwon¹, Antonio Brucato⁶, Fang Fang⁷, Antonella Insalaco⁸, Martin LeWinter⁹, Basil S Lewis¹⁰, Liangxing Zou⁷, Stephen J Nicholls¹¹, Allan L Klein¹, Massimo Imazio¹², John F Paolini⁷; RHAPSODY Investigators

Collaborators, Affiliations

Collaborators

RHAPSODY Investigators:
Antonio Abbate, Wael Abo-Auda, Asif Akhtar, Michael Arad, Shaul Atar, Bipul Baibhav, Karan Bhalla, Antonio Brucato, Sean Collins, David Colquhoun, Paul Cremer, David Cross, Girish Dwivedi, Alon Eisen, Nahum Freedberg, Shmuel Fuchs, Eliyazar Gaddam, Marco Gattorno, Eli Gelfand, Paul Grena, Majdi Halabi, David Harris, Massimo Imazio, Antonella Insalaco, Amin Karim, Allan Klein, Kirk Knowlton, Apostolos Kontzias, Robert Kornberg, Faisal Latif, David Leibowitz, Martin LeWinter, David Lin, Dor Lotan, Pey Wen Lou, S Allen Luis, Mady Moriel, Stephen Nicholls, John Petersen, Michael Portman, Philip Roberts-Thomson, Elad Schiff, Robert Siegel, Michael Stokes, Paul Sutej, Samuel Wittekind, Valentin Witzling, Robert Zukermann

Affiliations

¹ Center for the Diagnosis and Treatment of Pericardial Diseases, Section of Cardiovascular Imaging, Department of Cardiovascular Medicine, Heart, Vascular, and Thoracic Institute, Cleveland Clinic, 9500 Euclid Avenue, Desk J1-5, Cleveland, OH 44195, USA.
² Minneapolis Heart Institute, Abbott Northwestern Hospital, Minneapolis, MN, USA.
³ Division of Cardiovascular Ultrasound, Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN, USA.
⁴ Swedish Medical Center, Seattle, WA, USA.
⁵ Pauley Heart Center, Virginia Commonwealth University, Richmond, VA, USA.
⁶ Department of Biomedical and Clinical Science, University of Milan, Fatebenefratelli Hospital, Milan, Italy.
⁷ Kiniksa Pharmaceuticals Corp., Lexington, MA, USA (at time of study).
⁸ Division of Rheumatology, IRCCS Ospedale Pediatrico Bambino Gesù, Rome, Italy.
⁹ Cardiology Unit, University of Vermont Medical Center, Burlington, VT, USA.
¹⁰ Cardiovascular Clinical Research Institute, Lady Davis Carmel Medical Center and Technion-Israel Institute of Technology, Haifa, Israel.
¹¹ Monash Cardiovascular Research Centre, Victorian Heart Institute, Monash University, Clayton, Victoria, Australia.
¹² Cardiothoracic Department, University Hospital 'Santa Maria della Misericordia,' ASUFC, Udine, Italy.

PMID: 39044797
PMCID: PMC11240150
DOI: 10.1093/ehjimp/qyad003

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

Paul C Cremer et al. Eur Heart J Imaging Methods Pract. 2023.

. 2023 May 26;1(1):qyad003.

doi: 10.1093/ehjimp/qyad003. eCollection 2023 May.

Authors

Collaborators

RHAPSODY Investigators:
Antonio Abbate, Wael Abo-Auda, Asif Akhtar, Michael Arad, Shaul Atar, Bipul Baibhav, Karan Bhalla, Antonio Brucato, Sean Collins, David Colquhoun, Paul Cremer, David Cross, Girish Dwivedi, Alon Eisen, Nahum Freedberg, Shmuel Fuchs, Eliyazar Gaddam, Marco Gattorno, Eli Gelfand, Paul Grena, Majdi Halabi, David Harris, Massimo Imazio, Antonella Insalaco, Amin Karim, Allan Klein, Kirk Knowlton, Apostolos Kontzias, Robert Kornberg, Faisal Latif, David Leibowitz, Martin LeWinter, David Lin, Dor Lotan, Pey Wen Lou, S Allen Luis, Mady Moriel, Stephen Nicholls, John Petersen, Michael Portman, Philip Roberts-Thomson, Elad Schiff, Robert Siegel, Michael Stokes, Paul Sutej, Samuel Wittekind, Valentin Witzling, Robert Zukermann

Affiliations

¹ Center for the Diagnosis and Treatment of Pericardial Diseases, Section of Cardiovascular Imaging, Department of Cardiovascular Medicine, Heart, Vascular, and Thoracic Institute, Cleveland Clinic, 9500 Euclid Avenue, Desk J1-5, Cleveland, OH 44195, USA.
² Minneapolis Heart Institute, Abbott Northwestern Hospital, Minneapolis, MN, USA.
³ Division of Cardiovascular Ultrasound, Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN, USA.
⁴ Swedish Medical Center, Seattle, WA, USA.
⁵ Pauley Heart Center, Virginia Commonwealth University, Richmond, VA, USA.
⁶ Department of Biomedical and Clinical Science, University of Milan, Fatebenefratelli Hospital, Milan, Italy.
⁷ Kiniksa Pharmaceuticals Corp., Lexington, MA, USA (at time of study).
⁸ Division of Rheumatology, IRCCS Ospedale Pediatrico Bambino Gesù, Rome, Italy.
⁹ Cardiology Unit, University of Vermont Medical Center, Burlington, VT, USA.
¹⁰ Cardiovascular Clinical Research Institute, Lady Davis Carmel Medical Center and Technion-Israel Institute of Technology, Haifa, Israel.
¹¹ Monash Cardiovascular Research Centre, Victorian Heart Institute, Monash University, Clayton, Victoria, Australia.
¹² Cardiothoracic Department, University Hospital 'Santa Maria della Misericordia,' ASUFC, Udine, Italy.

PMID: 39044797
PMCID: PMC11240150
DOI: 10.1093/ehjimp/qyad003

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.

Clinicaltrialsgov identifier: NCT03737110.

Keywords: cardiac MRI; pericarditis; recurrence; rilonacept.

Plain language summary

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.

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Conflict of interest statement

P.C. Cremer: Cremer reports grants and personal fees from Kiniksa Pharmaceuticals; grants from Novartis Pharmaceuticals; and personal fees from SOBI Pharmaceuticals outside the submitted work. D. Lin: None. S.A. Luis: Luis reports consultant fees for Kiniksa Pharmaceuticals, SOBI Pharmaceuticals, and Medtronic. J. Petersen: None. A. Abbate: Abbate reports grants and personal fees from Kiniksa Pharmaceuticals during the conduct of the study; grants and personal fees from Olatec, Serpin, Novartis, and Janssen; and personal fees from Novo-Nordisk and Cromos Pharma outside the submitted work. C.L. Jellis: None. D. Kwon: None. A. Brucato: Brucato reports institutional funding from Kiniksa Pharmaceuticals as an investigative site; an unrestricted research grant from SOBI and ACARPIA; and travel and accommodation for the advisory committee from SOBI and Kiniksa Pharmaceuticals. F. Fang: Fang reports personal fees and others from Kiniksa Pharmaceuticals outside the submitted work at the time the study was conducted. A. Insalaco: Insalaco reports personal fees from SOBI. M. LeWinter: LeWinter reports grants and advisory board, consulting, and other fees from Kiniksa Pharmaceuticals outside the submitted work and consulting fees from SOBI Pharmaceuticals outside the submitted work. B.S. Lewis: Lewis reports personal fees from Kiniksa Pharmaceuticals during the conduct of the study. L. Zou: Zou reports personal fees and others from Kiniksa Pharmaceuticals outside the submitted work. S.J. Nicholls: Nicholls reports grants and personal fees from Kiniksa Pharmaceuticals during the conduct of the study; grants and personal fees from AstraZeneca, Anthera, Resverlogix, Sanofi-Regeneron, and Esperion; personal fees from Akcea, Eli Lilly, Omthera, Merck, Takeda, CSL Behring, and Boehringer Ingelheim; and grants from Amgen, Novartis, Abionyx (formerly Cerenis), The Medicines Company, Liposcience, Roche, and InfraReDx outside the submitted work. A.L. Klein: Klein reports grants and others from Kiniksa Pharmaceuticals during the conduct of the study and other fees from Cardiol Therapeutics, SOBI Pharmaceuticals, and Pfizer Pharmaceuticals outside the submitted work. M. Imazio: Imazio reports no disclosures. J.F. Paolini: Paolini reports personal fees and others from Kiniksa Pharmaceuticals outside the submitted work and is a patent inventor on pending patent applications licensed to Kiniksa Pharmaceuticals covering methods of using rilonacept for treating RP.

Figures

**Figure 1**
Time to pericarditis recurrence by treatment and baseline pericardial LGE severity. Time to pericarditis recurrence was defined as time from randomization to placebo or rilonacept (following a 12-week RI of rilonacept treatment in all patients) to date of first recurrence. Accompanying footnoted images are illustrative CMR-PSIR short-axis sequences from two representative cases with mild^a or severe^b pericardial LGE at baseline (arrows indicate pericardial LGE). CI, confidence interval; CMR, cardiac magnetic resonance imaging; LGE, late gadolinium enhancement; NE, not estimable; PSIR, phase-sensitive inversion recovery; RI, run-in; SC, subcutaneous.

See this image and copyright information in PMC

References

1. Klein A, Cremer P, Kontzias A, Furquan M, Tubman R, Roy Met al. . US Database study of clinical burden and unmet need in recurrent pericarditis. J Am Heart Assoc 2021;10:e018950. - PMC - PubMed
1. Klein AL, Imazio M, Cremer P, Brucato A, Abbate A, Fang Get al. . Phase 3 trial of interleukin-1 trap rilonacept in recurrent pericarditis. N Engl J Med 2021;384:31–41. - PubMed
1. Chetrit M, Xu B, Kwon DH, Ramchand J, Rodriguez RE, Tan CDet al. . Imaging-guided therapies for pericardial diseases. JACC Cardiovasc Imaging 2020;13:1422–37. - PubMed
1. Klein AL, Lin D, Cremer PC, Nasir S, Luis SA, Abbate Aet al. . Efficacy and safety of rilonacept for recurrent pericarditis: results from a phase II clinical trial. Heart 2021;107:488–96. - PMC - PubMed
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Pericardial late gadolinium enhancement and time to recurrence: a substudy from RHAPSODY, a phase 3 clinical trial of rilonacept in recurrent pericarditis

Collaborators

Affiliations

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

Authors

Collaborators

Affiliations

Abstract

Plain language summary

Conflict of interest statement

Figures

References

Associated data

LinkOut - more resources

Full Text Sources

Medical

Research Materials

Miscellaneous