Effects of Abatacept on Myocarditis in Rheumatoid Arthritis

Summary

This study aims to evaluate the effects of abatacept, a CTLA4-Ig fusion protein that binds cluster of differentiation antigen 80 (CD80)/86 (B7-1/B7-2), on subclinical myocarditis in rheumatoid arthritis (RA) through its effect on T cell subpopulations. RA patients without clinical CVD, biologic naïve, and with inadequate response to methotrexate (MTX), will undergo cardiac fluorodeoxyglucose (FDG) positron emission tomography (PET)/computerized tomography (CT) imaging to assess myocardial inflammation. Studies that investigate the impact of treatment on subclinical myocarditis in RA, a possible contributor to heart failure, while exploring potential underlying mechanisms (i.e., different T cell subpopulations), are needed for a better understanding of their relevance in the pathogenesis of heart failure in RA and survival improvement in these patients with excess risk for cardiovascular death. If the investigator hypothesis is confirmed and treatment with abatacept decreases and/or suppresses or prevents myocardial inflammation in RA, this will have multidisciplinary implications that could lead to changes in the current management of RA patients at high risk for cardiovascular events. Similarly, identification of T cell subpopulations in RA patients with myocardial FDG uptake will shed light into the underlying cellular mechanisms of myocardial injury and serve to guide the use of therapies that prevent their pathogenicity. The objectives of this study are to compare the change in myocardial FDG uptake in RA patients treated with abatacept vs adalimumab, and identify T cell subpopulations associated with myocardial FDG uptake in each treatment arm. RA patients will be randomized in an unblinded, 1:1 ratio to treatment with abatacept vs adalimumab. A cardiac FDG PET/CT will be performed at baseline and 16 weeks post-biologic treatment. T cell subpopulations associated with myocardial FDG uptake will be evaluated at both points in time with their transcriptional phenotype outlined by RNA sequencing.

Timeline

Start

2019-07-10

Primary completion

2021-09-15

Completion

2021-09-15

Publications

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• Background Solomon DH, Karlson EW, Rimm EB, Cannuscio CC, Mandl LA, Manson JE, Stampfer MJ, Curhan GC. Cardiovascular morbidity and mortality in women diagnosed with rheumatoid arthritis. Circulation. 2003 Mar 11;107(9):1303-7. doi: 10.1161/01.cir.0000054612.26458.b2.
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• Background Solomon DH, Goodson NJ, Katz JN, Weinblatt ME, Avorn J, Setoguchi S, Canning C, Schneeweiss S. Patterns of cardiovascular risk in rheumatoid arthritis. Ann Rheum Dis. 2006 Dec;65(12):1608-12. doi: 10.1136/ard.2005.050377. Epub 2006 Jun 22.
• Background Wolfe F, Freundlich B, Straus WL. Increase in cardiovascular and cerebrovascular disease prevalence in rheumatoid arthritis. J Rheumatol. 2003 Jan;30(1):36-40.
• Background LEBOWITZ WB. The heart in rheumatoid arthritis (rheumatoid disease). A clinical and pathological study of sixty-two cases. Ann Intern Med. 1963 Jan;58:102-23. doi: 10.7326/0003-4819-58-1-102. No abstract available.
• Background CATHCART ES, SPODICK DH. Rheumatoid heart disease. A study of the incidence and nature of cardiac lesions in rheumatoid arthritis. N Engl J Med. 1962 May 10;266:959-64. doi: 10.1056/NEJM196205102661901. No abstract available.
• Background SOKOLOFF L. CARDIAC INVOLVEMENT IN RHEUMATOID ARTHRITIS AND ALLIED DISORDERS: CURRENT CONCEPTS. Mod Concepts Cardiovasc Dis. 1964 Apr;33:847-50. No abstract available.
• Background Han B, Jiang H, Liu Z, Zhang Y, Zhao L, Lu K, Xi J. CTLA4-Ig relieves inflammation in murine models of coxsackievirus B3-induced myocarditis. Can J Cardiol. 2012 Mar-Apr;28(2):239-44. doi: 10.1016/j.cjca.2011.11.014. Epub 2012 Feb 14.
• Background Matsui Y, Inobe M, Okamoto H, Chiba S, Shimizu T, Kitabatake A, Uede T. Blockade of T cell costimulatory signals using adenovirus vectors prevents both the induction and the progression of experimental autoimmune myocarditis. J Mol Cell Cardiol. 2002 Mar;34(3):279-95. doi: 10.1006/jmcc.2001.1511.
• Background Abe S, Hanawa H, Hayashi M, Yoshida T, Komura S, Watanabe R, Lie H, Chang H, Kato K, Kodama M, Maruyama H, Nakazawa M, Miyazaki J, Aizawa Y. Prevention of experimental autoimmune myocarditis by hydrodynamics-based naked plasmid DNA encoding CTLA4-Ig gene delivery. J Card Fail. 2005 Sep;11(7):557-64. doi: 10.1016/j.cardfail.2005.04.005.
• Background Liu W, Gao C, Zhou BG, Li WM. Effects of adenovirus-mediated gene transfer of ICOSIg and CTLA4Ig fusion protein on experimental autoimmune myocarditis. Autoimmunity. 2006 Mar;39(2):83-92. doi: 10.1080/08916930500507870.
• Background Johnson DB, Balko JM, Compton ML, Chalkias S, Gorham J, Xu Y, Hicks M, Puzanov I, Alexander MR, Bloomer TL, Becker JR, Slosky DA, Phillips EJ, Pilkinton MA, Craig-Owens L, Kola N, Plautz G, Reshef DS, Deutsch JS, Deering RP, Olenchock BA, Lichtman AH, Roden DM, Seidman CE, Koralnik IJ, Seidman JG, Hoffman RD, Taube JM, Diaz LA Jr, Anders RA, Sosman JA, Moslehi JJ. Fulminant Myocarditis with Combination Immune Checkpoint Blockade. N Engl J Med. 2016 Nov 3;375(18):1749-1755. doi: 10.1056/NEJMoa1609214.
• Background Varricchi G, Galdiero MR, Tocchetti CG. Cardiac Toxicity of Immune Checkpoint Inhibitors: Cardio-Oncology Meets Immunology. Circulation. 2017 Nov 21;136(21):1989-1992. doi: 10.1161/CIRCULATIONAHA.117.029626. No abstract available.

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