Effects of Abatacept on Myocarditis in Rheumatoid Arthritis

Rheumatoid Arthritis Clinical Trial

— AMiRA  

Official title:

Effects of Abatacept on Myocarditis in Rheumatoid Arthritis

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT03619876
• Other study ID #: AAAS2235
• Status: Terminated
• Phase: Phase 4
• Start date: July 10, 2019
• Est. completion date: September 15, 2021

Study information

• Verified date: April 2023
• Source: Columbia University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Description:

Rheumatoid arthritis (RA) is a systemic inflammatory disease that affects ~1% of the population. Regardless of the novel therapies developed in the last decades, studies report an increased standard mortality ratio as high as 3.0 when compared with the general population. Cardiovascular disease (CVD) is the leading cause of mortality in RA subjects in whom the average lifespan is reduced by 8-15 years compared to matched controls. RA patients are at increased risk for developing heart failure and inflammatory myocarditis potentially contributes to this excess risk. Although subclinical myocarditis remains poorly characterized to date in RA, costimulatory molecules such as CD80/86 (B7s) and CD40 are known to play a pivotal role for cytokine production and antigen-specific T cell activation in viral myocarditis, and in murine models, blocking CD40L/B7-1 and CTLA4 significantly decreases myocardial inflammation, damage, and mortality. In addition, the recent increase in the use of immune checkpoint inhibitors for the treatment of numerous cancers, has raised awareness of the occurrence of fulminant autoimmune lymphocytic myocarditis as a complication of these drugs including anti-CTLA4 due to a presumed uncontrolled immune response resulting in T-cell mediated myocardial injury. Interestingly, pilot data showed lower myocardial FDG uptake in RA patients on the a CTLA4-Ig fusion protein abatacept compared with other DMARDs. These data raise the possibility of immunotherapy for the treatment of myocarditis in RA, suggesting a role for T cell infiltration in its pathogenesis, and a particular benefit for treatment with abatacept vs non-abatacept biologic DMARDs.

In a single RHeumatoid arthritis studY of THe Myocardium (RHYTHM study), a total of 119 RA patients without clinical CVD underwent cardiac FDG-PET/CT, with myocardial inflammation assessed qualitatively and quantitatively by visual inspection and by calculation of the standardized-uptake-value (SUV) units. Qualitative myocardial FDG uptake was observed in 39% of the patients. Animal data showing decreased myocardial inflammation, damage, and mortality, and improved cardiac function with CD40L/B7-1 and CTLA4 blockage, coupled with preliminary findings of lower myocardial inflammation in RA patients on abatacept vs other DMARDs, suggest that abatacept treatment has potential myocardial benefits. In RA patients, the proportion of peripheral T cell subsets significantly differs from normal controls and include differentiation to memory effector subsets, acquisition of natural killer (NK) receptors, exhaustion markers, and enhanced inflammatory cytokine expression. Importantly, T cell lymphocytic infiltration described in autoimmune myocarditis resulting as a complication of CTLA4 immune checkpoint inhibition, suggests a role for T cell subsets in the pathogenesis of myocarditis in RA with potential differences depending on mechanism of action of the DMARD in use. 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.

This is a single-center study. Twenty RA patients will be recruited over a planned recruitment period of 24 months, and randomized with aims of enrolling 10 patients per year, the enrollment rate is estimated as 1 patient per month. The target population consists of patients who are deemed methotrexate-inadequate responders by the patient's treating rheumatologist, and who have not yet stepped up to additional treatment with a biologic DMARD.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 11
• Est. completion date: September 15, 2021
• Est. primary completion date: September 15, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Written informed consent signed by the subject.

• Patients age > 18 years.

• Fulfilling the American College of Rheumatology 2010 classification criteria for RA.

• MTX for = 8 weeks at = 15mg weekly or on at least 7.5mg of methotrexate weekly for =8 weeks with a documented intolerance of higher MTX doses, and on a stable dose for the previous 4 weeks;

• Naïve to biologic treatment.

• If the subject is a woman with childbearing potential, a urine sample will be taken for a pregnancy test. The results of the pregnancy test must be negative.

Exclusion Criteria:

• Prior biologic use.

• Any prior self-reported physician diagnosed CV event (myocardial infarction; angina; stroke or Transient Ischemic Attack (TIA); heart failure; prior CV procedure (i.e., coronary artery bypass graft, angioplasty, valve replacement, pacemaker).

• Active history of cancer.

• Prior use of immune checkpoint inhibitors.

• Known pregnancy, HIV, hepatitis B, hepatitis C, active (or untreated latent) tuberculosis.

Related Conditions & MeSH terms

• Arthritis
• Arthritis, Rheumatoid
• Inflammation
• Myocardial Inflammation
• Myocarditis
• Rheumatoid Arthritis

Intervention

Drug:
• Abatacept
125 MG/ML subcutaneous injections
• Adalimumab
40 Mg/0.8 mL Subcutaneous Kit

Locations

Country	Name	City	State
United States	Columbia University Medical Center	New York	New York

Sponsors (2)

Lead Sponsor	Collaborator
Columbia University	Bristol-Myers Squibb

Country where clinical trial is conducted

United States, 

References & Publications (14)

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

Sihvonen S, Korpela M, Laippala P, Mustonen J, Pasternack A. Death rates and causes of death in patients with rheumatoid arthritis: a population-based study. Scand J Rheumatol. 2004;33(4):221-7. doi: 10.1080/03009740410005845. Erratum In: Scand J Rheumatol. 2006 Jul-Aug;35(4):332. — View Citation

SOKOLOFF L. CARDIAC INVOLVEMENT IN RHEUMATOID ARTHRITIS AND ALLIED DISORDERS: CURRENT CONCEPTS. Mod Concepts Cardiovasc Dis. 1964 Apr;33:847-50. No abstract available. — View Citation

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. — View Citation

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. — View Citation

Symmons DP, Jones MA, Scott DL, Prior P. Longterm mortality outcome in patients with rheumatoid arthritis: early presenters continue to do well. J Rheumatol. 1998 Jun;25(6):1072-7. — View Citation

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. — View Citation

Wolfe F, Freundlich B, Straus WL. Increase in cardiovascular and cerebrovascular disease prevalence in rheumatoid arthritis. J Rheumatol. 2003 Jan;30(1):36-40. — View Citation

* Note: There are 14 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change in Myocardial FDG Uptake in Rheumatoid Arthritis (RA) Patients Treated With Abatacept vs Adalimumab.	Using FDG PET cardiac imaging to identify myocardial inflammation at baseline and post-treatment, the study will quantitatively compare the change in myocardial FDG uptake in biologic naïve RA patients without clinical CVD and with inadequate methotrexate response, following randomization to 16-week treatment with abatacept vs the TNF-inhibitor adalimumab. Conventional cardiovascular disease (CVD) risk factors and measures of RA disease activity and severity will be ascertained.	Baseline, 16 weeks
Secondary	Prevalence of T Cell Subpopulations Associated With Myocardial FDG Uptake in RA Patients Treated With Abatacept vs Adalimumab.	This is to test whether elevations in different T cell subsets are associated with myocardial FDG uptake in RA patients treated with abatacept vs adalimumab. Subsequently, the transcriptional phenotype of candidate subpopulations.	Baseline, 16 weeks