Effects of Abatacept on Myocarditis in Rheumatoid Arthritis

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 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 patients treating
rheumatologist, and who have not yet stepped up to additional treatment with a biologic
DMARD.

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.