Clinical trial NCT03619876
Conditions: Rheumatoid Arthritis Myocardial Inflammation
Keywords: CTLA4-Ig Abatacept Myocarditis RA
Sponsor: Columbia University
Start date: 2019-07-10; Completion date: 2021-09-15
Enrollment: 11 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief 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.

Detailed 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.

Arms: arm 1: Treatment with abatacept will consist of weekly subcutaneous (SQ) injections at a dose of 125mg. arm 2: Treatment with a adalimumab, as the TNF-inhibitor arm, will consist of every 2 weeks SQ injections at a dose of 40mg.
Interventions: intervention 1: Abatacept intervention 2: Adalimumab
Intervention descriptions: intervention 1: 125 MG/ML subcutaneous injections intervention 2: 40 Mg/0.8 mL Subcutaneous Kit

Protocol documents:
Prot_SAP_000.pdf: 
1
Effects of Abatacept on Myocarditis in Rheumatoid Arthritis 
(AMiRA) 
Clinical Trial Protocol 
IRB Protocol #: AAAS2235 
BMS protocol #IM101-782 
Investigators: 
Laura Geraldino-Pardilla, MD, MSc (PI). T- (212) 305-4308 
Joan M Bathon, MD (co-I). T- (212) 305-6327 
Robert Winchester, MD (co-I). T- (212) 305-8250 
Sabahat Bokhari, MD (co-I). T- (212) 305-5996 
Rachel Broderick, MS (Research coordinator). T- (212) 342-2713 
Christopher Depender (Research Coordinator). T- (212)305-4114 
Trial Registration Number: NCT03619876 
Version 4.3: DEC 06 2019 
NCT03619876


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STUDY SYNOPSIS 
 
Animal data showing decreased myocardial inflammation, damage, and mortality, and improved 
cardiac function with CD40L/B7-1 and CTLA4 blockage, coupled with our 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. 
 
 
 
 
This study aims to evaluate the effects of abatacept, a CTLA4-Ig fusion protein that binds 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 FDG PET/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 our 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 


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FDG uptake will be evaluated at both points in time with their transcriptional phenotype outlined 
by RNA seq. 
 
 
 
 
Inclusion/Exclusion Criteria. 
 
Inclusion Criteria:  Patients age > 18 years, fulfilling the American College of Rheumatology 2010 
classification criteria for RA (60), with inadequate response to MTX, and not on recent biologic 
treatment, will be recruited from the rheumatology clinics of Columbia University Medical Center 
and by referral from local rheumatologists. 
 
 
 
 
Exclusion criteria:  1) Prior biologic use in the past 3 months, or rituximab use in the past 6 
months; 2) 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); 3) Active or on-treatment cancer 
within 5 years of baseline visit or prior use of immune checkpoint inhibitors; 4) Known pregnancy, 
HIV, hepatitis B, hepatitis C, active (or untreated latent) tuberculosis; 5) Prisoners or subjects who 
are compulsory detained 
 
 
 
Statistical Analysis. Summary statistics for outcomes and predictor variables will be examined; 
with comparisons made using student t-test and Wilcoxon rank-sum test for normally and non- 
normally distributed continuous variables, respectively. Counts and percentages will be calculated 
for categorical variables and compared using the chi-square or Fisher’s exact test, as appropriate. 
In Aim 1, using generalized estimating equations (GEE), models will be constructed to explore 
the association between treatment arms (abatacept vs adalimumab) and change in myocardial 
FDG uptake treated as a continuous variable (measured by SUV units) to take into account 
patients’ baseline uptake values. Similarly, linear mixed effects models will be used to define the 
association between T cell subpopulations and myocardial FDG uptake per treatment arm strata. 
Given the small sample size of the study, we will not have the power to adjust for multiple variables 
with the exception of anti-CCP seropositivity, but the two treatment arms will be matched for age, 
sex, and disease activity, and the contribution of RA-disease characteristics and traditional CVD 
risk factors to the variability of myocardial FDG uptake will be ascertained in the univariate 
analysis. All statistical calculations will be performed using SAS 9.4. In all tests, a 2-tailed α of 
1.5  will define statistical significance. 


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Accrual goal and rate. Patient  enrollment  will take  place  over a period  of 2 years  from  initiation 
of the  study.  With  aims  of enrolling   10 patients  per year,  the  enrollment   rate  is estimated  as 1 
patient per month. 


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CONSORT Flow Diagram 
 
 
 
 
 
 
Enrollment 
Assessed for eligibility (n=~60) 
 
 
 
Excluded (n= 40) 
♦ Not meeting inclusion criteria (n= 30) 
♦ Declined to participate (n= 8) 
♦  Other reasons (n= 2) 
 
 
 
Randomized (n= 20) 
 
 
 
 
 
 
Allocated to Abatacept (n= 10) 
♦ Received allocated intervention (n= 10) 
♦ Did not receive allocated intervention (n= 0) 
Allocation 
 
 
Allocated to intervention (n= 10) 
♦ Received allocated intervention (n=10) 
♦ Did not receive allocated intervention (n= 0) 
 
 
 
 
 
Lost to follow-up (give reasons) (n= 0) 
Discontinued intervention (poor tolerance) (n=1) 
Follow‐Up 
 
Lost to follow-up (give reasons) (n= 0) 
Discontinued intervention (poor tolerance) (n=1) 
 
 
 
 
 
 
Analysed (n= 10) 
♦ Excluded from analysis (n= 0) 
Analysis 
 
 
Analysed (n= 10) 
♦ Excluded from analysis (n= 0) 


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TABLE OF CONTENTS 
 
1. 
Background……………………………….………………………………………………… ... 9 
 
1.1 
Background information……………………………………………………..………………..9 
 
1.1.1 Overview………………………………………………………………………9 
 
1.1.2 Myocarditis in Rheumatoid Arthritis…………………………………….…..9 
 
1.1.3 Cytotoxic T lymphocyte–associated antigen 4 (CTLA4), CTLA4-Ig, 
and Myocarditis……………………………………………………………..10 
1.1.4 T cells in RA…………………………………………………………………11 
 
2. 
Rationale………………………………………………………………………………………11 
 
2.1. Preliminary Data…………………………………………………………………………11 
 
2.2. Scientific Premise……………………………………………………………………….13 
 
3. 
Study Objectives……………………………………………………………………………..14 
 
3.1. Primary Objective……………………………………………………………………….14 
 
3.2. Secondary Objective……………………………………………………………………14 
 
 
 
 
4. 
Ethical Considerations / Informed Consent………………………………………………..15 
 
4.1. Statement of Compliance………………………………………………………………15 
 
4.2. Informed Consent……………………………………………………………………….15 
 
4.3. Institutional Review Board………………………………………………………… ......15 
 
4.4. Training of Site Investigators and Staff for the Study Protocol…………………….16 
 
 
 
 
5. 
Study Design / Methodology………………………………………………………………..16 
 
5.1. Overview…………………………………………………………………………………16 
 
5.2. Study Population………………………………………………………………………..16 
 
5.3. Study Visits………………………………………………………………………………17 
 
5.4 Imaging……………………………………………………………………………………17 


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5.5. Main Predictors. Treatment Arms: Abatacept vs Adalimumab………………….17 
 
5.6. Immunophenotyping of peripheral T cell subpopulations………………………..17 
 
5.7. Covariates and potential Confounders…………………………………………….20 
 
5.8. Potential Limitations…………………………………………………………………21 
 
 
 
 
6. 
Eligibility…………………………………………………………………………………...21 
 
6.1. Inclusion Criteria…………………………………………………………………….21 
 
6.2. Exclusion criteria………………………………………………………………….…22 
 
 
 
 
7. 
Recruitment and Blinding………………………………………………………………..22 
 
7.1. Recruitment Plan……………………………………………………………………22 
 
7.2. Randomization and Blinding…………………………………………………….…23 
 
 
 
 
8. 
Retention and Withdrawal………………………………………………………………23 
 
8.1. Subject Retention…………………………………………………………………..23 
 
8.2. Subject Withdrawal…………………………………………………………………23 
 
 
 
9. 
Treatment / Study Drug…………………………………………………………………24 
 
9.1. Description of Treatment Medications…………………………………………...25 
 
9.2. Treatment Algorithm……………………………………………………………….26 
 
9.3. Concomitant Medications………………………………………………………. 26 
 
 
 
 
10. 
Schedule of Assessments………………………………………………………………27 
 
 
 
 
11. 
Safety and Reporting……………………………………………………………………28 
 
11.1. Adverse Events…………………………………………………………………...28 
 
11.1.1. Definition of an Adverse Event……………………………………….28 


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11.1.2. Serious Adverse Event……………………………………………………..28 
 
11.1.3. Relationship of an Adverse Event to Study Intervention………………..30 
 
11.1.4 Severity of an Adverse Event……………………………………………...30 
 
11.2. Unanticipated Problems……………………………………………………………….31 
 
11.3. Reporting of Adverse Events, Serious Adverse Events, and Unanticipated 
Problems………………………………………………………………………………...31 
 
11.3.1. Reporting to BMS……………………………………………………………33 
 
11.4. Pregnancy……………………………………………………………………………….34 
 
11.5. Non-Serious Adverse Events………………………………………………………….35 
 
11.6. Laboratory Tests Abnormalities.………………………………………………………36 
 
11.7. Potential Drug Induced Liver Injury (DILI)………………………………………… ...36 
 
11.8. Overdose………………………………………………………………………………...36 
 
11.9. Other Safety Considerations…………………………………………………………..37 
 
 
 
 
12. 
Statistical Analysis…………………………………………………………………………….37 
 
12.1. Overview…………………………………………………………………………………37 
 
12.2. Sample Size and Power Analysis………………………………………….………….37 
 
 
 
 
13. 
Other and Administrative Considerations…………………………………………………..38 
 
13.1. Data Management…………………………………………………………………. 38 
 
13.2. Confidentiality…………………………………………………………………………38 
 
13.3. Potential Risk………………………………………………………………………….39 
 
13.4. Potential Benefit………………………………………………………………………40 
 
13.5. Records Retention……………………………………………………………………41 
 
13.6. Publication Strategy………………………………………………………………….41 
 
 
 
14. 
Reference List…………………………………………………………………………………42 


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1.BACKGROUND 
 
 
 
 
1.1.Background information. 
 
1.1.1 Overview. 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 
(1). 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 (1-5). RA patients are 
at  increased risk  for  developing heart failure  (2,3)  and  inflammatory myocarditis potentially 
contributes to this excess risk (9-11). 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 (15-18). 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 (19,20). Interestingly, our 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. 
 
 
 
 
1.1.2. Myocarditis in Rheumatoid Arthritis. Autopsy studies of RA hearts from the 1960s 
suggest that myocarditis may occur in as many as 16% of patients (9-11). There is scarce data 
on myocarditis in contemporaneous RA history which is itself restricted to data in patients with 
known history of CVD (12). Direct examination of the RA myocardium has been limited due to 
reliance on endomyocardial biopsy (EMB), which is invasive and has poor sensitivity to detect 
myocarditis due to its heterogeneous and patchy nature (13-14). This, coupled with its 
invasiveness, expense and risk of complications, has limited investigations of subclinical 
myocarditis in RA. However, recent advances in myocardial imaging techniques have shown 
great promise in detecting myocardial inflammation. Cardiac MRI studies in RA using late 


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gadolinium enhancement (LGE) suggest an increased prevalence of cardiac LGE in RA 
compared with controls (30-32). Yet, the detection of myocardial LGE is performed by contrast to 
the background enhancement, rendering the visualization of diffuse LGE difficult to assess (30, 
32-33), and makes it a suboptimal tool for diagnosing myocarditis in RA due to its limitation in 
distinguishing inflammation, from fibrosis, edema, and necrosis. A more recently used MRI 
technique: T2-weighted imaging allows for better specificity in regards to inflammation but seems 
to be less sensitive and currently data on RA patients without CVD using this imaging modality 
remains scarce (31). While there hadn’t been any data in RA using cardiac FDG-PET-CT prior to 
our recent study, this technique is proving to be a valuable diagnostic tool in other inflammatory 
disorders such as cardiac sarcoidosis and viral myocarditis where it can detect myocardial 
inflammation with greater sensitivity than EMB (34-36). FDG is a glucose analog taken up by 
metabolically active cells including macrophages in regions of inflammation (37-40) and cellular 
FDG uptake reflects the rate of tissue glycolysis (high in inflamed tissues), thus resulting in avid 
uptake (41-43). In experimental models of myocarditis and atherosclerosis, FDG uptake was 
confirmed to correlate with histological demonstration of infiltrating macrophages and/or CD3+ T 
cells (44-45). Because cardiomyocytes are also metabolically active but have different glucose 
receptors compared to inflammatory cells, cardiomyocyte glucose uptake can be suppressed and 
inflammatory cell uptake isolated and detected (41-43). To date, data on FDG myocardial uptake 
response to DMARDs in RA is lacking. 
 
 
 
 
1.1.3. Cytotoxic T lymphocyte–associated antigen 4 (CTLA4), CTLA4-Ig, and Myocarditis. 
CTLA4 is an essential costimulatory molecule involved in the downregulation of T-cell activation. 
CTLA4 is expressed on the activated T-cell surface and inhibits responses by competing with 
CD28 for CD80/86 (B7s) binding, effectively preventing CD80/86 (B7s)-CD28 interactions. 
CTLA4-Ig is a fusion protein that combines the CTLA4 extracellular domain and has high affinity 
for ligand CD80/86 (B7-1/B7-2), hence blocking T-cell costimulation. This mechanism is of 
particular interest in viral myocarditis as T-cell mediated cellular immunity is considered the most 
important histopathological feature in this condition (46). In experimental autoimmune myocarditis 
models, CTLA4-Ig has been shown to decrease or inhibit myocardial inflammation, virus 
replication, and mouse mortality, as well as improve cardiac function, presumably by influencing 
the balance of TH1 to TH2 T cells (15-18). Furthermore, the development of myocarditis in 
patients treated with immune checkpoint inhibitors is a recently recognized complication. Early, 
progressive and refractory cardiac electrical instability, and myocarditis with a robust presence of 


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T cell and macrophage infiltrates have been described in 0.27% of patients treated with a 
combination of anti-CTLA4 and anti-PD-1 therapies, and can result in a potentially fatal, T cell 
driven myocardial injury (19). Of note, the histopathology of these cases show a patchy 
lymphocytic infiltrate within the myocardium that also involves the cardiac sinus and atrio- 
ventricular  nodes,  with  lymphocytic  destruction  of  isolated  myocytes,  and  predominantly 
infiltrating CD3+ (rich in both CD4+ and CD8+ T cells, and negative for CD20) or CD68+ cells 
(19). Overall, the deletion of CTLA4 and PD-1 axes can cause autoimmune myocarditis and 
dilated cardiomyopathy, supporting that these molecules play a role in the prevention of T-cell 
mediated autoimmune myocarditis (19,20). 
 
 
 
 
1.1.4. T cells in RA. In an adaptive immune response, activation of antigen-specific T cells, often 
denoted by HLA-DR expression (47), is followed by clonal expansion and progressive T cell 
differentiation along defined maturation pathways involving transcriptional regulation of various 
molecules governing recognition and response. Their patterns of acquisition and loss define 
functionally different T cell subsets involved in protective memory and immune effector functions 
(48). Their differentiation from the naïve state to a memory-effector phenotype is denoted by 
extinction of the expression of CD28 (CD4+CD28null T cells) and a shift from the CD45RA isoform 
to CD45RO, with pro-inflammatory and autoreactive potential (49-53). Activated, expanded, and 
differentiated memory effector T cells are widely considered to be an intrinsic feature of RA 
(54,55). Furthermore, in some RA patients, expression of natural killer (NK) cell receptors (CD56 
and CD57) is also noted (56-58), and is of particular interest as it enables the CD4+CD28null T 
cells to be triggered by danger signal ligands expressed by stressed or injured cells (59), providing 
a new second stimulatory signal that along with the T cell receptor engagement result in cell 
activation in a site of injury or inflammation. However, the role of different T cell subsets in the 
pathogenesis of myocarditis in RA remains unclear. 
 
 
 
 
2.RATIONALE. 
 
2.1. Preliminary Data. 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 (Figure 1). By quantitative assessment, the median 


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myocardial SUV mean was 1.9 (inter-quartile range [IQR]: 1.5-2.6), and the median SUV max 
was 3.0 (IQR: 2.1-4.5). 
 
 
 
Figure 1. Example of diffuse Myocardial 18F-FDG uptake Scan in an RA patient. Short Axis for a, b and 
c; horizontal axis for d; and vertical long axis for e. 
 
 
 
a 
b 
c 
d 
e 
 
 
 
 
 
 
 
 
 
 
 
 
 
As expected, RA patients with visually detected FDG uptake had higher SUVs by quantitative 
assessment than patients without visually detected FDG uptake (median SUV mean of 2.8 [IQR: 
2.2-4.9] vs 1.6 [IQR: 1.4-1.9], p <0.0001), and median SUV max of 4.9 [IQR: 3.6-9.4] vs 2.3 [IQR 
2,0-2.9], p <0.0001, respectively). Interestingly, when comparing the degree of myocardial FDG 
uptake in RA patients on abatacept vs no biologic agents; abatacept treatment (n=8) was 
associated with a lower SUV mean. This association remained statistically significant with an 
18% lower myocardial SUV mean seen after adjusting for disease activity (Clinical Disease Activity 
Index less vs greater or equal to 10) (beta=-0.36) (Figure 2). No significant difference was seen 
between myocardial FDG uptake in those on non-biologic DMARDs vs TNF-inhibitors (p=0.69). In 
addition, higher CDAI and DAS-28 scores, non-Hispanic black race, and body mass index (BMI) 
were significantly associated with a higher SUV mean. A CDAI ≥10 (moderate/high disease 
activity) was associated with a 0.31 increase in SUV mean when compared to the 
group with CDAI in remission or low disease activity (CDAI<10) (beta=0.31, p=0.006). A similar 
relationship was observed with DAS-28.  Non-Hispanic black RA patients had 22% higher SUV 
mean than non-Hispanic whites (beta=0.31, p=0.006). However, in adjusted analyses, only the 
CDAI≥10 remained significantly associated with a higher SUV mean. 


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Figure 2. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2.2. Scientific Premise. This study aims to evaluate the effects of abatacept, a CTLA4-Ig fusion 
protein that binds CD80/86 (B7-1/B7-2), on subclinical myocarditis in rheumatoid arthritis (RA) 
through its effect on T cell subpopulations. Animal data showing decreased myocardial 
inflammation, damage, and mortality, and improved cardiac function with CD40L/B7-1 and 
CTLA4 blockage, coupled with our 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 our 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 


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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. 
 
 
 
3.STUDY OBJECTIVES 
 
The aim of this study is to evaluate the effects on myocarditis in rheumatoid arthritis (RA) of 
abatacept, a CTLA4-Ig fusion protein that binds CD80/86 (B7-1/B7-2). 
 
 
3.1. Primary Objective. Compare the change in myocardial FDG uptake in RA patients treated 
with abatacept vs adalimumab. Rationale: In murine models, CD40L/B7-1 and CTLA4 blockade 
decreases myocardial inflammation, damage and mortality. Additionally, our pilot data suggests 
that lower myocardial FDG uptake in seen in RA patients on abatacept compared with other 
DMARDs. Approach: Using FDG PET cardiac imaging to identify myocardial inflammation at 
baseline and post-treatment, we 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 CVD risk factors and measures of RA disease activity and severity 
will be ascertained. 
 
 
3.2. Secondary Objective. Identify T cell subpopulations associated with myocardial FDG uptake 
in RA patients treated with abatacept vs adalimumab. Rationale: Reflecting the adaptive immune 
response underlying RA, the proportion of peripheral T cell subsets in RA patients significantly 
differs from normal controls. These include differentiation to memory effector subsets, acquisition 
of NK receptors, exhaustion markers, and enhanced inflammatory cytokine expression. 
Furthermore, T cell lymphocytic infiltration has   been described in autoimmune  myocarditis 
resulting as a complication of CTLA4 immune checkpoint inhibition. These data suggest a role for 
T cell subsets in the pathogenesis of myocarditis in RA with potential differences depending on 
mechanism of action of the DMARD. Approach: We will 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 isolated 
by cell sorting will be comprehensively delineated by low cell input RNAseq to define the specific 
immunobiologic  characteristics  of  these  particular  cellular  subsets  that  are  mechanistic 
candidates to mediate myocardial inflammation. 


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4.ETHICAL CONSIDERATIONS / INFORMED CONSENT 
 
 
 
 
4.1. Statement of Compliance. The study will be conducted in accordance with the 
International Conference on Harmonisation guidelines for Good Clinical Practice (ICH E6) and 
the Code of Federal Regulations on the Protection of Human Subjects (45 CFR Part 46). All 
personnel involved in the conduct of this study have completed human subject’s protection 
training. 
 
 
 
 
4.2. Informed Consent. The principal investigator, co-investigators and research staff are 
responsible for obtaining informed consent before any subject may participate in the study. 
Informed consent requires adequate explanation of the aims, methods, anticipated benefits, and 
potential hazards of the study. No protocol-specific screening procedures or any study 
medications will be prescribed prior to obtaining informed consent.  Acquisition of informed 
consent will be documented in the subject’s medical records and the informed consent form 
should be signed and personally dated by the subject as well as by the person who conducted 
the informed consent discussion.  The signed consent form will be retained according to 
institutional policy. A copy of the signed consent form will be provided to the subject. The 
subject may withdraw consent to participate in the study at any time. The approved informed 
consent form will adhere to the ethical principles that have their origin in the Declaration of 
Helsinki. 
 
 
 
 
4.3. Institutional Review Board. The study will be conducted under the monitoring of the local 
Institutional Review Board (IRB). The PI will be responsible for submitting the clinical trial 
protocol, the Informed Consent form, any advertisements, and all other relevant study related 
documents to the local IRB for approval. All unanticipated problems, as well as protocol 
deviations and violations that occur during the conduct of the trial will be reported by the PI to 
the IRB. Adverse events will be submitted regularly to the IRB. The IRB must approve all 
protocol changes prior to implementation unless emergency action is clinically indicated. The PI 
 
will be responsible for preparing annual reports to the IRB. 


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4.4. Training of Investigators and Staff for the Study Protocol. The investigators and all staff 
involved in the study will have completed their required Collaborative IRB Training Initiative (CITI). 
Each study staff member will be trained in the protocol and specific procedures for each study 
visit by the study investigators. New study staff members will be trained on the protocol and, if 
necessary, spend a visit shadowing another trained staff member before carrying out protocol 
tasks on their own. 
Prior to conducting subject visits, investigators will be asked to sign 
off that the staff members have been appropriately trained in the study protocol. Training and 
delegation of responsibility will be documented in a delegation of responsibility log. 
 
 
 
 
5.STUDY DESIGN AND METHODOLOGY 
 
 
 
 
5.1. Overview. The aim of this study is to prospectively evaluate the effects on myocarditis in 
RA of abatacept, a CTLA4-Ig fusion protein that binds CD80/86 (B7-1/B7-2), through its effect 
on T cell regulation. RA patients without clinical CVD, not on recent biologic DMARDs, and 
with inadequate response to methotrexate (MTX), will undergo cardiac FDG PET/CT imaging 
at baseline to assess myocardial inflammation. RA patients will be randomized in an 
unblinded, 1:1 ratio to treatment with abatacept vs adalimumab. A repeat cardiac FDG PET/CT 
will be performed16(±2) 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 RNAseq. Conventional CVD risk factors and measures of RA disease 
activity will be ascertained. 
 
 
 
 
5.2. Study Population. Patients age > 18 years, fulfilling the American College of 
 
Rheumatology 2010 classification criteria for RA (60), with inadequate response to MTX, and not 
on recent biologic DMARD treatment, will be recruited from the rheumatology clinics of Columbia 
University Medical Center and by referral from local rheumatologists. Exclusion criteria: 1) prior 
biologic use, other than rituximab in the past 3 months, or Rituximab use in the past 6 months; 
2) 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); 3) active or on-treatment cancer within 5 
years of baseline visit or prior use of immune checkpoint inhibitors; 4) Known pregnancy, HIV, 


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5.3. Study visits. Patients will be evaluated at baseline and 16 (±2) weeks post-biologic 
treatment, with an interim safety visit at week 8 (±2wks), and a final safety visit at week 20 (±2). 
 
 
 
5.4. Imaging. Cardiac 18F-FDG PET CT: Myocardial FDG uptake images will be assessed by 
FDG PET CT scanning. To suppress physiological uptake of FDG by cardiomyocytes, patient 
preparation will include a high fat non-carbohydrate diet the day before, and a 12-hour fast the 
evening prior to the scan (61-62). Dietary adherence will be interrogated the day of the scan. 
Imaging will be performed on a MCT 64 PET/CT scanner (Siemens Medical Solutions USA, INC., 
Knoxville, TN). A low dose CT transmission scan (120 kV, 25 mA) will be obtained for attenuation 
correction of PET data. Patients will be injected with  10 mCi ± 10% of 
18F-FDG 
intravenously. A list mode 3D PET scans will be acquired for 10 minutes following a 90-minute 
uptake period post-18F-FDG injection. Non-gated attenuation-corrected images will be 
reconstructed yielding ~3 mm effective resolution. Corridor 4DM software will be used to visually 
assess myocardial 18FDG uptake as well as semi-automatically quantify mean radiotracer uptake 
in the myocardium. Cardiac axes will be manually defined by marking the base on the vertical 
long axis, apex on the horizontal long axis, and the left ventricular cavity on the sagittal axis. FDG 
uptake will be assessed quantitatively as standardized uptake value (SUV), a measure of 
radiotracer uptake  normalized for  injected dose  and  patient  weight, using  polar  maps  and 
Corridor4DM v. 7.0 (Invia Medical Imaging Solutions, Ann Arbor, MI). Left ventricular segments 
will be defined by the segmentation nomenclature of the American Heart Association (63). 
Contours will be placed on the myocardial walls and automated SUV calculations for the mean 
SUV and the max SUV for each of the segments will be derived. The mean of the means (SUV 
mean) and the mean of the max SUVs (SUV max) will then be obtained. 
 
 
 
 
5.5. Main Predictors. Treatment Arms: Abatacept vs Adalimumab. Treatment with abatacept 
will consist of weekly subcutaneous (SQ) injections at a dose of 125mg. Treatment with a 
adalimumab, as the TNF-inhibitor arm, will consist of every 2 weeks SQ injections at a dose of 
40mg. 
 
 
 
 
 
5.6. Immunophenotyping of peripheral T cell subpopulations. High-dimensional analysis of 
the mononuclear cells (MNLs) will be performed by multiparameter flow cytometry assessing the 


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per cell expression of over 50 differentially expressed molecules. These results will be used to 
delineate candidate predictor subsets that will be then used as variables to determine the 
presence of an association with myocardial uptake of FDG. Panels developed in Dr. Robert 
Winchester’s laboratory will be used and will specifically focus on identifying the T reg subset, 
activated markers on T cells, exhaustion markers, and NK cells. This should result in a much 
more comprehensive immunologic characterization of the peripheral mononuclear cell alterations 
in RA and better enable identification of subsets related to myocardial inflammation. Distinctive 
populations not present in a reference set of RA cases with low or no myocardial FDG uptake will 
be identified by dimensional reduction analyses and corroborated by gating and biaxial plot 
analysis. The first step will be flow cytometry and will involve five panels, with each having a 
Zombie dye for live dead discrimination, CD3, CD4, CD8, CD45RA and CCR7 for identifying 
subsets across most panels, and on the T cell panels various combination of CD40L, CD31, HLA- 
DR, CD38, CD69, TIGIT, KLRG1, CD57, CD160, NKG2D, CD28, CD27, CD45RO, PD-1, CD95, 
CCR2, CCR4, CXCR3, CD39, CXCR5, CD62L, CCR6, CD25, CD161, IFN-γ, IL-17, TNF-α, 
FOX3P, RORγt, TBX21, GATA3, BCL6, HELIOS, IL-2. The NK/T activation panel also contains 
CD56, CD16, CD161, CD117, NKp44, NKG2A, CD158a, NKG2D, and CD94. Staining for each 
panel will be done in 30ul volumes on ~2 x106 MNLs. The cytometry will be done on a 6 laser 
LSRII. Samples will be run in batches, including samples from different clinical groups within each 
batch, with care taken to minimize inter-batch variation in staining. Every batch will include a 
cryopreserved reference normal MNL pool obtained by leukopheresis from 9 normal blood donors 
by the NY Blood Center, each validated for having a generally normal distribution of subsets and 
cryopreserved. This reference population will serve as a critical control for machine and technical 
variations in reagent performance, and will enable the identification of anomalous samples with 
low viability, enhanced aggregation, or other features suggesting sample processing or transport 
artifacts. Compensation will be done before each batch. In addition to the classic gating performed 
in FCS Express software, we will use multiple, complementary dimensional reduction approaches 
to analyze the multiparametric flow cytometry data (viSNE) as a way to obtain unbiased measures 
of  the  cell  population  alterations.  First  we  will  use  the  t-Distributed Stochastic  Neighbor 
Embedding (t-SNE) algorithm viSNE (64) to visualize the multidimensional data and the various 
MNL subpopulations among circulating leukocytes (65). Here, the positions of cells on a 2D viSNE 
plot reflect their proximity in high-dimensional parameter space, including information from each 
of the dimensions. This unbiased alternative to traditional gating and biaxial subset representation 
preserves the  geometry and  nonlinearity of  the  data,  delineates both  abundant and  rare 
populations without setting a priori expression criteria, and provides an interpretable data view 


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using color as a third dimensional to show the expression of particular differentiation and 
activation molecules. A generally similar implementation of viSNE is available in Cytobank, and 
both algorithms will be used in the delineation of distinctive MNL populations. In viSNE, the gene 
expression patterns of reference MNLs map into shapes that discriminate between immune 
subtypes, and the shape of these per cell patterns is altered in disease due to differences in gene 
expression resulting in patterns that are distinct from the referent control map. The area of the 
shape is proportional to the size of the population, and viSNE can identify populations consisting 
of 0.2% of the cell input (64). To compare the T cell subsets, we will first develop a referent viSNE 
map by overlying similarly grouped subpopulations and cells from the RA patients without 
myocardial FDG uptake. The similarity of each case subpopulation forming the referent 
distribution will be determined using the Shannon Diversity Index (SDI)(66), to quantify the 
similarity between the samples used to make the referent viSNE map. Samples used to make the 
referent map will be included if their SDI divergence between each pair is <0.05. We will then 
compare the immune cell populations in those with elevated myocardial FDG uptake by overlying 
their viSNE transformation to the referent viSNE map of those without FDG myocardial uptake, to 
define one or more multidimensional phenotypes that differ in each myocarditis patient from the 
referent. The relation of the population expression patterns to conventional immune subtypes can 
be corroborated by manual gating of a series of biaxial plots using the molecular markers 
distinguished in the viSNE plot. The comprehensively defined novel and conventional populations 
will be designated and their quantitative distribution across the subjects will be tabulated for 
analysis as predictor variables for Aim 2. As a second alternative and complementary dimensional 
reduction approach, we will utilize the CITRUS (cluster identification, characterization, and 
regression) (67) approach implemented through Cytobank (www.premium.cytobank.org). In this 
method, a modification of SPADE, cells are hierarchically clustered into nodes based on their 
multidimensional phenotype, and the occupancy of different nodes can be compared 
quantitatively across individual patients and patient groups. This allows the identification of unique 
cell populations based on multidimensional phenotypes and then assess for subpopulations that 
are increased or decreased in groups of patients of interest. Once an altered node is identified, 
the expression of markers can be assessed to determine defining features of cells in that node. 
An important feature of CITRUS is that the discovery of statistically significant stratifying MNL 
subpopulations in these datasets is facilitated by its structure that compares sets of cases across 
multiple discriminating characteristics (i.e., FDG myocardial uptake positive versus FDG uptake 
negative). The features of the population(s) defined in viSNE will then be compared with those 
identified in CITRUS to provide a common set of weighted features. Differences in the putative 


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same population between the two methods can be resolved by back gating and analysis of the 
differences by conventional biaxial displays to characterize the phenotypic elements responsible 
for divergent classification. Thus, our overall approach in subset definition and discovery 
combines the respective strengths of CITRUS and viSNE using two different dimensional 
reduction methods with different down-sampling approaches to confirm the identification of the 
identified populations, that is ultimately represented in terms of classic biaxial plots. Finally, to 
further evaluate the potential pathologic functions of candidate expanded T cell populations, the 
transcriptional phenotype of the cells will be comprehensively delineated by low cell input 
RNAseq. This will help define the specific immunobiologic characteristics of these particular 
cellular subsets that are mechanistic candidates to mediate myocardial inflammation. Detailed 
transcriptomic analyses of selected immune subpopulations will be generated using a method 
established to characterize PD-1++CD4+ T cells in the circulation of patients with active, 
seropositive RA (65). 
 
 
 
 
5.7. Covariates and potential Confounders. Demographics, lifestyle characteristics and non- 
RA medications will be assessed by structured interview. Resting blood pressure (BP) will be 
measured 3 times in the seated position, and the average of the last 2 measurements will be 
used. Hypertension will be defined as a systolic BP of ≥140 mm Hg, a diastolic BP of ≥90 mm 
Hg, or use of antihypertensive medications. Diabetes will be defined as a fasting serum glucose 
level of ≥126 mg/dl, a HbA1c >6.4%, or use of antidiabetic medications. Body mass index will 
be calculated by dividing the patient’s weight (in kilograms) by height (in square meters). RA 
disease duration will be assessed by patient self-report of the date of diagnosis. RA disease 
activity will be calculated with the Clinical Disease Activity Index (CDAI) and the Disease 
Activity Score (DAS28) using C-reactive protein (CRP) level (68-70). The Health Assessment 
Questionnaire (HAQ) will be employed as a measure of self-reported disability (71). Additional  
questionnaires, including Medical History, Personal History, RA Medications, RA History, and a 
Visual Analog Scale (VAS) will be used. Current and past use of steroids and disease- 
modifying anti-rheumatic drugs (DMARDs) will be queried by detailed, examiner-administered 
questionnaires. Phlebotomy will be performed on the morning of each PET CT scan after 
overnight fast. Sera and plasma will be separated by centrifugation and frozen at -80oC. 
Rheumatoid factor will be measured by enzyme-linked immunosorbent assay (ELISA), with 
seropositivity defined at a level of ≥40 units (IBL America, Minneapolis, MN). Anti–cyclic 
citrullinated peptide antibody (anti-CCP) will be measured by ELISA (using the CCP3 kit), with 


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seropositivity defined at a level of ≥60 units (Inova Diagnostics, Woburn, MA). The levels of 
CRP, interleukin-6 (IL-6), troponins, pro-basic natriuretic peptide (pro-BNP), and lipids will be 
measured in the Core Laboratory of the Columbia University Medical Center. Comprehensive 
metabolic panels (CMP) and complete blood counts (CBC) will be collected for standard-of-
care hematology and hepato-renal safety. 
 
 
 
 
5.8. Potential Limitations. The exact magnitude of the change in myocardial SUV units that is 
clinically significant and could translate into improved cardiac outcomes is not known, hence it is 
possible that the sample size chosen for this proposal under or overestimates it. Similarly, it is 
conceivable that we do not detect T cell subsets associated with FDG myocardial uptake given 
the small sample size and the specified panels used to evaluate the T cell subpopulations. 
Adjusting for potential confounders (i.e., conventional CVD risk factors, CCP Ab, RA disease 
activity) will also be restricted by our sample size. Additionally, while the nuclear cardiologist will 
be blinded to treatment assignment, our study is not blinded to treatment arm. If our preliminary 
data is confirmed with the current proposal, a subsequent larger and blinded randomized 
controlled trial will be required. Finally, as our proposal focuses on RA patients without clinical 
cardiovascular disease, the study of the effects of abatacept on RA patients with CVD will need 
to be explored in a different study. 
 
 
 
6.ELIGIBILITY 
 
This is a single-center study. Twenty RA patients will be recruited over a planned recruitment 
period of 24 months, and randomized. The target population consists of patients who are 
deemed methotrexate-inadequate responders by their treating rheumatologist, and who have 
not recently received a biologic DMARD. Informed consent will be obtained by the Principal 
Investigator, co-investigator, or Study Coordinator. Study procedures including screening 
procedures will not begin until signed informed consent has been obtained. 
 
 
 
 
6.1. Inclusion Criteria: Subjects who meet all of the following criteria are eligible for enrollment 
into the study: 
 
- 
Written informed consent signed by the subject. 
 
- 
Patients age > 18 years. 
 


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- 
Fulfilling the American College of Rheumatology 2010 classification criteria for RA (60). 


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- 
 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; 
- 
No recent biologic DMARD treatment defined as prior biologic use other than rituximab in 
the past 3 months, or rituximab use in the past 6 months. 
 
- 
 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. 
 
 
 
6.2. Exclusion criteria: 
 
- 
Prior biologic use other than rituximab in the past 3 months, or rituximab use in the past 6 
months. 
 
- 
 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 or on-treatment cancer within 5 years of baseline visit 
 
- 
Prior use of immune checkpoint inhibitors. 
 
- 
Known pregnancy, HIV, hepatitis B, hepatitis C, active (or untreated latent) tuberculosis. 
 
- 
Prisoners or subjects who are compulsory detained. 
 
 
 
 
7.RECRUITMENT AND BLINDING 
 
 
7.1. Recruitment Plan 
 
 
The target population to be recruited is patients 18 years and older with a clinical diagnosis of 
RA who are deemed methotrexate-inadequate responders (MTX-IR) by their treating 
rheumatologist. Patients will be recruited from the rheumatology clinics of Columbia University 
Medical Center or referred from local rheumatologists. The treating rheumatologists will alert 
study staff when a patient is deemed a MTX-IR, prior to a switch or escalation of DMARDs. The 
Site Coordinator will speak with the patient to go over pre-screening inclusion/exclusion criteria, 
explain the trial, and assess interest. 
 
If the patient is interested in participating, the PI or Site Coordinator must obtain informed 
consent prior to any screening procedures. The research protocol will be explained in detail, 
including all possible risks and benefits. During the consent process, the study coordinator or 
investigator probes the patient’s understanding of the protocol.  All participants will be told that 
the study is voluntary, that they have no obligation to participate, and that they may decline or 


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withdraw at any time without compromising their care.  Subjects will have ample opportunity to 


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ask questions prior to signing the consent form. Eligible subjects will be allowed as much time 
as necessary to determine whether they wish to participate in the study. 
 
 
 
 
7.2. Randomization and Blinding 
 
 
Upon confirmation of subject eligibility, the Study Coordinator will determine treatment 
assignment through an unblinded 1:1, consecutively, alternating randomization. The nuclear 
cardiologist reading the FDG-PET/CT scans will be blinded to treatment assignment. 
Laboratory staff who run bioassays on biospecimen samples will also be blinded to treatment 
assignment. Subjects will be instructed NOT to discuss their treatment with the nuclear 
cardiologist and the staff. The nuclear cardiologist and the staff will also be instructed to remind 
the subject that treatment should not be discussed. 
 
 
 
 
8.RETENTION, AND WITHDRAWAL 
 
 
8.1. Subject Retention 
 
 
Once patients are enrolled, a proactive plan for retention will be implemented that includes 
elements such as regular phone and mailed reminders for each study visit. As commonly used 
strategies to maximize retention and minimize loss to follow-up, subject relations and subject 
satisfaction will be emphasized with efforts focusing on congeniality, respectfulness and 
friendliness in interactions with participants. 
 
 
 
 
8.2. Subject Withdrawal 
 
In this study, all subjects receive active therapy and given the short duration of the trial, we 
anticipate few to no withdrawals.  While great effort will be made to retain subjects in the study, 
subjects have the right to refuse treatment or completely withdraw from the study at any time for 
any reason. An explanation of why the subject is withdrawing from the study will be recorded. 
The investigator also has the right to withdraw subjects from the study treatment in the event of 
AE, protocol violations, administrative reasons, or for other reasons. When applicable, subjects 
should be informed of circumstances under which their participation may be terminated by the 
investigator without the subject’s consent. Any administrative or other reasons for withdrawal 


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must be documented and explained to the subject. If the reason for removal of a subject from 
the study is an adverse event, the principal specific event will be recorded. The subject should 
be followed until the AE has resolved. If it appears that a subject is lost to follow-up, the 
investigator must attempt to contact the subject or a responsible relative by telephone, to 
determine if any new AEs occurred, follow-up of any ongoing AE, and to establish as completely 
as possible the reason for the withdrawal. 
 
Study treatment may be discontinued for any subject who experiences any of the following: 
 
 
• 
Malignancy other than basal or squamous cell 
 
 
• 
Repeated subject non-compliance or loss to follow-up 
 
 
• 
The subject withdraws consent 
 
 
• 
The investigator believes it is in the best interest of the subject 
 
 
• 
The study is terminated 
 
 
If study treatment is discontinued (e.g., for an adverse event) and there is no safety issue 
precluding it, the subject will be asked to return for the follow-up FDG PET/CT scan if he/she 
has received at least eight weeks of the randomized treatment prior to withdrawal. 
 
In addition, if the subject decides to withdraw from treatment assignment before trial completion, 
the subject will be asked to come in for a follow-up FDG PET/CT scan within 2 weeks of stopping 
their randomized treatment assignment and before initiating any new treatment. Subjects will only 
be asked to come for a follow-up FDG PET/CT if they have been on the trial assigned treatment 
for at least 8 weeks. If they have been on less than 8 weeks of study treatment before wanting 
to withdraw, they will not undergo a second scan. 
 
 
If the subject withdraws consent, all study related visits, exams, procedures and data collection 
are terminated. 
 
 
 
 
9.TREATMENT PLAN AND STUDY DRUGS 
 
 
All study medications will be provided to participating subjects excluding methotrexate. As 
participants entering the study are already taking methotrexate and will be continuing to take 


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that medication for the duration of the study, subjects will continue to obtain their methotrexate 
through their previously utilized source. 
 
Upon completion determination that the subject is eligible for inclusion in the trial, the subject will 
be randomized to trial treatment. Once a subject has been assigned to treatment, the 
appropriate treatment will be provided. Subjects will begin their treatment arm on the date of the 
baseline visit. 
 
As the study drugs are FDA approved, they will be stored in accordance with the package insert 
in a secure area and under the appropriate environmental conditions. A disposition record of 
both abatacept (supplied by BMS) and adalimumab, will be maintained where these drugs will 
be inventoried and dispensed. Procedures for proper disposal of drug when appropriate will take 
place in accordance to institutional regulations and procedures. 
 
 
 
9.1. Description of Treatment Medications 
 
 
A brief description of each of the study medications (all of which are FDA approved) is provided 
below. More detailed descriptions of each drug are provided in the following links to the FDA 
approved package inserts: 
 
1)  Adalimumab: http://www.rxabbvie.com/pdf/humira.pdf 
 
2)  Abatacept: https://packageinserts.bms.com/pi/pi_orencia.pdf 
 
3)  Methotrexate Injection: 
 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/011719s117lbl.pdf 
 
4)  Methotrexate tablets: http://www.rheumatrex.info/pdf/RheumatrexPackageInsert.pdf 
 
 
 
 
 
Adalimumab. The standard initial dose of adalimumab is 40 mg SC once every other week. It is 
provided already diluted to the appropriate concentration in pre-filled syringes. It is also injected 
into the abdomen or thigh and must be refrigerated. 
 
Abatacept. Treatment with abatacept will consist of weekly subcutaneous (SQ) injections at a 
dose of 125mg. Similar to adalimumab, it is provided already diluted to the appropriate 
concentration in pre-filled syringes and autoinjector pen, and also injected into the abdomen or 
thigh and must be refrigerated. At the end of the study period, Bristol-Myers Squibb Company 
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supply study drug to subjects/investigators unless the Sponsor-Investigator chooses to extend 
their study. The investigator is responsible to ensure that the subject receives appropriate 
standard of care or other appropriate treatment in the independent medical judgement of the 
Investigator to treat the condition under study. 
 
 
 
 
9.2. Treatment Algorithm 
 
Figure 3. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Safety Visit 
Safety Visit 
 
 
 
 
 
Subjects will be randomized in an unblinded, 1:1, consecutive, alternating randomization to 
treatment with adalimumab 40 mg SQ every other week or abatacept 125 mg SQ weekly, each 
in addition to concomitant MTX. Subjects will remain on this new medication until the end of the 
treatment at 16 weeks. 
 
 
 
 
9.3. Concomitant Medications. 
 
 
Corticosteroids. Patients who are not receiving corticosteroids and those receiving low dose 
steroids (≤ 15 mg/day of prednisone or equivalent) will be considered eligible for the study 
provided other entry criteria are met. Excessive dosages of steroids may suppress FDG uptake 
independently of the randomized treatment. No oral corticosteroid “bursts” will be allowed 


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unless there is reason that an intra-articular injection is not possible. If a burst is required, it can be 
no more than 15mg per day (prednisone equivalent) at maximum and no longer than 14 days in 
duration. Corticosteroid bursts cannot occur within 14 days of either of the FDG PET/CT scans. 
 
 
 
 
10.SCHEDULE OF ASSESSMENTS 
 
Consent will be obtained at the beginning of the Screening/baseline visit (Visit 1). Patients who 
meet eligibility criteria and provide informed consent will be considered enrolled and will undergo 
the additional procedures outlined above in Table 1, including completion of questionnaires, 
screening laboratory tests including hepatitis B and C screens and tuberculosis screening (if none 
in the past six months). Subjects found to have active hepatitis or active infection 
(including tuberculosis) will be excluded. If the required screening blood work was completed by 
the subject within 2 weeks of the screening visit, these tests do not need to be repeated. 
 
If the subject has been on stable methotrexate or prednisone for the 8 weeks preceding the 
screening/baseline visit, then safety labs performed during those 8 weeks do not need to be 
repeated at the screening/baseline visit. If these additional laboratory- and imaging-based 
eligibility criteria are met and eligibility is confirmed, the cardiac FDG PET/CT scan will be 
scheduled. For the cardiac FDG PET/CT, the subject will be given instructions for an overnight 
fast for the purposes of the PET/CT scan. If nothing is found on the FDG PET/CT that would 
preclude the subject from randomization, the subject will be randomized into the study. The 
subject will complete additional questionnaires at baseline. An interim/safety visit at 8 weeks will 
take place, followed by a final visit at week 16. Blood will be drawn at each visit. A repeat cardiac 
FDG PET-CT scan will be performed at 16 weeks. An additional safety visit at week 20 will be 
performed to assess potential adverse events. 
 
 
 
Treatment drug will be dispensed at the baseline and the week 8 study visits. 
 
 
 
Table 1. 
 
 
Study Procedures 
Baseline
8 weeks
(± 2) 
16 weeks
(± 2) 
20 weeks 
(± 2) 


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Eligibility/ Informed consent 
X
 
 
 
Demographics, medical history 
X
 
 
 
Conventional CVD risk factors 
X
X
X
 
Physical Exam 
X 
X 
X 
X 
Cardiac FDG PET CT 
X
 
X
 
RA Activity Assessment1 
X
X
X
X 
T cell immunophenotyping 
X
 
X
 
Laboratory assessments2,3,4 
X
X
X
X 
Study Drug dispensation 
X
X
 
 
Adverse Events Assessment 
 
X
X
X 
1 CDAI, DAS-28. 2 CRP, ESR, IL-6, CCP Ab, RF, hemoglobin A1c,
lipid panel, troponins, pro-BNP, CMP, CBC. 3 Hepatitis B and C, 
quantiferon gold 
TB: only performed at baseline. 4 Pregnancy test if applicable.
 
 
 
 
11.SAFETY REPORTING 
 
11.1. Adverse Events 
 
 
11.1.1. Definition of an Adverse Event 
 
An adverse event (AE) is any untoward or unfavorable medical occurrence in a human subject, 
including any abnormal sign (for example, abnormal physical exam or laboratory finding), 
symptom, or disease, temporally associated with the subject’s participation in the research, 
whether or not considered related to the subject’s participation in the research. 
 
 
 
 
11.1.2. Serious Adverse Event 
 
A serious adverse event (SAE) is defined as any AE which: 
 
 
• 
Results in death 


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• 
 Is life-threatening (refers as any event in which the patient was at risk of death at the 
time of the event, it does not refer to an event that hypothetically might have caused 
death if more severe) 
 
• 
Results in inpatient hospitalization or prolongation of existing hospitalization 
 
 
• 
Results in a persistent or significant disability or incapacity 
 
 
• 
Results in a congenital anomaly or birth defect 
 
 
• 
 An important medical event that may not result in death, be life threatening, or require 
hospitalization may be considered an SAE when, based upon appropriate medical 
judgment, the event may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. 
 
 
• Suspected transmission of an infectious agent (eg, pathogenic or nonpathogenic) via the 
study drug is an SAE. 
 
 
Although pregnancy, overdose, potential drug-induced liver injury (DILI), and cancer are not 
always serious by regulatory definition, these events will be handled as SAEs. 
 
Any component of a study endpoint that is considered related to study therapy will be reported as 
an SAE (eg, death is an endpoint, if death occurred due to anaphylaxis, anaphylaxis must be 
reported). 
 
The following hospitalizations will not be considered SAEs in agreement with the PI and BMS 
 
clinical studies: 
 
 
A visit to the emergency room or other hospital department < 24 hours, that does not 
result in admission (unless considered an important medical or life-threatening event). 
 
Elective surgery, planned prior to signing consent. 
 
Admissions as per protocol for a planned medical/surgical procedure. 
 
Routine health assessment requiring admission for baseline/trending of health status (eg, 
routine colonoscopy). 
 
Medical/surgical admission other than to remedy ill health and planned prior to entry into 
the study. Appropriate documentation is required in these cases. 


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Admission encountered for another life circumstance that carries no bearing on health 
status and requires no medical/surgical intervention (eg, lack of housing, economic 
inadequacy, caregiver respite, family circumstances, administrative reason). 
 
Admission for administration of anticancer therapy in the absence of any other SAEs 
 
(applies to oncology protocols). 
 
 
 
 
11.1.3. Relationship of an Adverse Event to Study Intervention 
 
Medical judgment should be used to assess the causal relationship of an event to study 
intervention considering all relevant factors, the following guidelines are used: 
 
1.  Related (Possible, Probable, Definite) 
 
 
a. 
The event is known to occur with the study intervention. 
 
 
b. 
 There is a temporal relationship between the intervention and event onset. 
c. 
The event abates when the intervention is discontinued. 
d. 
The event reappears upon a re-challenge with the intervention. 
 
 
2.  Not Related (Unlikely, Not Related) 
 
 
a. 
 There is no temporal relationship between the intervention and event onset. 
b. 
An alternate etiology has been established. 
 
 
 
11.1.4. Severity of an Adverse Event 
 
The following scale will be used to grade adverse events: 
 
 
1.  Mild: Awareness of sign(s) or symptom(s) that is/are easily tolerated; no intervention 
required; no impact on activities of daily living (ADL) 
2.  Moderate: local, or non-invasive intervention indicated; enough discomfort or moderate 
impact on ADL 
3.  Severe: significant symptoms requiring invasive intervention or causing inability to work or 
to performed ADL; subject seeks medical attention, needs major assistance with ADL. 


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11.2. Unanticipated Problems 
 
The Office for Human Research Protections (OHRP) considers unanticipated problems 
involving risks to subjects or others to include, in general, any incident, experience, or outcome 
that meets all of the following criteria: 
 
• 
 Unexpected in terms of nature, severity, or frequency given (a) the research 
procedures that are described in the protocol-related documents, such as the IRB- 
approved research protocol and informed consent document; and (b) the 
characteristics of the subject population being studied; 
• Related or possibly related to participation in the research (“possibly related” means 
there is a reasonable possibility that the incident, experience, or outcome may have 
been caused by the procedures involved in the research); and 
• 
 Suggests that the research places subjects or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was previously 
known or recognized. 
 
 
 
11.3. Reporting of Adverse Events, Serious Adverse Events, and Unanticipated Problems 
 
 
 
 
The principal investigator and/or research staff will be monitoring for any possible adverse 
event/serious adverse event or unanticipated events at every study visit and/or throughout the 
subject participation in the study. Any AE will be documented in a study AE/SAE log with paper 
copies of any supplemental records that support the event, the PI will review the event and 
follow up as appropriate. All adverse events that are anticipated or unrelated will be kept in a AE 
log, reviewed by the PI and will be submitted regularly to the local IRB according to the local 
standard of procedure. All adverse event that are unanticipated and related or possibly related 
to the research and all Serious Adverse Events (SAEs) (regardless of expectedness, 
relatedness, or if they meet the definition for unanticipated problems) will be reported promptly 
within 24-48 hours from the PI receiving the notification of the event and the PI will be 
responsible to secure that the local IRB is promptly notified. Participants that sign a consent 
form will be considered enrolled until their participation is terminated or they withdraw consent. 
AEs/SAE/UE will be reported on all those enrolled. 
 
All SAE should be followed up and the report should include a description of the event, as well 
as the Investigator’s assessment of expectedness, relatedness and other information, as 


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relevant. Any action taken by the principal investigator and/or co-investigators should be 
provided in the report, as well as whether further action is recommended (e.g. collection of 
follow up information). 
 
Anticipated adverse events are specified on the package inserts of all study drugs and FDG 
PET-CT protocol. Those adverse events that occur, which are not specified on the package 
inserts or expected as per 18F-FDG PET-CT guidelines, will be considered unanticipated 
problems and will require reporting to the principal investigator and the IRB. 
 
Reports for unanticipated adverse events are to be submitted within 5 working days/7 calendar 
days of the date the investigator first becomes aware of the problem. Initial reports for SAEs 
should be submitted within 24-48 hours of initial awareness of the event, with a complete report 
to follow within 7 calendar days of initial awareness. 
 
All AEs (anticipated and unanticipated) will be collected, analyzed, and monitored by using an 
Adverse Event Form, which will also be used to track the AE/SAE. AEs identified in the protocol 
as critical to participant safety must be reported. All AEs experienced by the participant from the 
time of study enrollment through the end of study participation are to be reported. The research 
staff will record all reportable events with start dates occurring any time after informed consent 
is obtained until 7 (for non-serious AEs) or 14 days (for SAEs) after the last day of study 
participation. At each study visit, the investigator and/or research staff will inquire about the 
occurrence of AE/SAEs since the last visit 
 
Some incidental findings are likely to be identified in the PET/CT scans, or at other points 
throughout the study. The PI will be responsible for communicating any incidental findings to 
the participant’s primary care physician (PCP) or Rheumatologist. If the incidental finding is of 
an immediate nature (a medical emergency that requires immediate notification) such as 
suspected malignancy, notification to the primary care physician or Rheumatologist should 
occur within 24-48 hours of the availability of the on-site radiology report; urgent findings 
(abnormalities that require medical attention but not on an emergency basis) should be reported 
within 7 business days to the primary care physician (PCP) or Rheumatologist. The PI will be 
responsible for following up with this physician to determine whether any of the incidental 
findings will require withdrawal of the participant from the study.  Incidental findings will only be 
recorded as AEs in the data collection system if they are considered to be related to study 
treatment. 


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11.3.1 Reporting to BMS 
 
 
• 
All Serious Adverse Events (SAEs) that occur following the subject’s written consent to 
participate in the study through the last study visit on week 20, will be reported to BMS 
Worldwide Safety, whether related or not related to study drug. 
 
• 
 Following the subject’s written consent to participate in the study, all SAEs, whether related 
or not related to study drug, will be collected, including those thought to be associated with 
protocol-specified procedures. The investigator will report any SAE occurring after these 
aforementioned time periods, which is believed to be related to study drug or protocol- 
specified procedure. 
 
• 
 An SAE report will be completed for any event where doubt exists regarding its 
seriousness; 
 
• 
 If the investigator believes that an SAE is not related to study drug, but is potentially 
related to the conditions of the study (such as withdrawal of previous therapy or a 
complication of a study procedure), the relationship will be specified in the SAE Report 
Form. 
 
The CIOMS SAE form (http://www.cioms.ch/index.php/cioms-form-i) will be used to report SAEs 
and pregnancies to BMS via email: Worldwide.Safety@bms.com, 
aepbusinessprocess@bms.com, or fax: +1 609-818-3804. The BMS Protocol number will be 
included on the SAE form or on the cover sheet with the SAE form transmission. 
 
 
• 
 In accordance with local regulations, BMS will notify investigators of all reported SAEs that 
are suspected (related to the investigational product) and unexpected (ie, not previously 
described in the IB). An event meeting these criteria is termed a Suspected, Unexpected 
Serious Adverse Reaction (SUSAR). Investigator notification of these events will be in the 
form of a SUSAR Report. 
 
• 
 Other important findings which may be reported by BMS as an Expedited Safety Report 
(ESR) include: increased frequency of a clinically significant expected SAE, an SAE 
considered associated with study procedures that could modify the conduct of the study, 
lack of efficacy that poses significant hazard to study subjects, clinically significant safety 
finding from a nonclinical (eg, animal) study, important safety recommendations from a 


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study data monitoring committee, or sponsor decision to end or temporarily halt a clinical 
study for safety reasons. 
 
• 
 Upon receiving an ESR from BMS, the investigator must review and retain the ESR with 
the IB. Where required by local regulations or when there is a central IRB/IEC for the 
study, the sponsor will submit the ESR to the appropriate IRB/IEC. The investigator and 
IRB/IEC will determine if the informed consent requires revision. The investigator should 
also comply with the IRB/IEC procedures for reporting any other safety information. 
 
• 
 In addition to the Sponsor Investigator’s responsibility to report events to their local 
HA, suspected serious adverse reactions (whether expected or unexpected) shall 
be reported by BMS to the relevant competent health authorities in all concerned 
countries according to local regulations (either as expedited and/or in aggregate 
reports). SAEs, whether related or not related to study drug, and pregnancies will be 
reported to BMS within 1-2 business days of becoming aware of the event. If only limited 
information is initially available, follow-up reports will be submitted. If an ongoing SAE 
changes in its intensity or relationship to study drug or if new information becomes available, 
a follow-up SAE report will be sent within 1-2 Business Days to BMS using the same 
procedure used for transmitting the initial SAE report. All SAEs should be followed through 
the duration of the study. 
 
 
 
11.4. Pregnancy 
 
 
If the subject is a woman with childbearing potential, a urine sample will be taken for a 
pregnancy test from baseline through week 20, especially prior any study procedure at baseline 
and week 16. The results of the pregnancy test must be negative. Due to the possible 
teratogenic effect of the “radiation”, “medication”, highly effective contraception has to be 
performed and documented negative pregnancy test on the date of the study visit/s. 
 
In the rare case that a female subject participating in the study becomes pregnant after study 
intervention, the research staff must immediately report the event to the principal investigator and 
a serum pregnancy test should be performed. The PI should bring the subject for an evaluation, 
a written report and pregnancy form should follow as well as periodically follow up to monitor the 
outcome of the subject’s pregnancy. The pregnancy event should be reported to the 


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IRB within 24-48hrs of confirming the event. A copy of the report should be kept in the subject 
study binder. 
 
The following delineates specific responsibilities of staff members: 
 
 
• 
 The Research Coordinator will complete the Adverse Event Form (and Unanticipated 
Problems on the corresponding form); assist the PI to notify the IRB and Safety Officer 
of all SAEs, and assist them to prepare SAE reports to IRB and/or the Safety Officer. 
 
 
• 
 The Principal Investigator will confirm that all AEs and UPs are correctly documented 
by the coordinator; be available to answer any questions that the coordinators may have 
concerning AEs; The investigator together with her/his research staff will notify 
Worldwide.Safety@bms.com of this event via the CIOMS SAE form. 
 
• 
 Protocol-required procedures for study discontinuation and follow-up will be performed 
on the participant. 
 
• 
 Follow-up information regarding the course of the pregnancy, including perinatal and 
neonatal outcome and, where applicable, offspring information must be reported on the 
CIOMS, MedWatch, BMS Pregnancy Surveillance Form, or approved site SAE form. A 
BMS Pregnancy Surveillance Form may be provided upon request. will be provided 
through the duration of the study. 
 
Any pregnancy that occurs in a female partner of a male study participant should be reported to 
BMS. Information on this pregnancy will be collected on the Pregnancy Surveillance Form. In 
order for Sponsor or designee to collect any pregnancy surveillance information from the female 
partner, the female partner must sign an informed consent form for disclosure of this 
information. 
 
 
11.5. NONSERIOUS ADVERSE EVENT 
 
• 
 Non-serious Adverse Events (AE) will be provided to BMS as part of an annual reporting 
requirement. 
 
A non-serious adverse event is an AE not classified as serious. 
 
 
Non-serious Adverse Event Collection and Reporting 


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The collection of non-serious AE information will begin at initiation of study drug. All non-serious 
adverse events (not only those deemed to be treatment-related) will be collected continuously 
during the treatment period and for a minimum of 30 days following the last dose of study 
treatment. 
 
Non-serious AEs should be followed to resolution or stabilization, or reported as SAEs if they 
become serious. Follow-up is also required for non-serious AEs that cause interruption or 
discontinuation of study drug and for those present at the end of study treatment as appropriate. 
 
 
 
 
 
11.6. Laboratory Test Abnormalities 
 
All laboratory test results captured as part of the study will be recorded following institutional 
procedures. Test results that constitute SAEs will be documented and reported to BMS as such 
at the discretion of the PI in accordance with standard of care practice. 
 
The following laboratory abnormalities will be documented and reported appropriately: 
 
• 
any laboratory test result that is clinically significant or meets the definition of an SAE 
 
• 
 any laboratory abnormality that required the participant to have study drug discontinued or 
interrupted 
 
• 
any laboratory abnormality that required the subject to receive specific corrective therapy. 
 
 
It is expected that wherever possible, the clinical rather than laboratory term would be used by 
the reporting investigator (eg, anemia versus low hemoglobin value). 
 
 
 
 
 
11.7. Potential Drug Induced Liver Injury (DILI) 
 
 
Specific criteria for identifying potential DILI have not been identified for this protocol. Standard 
medical practice in identifying and monitoring hepatic issues will be followed. 
 
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An overdose is defined as the accidental or intentional administration of any dose of a product 
that is considered both excessive and medically important. All occurrences of overdose will be 
reported as an SAE. 
 
11.9. Other Safety Considerations 
 
Any significant worsening noted during interim or final physical examinations, 
electrocardiograms, X-rays, and any other potential safety assessments, whether or not these 
procedures are required by the protocol, should also be recorded as a non-serious or serious 
AE, as appropriate, and reported accordingly. 
 
 
 
 
12. 
STATISTICAL ANALYSIS 
 
 
12.1. Overview. This is a pilot study to evaluate the changes in FDG myocardial uptake post- 
biologic treatment of RA patients with abatacept vs adalimumab. Summary statistics for 
outcomes and predictor variables will be examined; with comparisons made using student t-test 
and Wilcoxon rank-sum test for normally and non-normally distributed continuous variables, 
respectively. Counts and percentages will be calculated for categorical variables and compared 
using the chi-square or Fisher’s exact test, as appropriate. In Aim 1, using generalized 
estimating equations (GEE), models will be constructed to explore the association between 
treatment arms (abatacept vs adalimumab) and change in myocardial FDG uptake treated as a 
continuous variable (measured by SUV units). Similarly, linear mixed effects models will be 
used to define the association between T cell subpopulations and myocardial FDG uptake per 
treatment arm strata. Given the small sample size of the study, we will not have the power to 
adjust for multiple variables, but the two treatment arms will be matched for age, sex, and 
disease activity, and the contribution of RA-disease characteristics and traditional CVD risk 
factors to the variability of myocardial FDG uptake will be ascertained. All statistical calculations 
will be performed using SAS 9.4. In all tests, a 2-tailed α of 0.05 will define statistical 
significance. 
 
 
 
12.2. Sample Size and Power Analysis. Data on what is considered a significant change in 
myocardial FDG uptake in RA is not yet known. Hence, based on our   preliminary data that 
included only 8 patients on abatacept, and as a proof of concept, for the proposed pilot 


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studies we will include 10 patients in the abatacept arm and compare them with 10 patients on 
adalimumab. Through normal approximation using the Z statistic, with a SD of 0.5 in the SUV 
units of myocardial FDG uptake seen in the RHYTHM study, we will have 80% power to detect 
an effect size of 0.6 between the groups, at an alpha level of 0.05. 
 
 
 
 
13. 
OTHER AND ADMINISTRATIVE CONSIDERATIONS 
 
 
13.1. Data Management 
 
 
For data collection and management purposes, subjects will be identified by a subject number 
only. All collected data will be transferred to a database exclusively using the SID only. The raw 
information for input into the database will be stored in binders in a locked cabinet in the PI’s 
office. The database will be saved in an encrypted computer and backed up onto an encrypted 
portable hard drive on a weekly basis, and the backups also kept in the locked cabinet. Hard- 
copy files will be stored in a locked cabinet in a locked room. Only the Principal Investigator and 
study staff will have access to these files. Those with access are held to the strictest standards 
of confidentiality. Data reported on the database must be consistent with the source data or the 
discrepancies must be explained. When needed, copies of supported documentation such as 
medical records current and/or previous should be requested and filed prior de-identification. All 
data must be derived from source documents. 
 
 
13.2. Confidentiality 
 
The confidentiality of participating subjects will be maintained. Subjects will be individually 
assigned a unique coded identification number The data file and the file that links the unique 
subject number to patient identity will be maintained separately in password protected files on 
password protected and fully encrypted computers in a locked office in the Division of 
Rheumatology. Hard-copy files will be stored in a locked cabinet in a locked room. Those with 
access are held to the strictest standards of confidentiality. Documents that identify the subject 
beyond subject number will not be released outside of Columbia University Medical Center 
and/or New York-Presbyterian Hospital (e.g., the signed informed consent document) and will 
be maintained in strict confidence by the investigator, except to the extent necessary to allow 
auditing by the regulatory authorities, study monitor, or sponsor representatives. 


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Standard HIPAA procedures and guidelines will be enforced. The consent form discloses to 
potential participants the individuals and/or agencies that are able to look at and copy research 
records, namely: 
 
- The principal investigator, co-investigators, study staff and other medical professionals who 
may be evaluating the study 
 
- Authorities from Columbia University and New York-Presbyterian Hospital, including the 
 
Institutional Review Board ('IRB') 
 
 
- The Office of Human Research Protections ('OHRP') 
 
 
- Representatives from and or of the FDA, federal or state government agencies, other health 
authorities and their commercial partners. 
 
- Information made available for inspection will be handled in strictest confidence and in 
accordance with local data protection laws. In addition to confidentiality disclosures described in 
the consent form, potential participants will also sign the attached study specific HIPAA Form 
before participating in this study. The consent discussion will take place in private locations (e.g. 
interview room; physician’s office; exam room). Participants will be given an ICF including the 
HIPAA form providing a specific description of the ways in which their personal health information 
will be used and disclosed in the course of this study. The Investigators or Research staff will 
explain and answer all the questions participants may have regarding their privacy protection. If 
they decide to participate, participants will be asked to sign the combined consent and HIPAA 
form authorizing the use and disclosure of their personal information before starting the study. 
 
 
 
 
13.3. Potential Risk 
 
 
A risk exists that despite all provisions to maintain participant’s confidentiality, confidentiality 
nonetheless may be compromised. As mentioned above every effort will be made to secure the 
data collected and separate identifying from de-identified information. 
 
Phlebotomy is associated with minor discomfort and occasional patients may experience a more 
severe vaso-vagal reaction and light-headedness. A minor risk of a skin infection at the site of 
phlebotomy also exists but may be treated with a short course of antibiotics should it occur. 


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The mortality of the PET-CT imaging is low and associated mainly with the administration of 
adenosine/regadenoson for evaluations under stress. In patients with established coronary 
artery disease, mortality is reported to be 2/10000patients. The risk for an acute myocardial 
infarction is also reported to be 2/10000. These numbers will not be applicable to our 
participants as candidates with prior cardiovascular events will be screened out. Furthermore, 
the mortality at the Columbia University PET center has been 0% for PET-CT stress tests for 
the last 15 years with over 11000 PET-CT stress tests performed. 
 
The radiation exposure/dosimetry with cardiac PET with: F18 FDG imaging is within FDA 
 
guidelines for research of this type. The radiation obtained during the PET CT-F18-FDG 
 
imaging examinations for this protocol would be 16.46 mSvs (1646 mrem) which is equivalent to 
about 5.4 years of natural and cosmic radiation. The patients will have to be fasting overnight 
when they present for their study visits and this may cause mild discomfort. 
 
In addition, study participants will be asked if they received radiation from imaging procedures 
outside the current protocol (for their regular clinical care). If other imaging studies have taken 
place, the cumulative radiation exposure will be calculated and if it exceeds the level of 50 mSv 
which is considered to be the maximum acceptable radiation exposure per year then the subject 
will not participate in the study. 
 
The testing performed in this study may unmask conditions that have been silent 
(asymptomatic). If a significant medical finding is noted during participation in this study, the PI 
will be notified immediately by the nuclear cardiologist, study personnel or the PET-CT center. 
 
 
 
 
13.4. Potential Benefit 
 
There are no direct benefits anticipated for the participating subjects. However, evaluating RA 
patients for early and potentially cardiac reversible changes such as the presence of myocardial 
inflammation will offer insight into the pathophysiology driving this disorder and guide an early 
intervention when warranted. The findings derived from this study could benefit the society by 
having multidisciplinary implications that could lead to the prevention of clinical vascular events 
and improvement in survival in patients with RA. 


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13.5. Records Retention 
 
 
Source documents provide evidence of the patient/subject existence and validate the integrity of 
the data collected. The trial site must retain the source documents, supported materials and any 
essential documents for as long as the principal investigator considers necessary. 
 
 
 
 
13.6. Publication Strategy 
 
 
The results of this research may be published in scientific journals or presented at medical 
meetings, but patient identity will not be disclosed. 


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14.  REFERENCE LIST 
 
 
1. 
Symmons DP, Jones MA, Scott DL, Prior P. Long-term mortality outcome in patients 
with rheumatoid arthritis: early presenters continue to do well. J Rheumatol. Jun 
1998;25(6):1072-1077. 
 
2. 
Solomon DH, Karlson EW, Rimm EB, Cannuscio CC, Mandl LA, Manson JE, et al. 
Cardiovascular morbidity and mortality in women diagnosed with rheumatoid arthritis. 
Circulation 2003;107:1303–7. 
3. 
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;33:221–7. 
 
4. 
Solomon DH, Goodson NJ, Katz JN, Weinblatt ME, Avorn J, Setoguchi S, et al. Patterns 
of cardiovascular risk in rheumatoid arthritis. Ann Rheum Dis 2006;65:1608–12. 
5. 
Wolfe F, Freundlich B, Straus WL. Increase in cardiovascular and cerebrovascular 
disease prevalence in rheumatoid arthritis. J Rheumatol 2003;30:36–40. 
6. 
Nicola PJ, Maradit-Kremers H, Roger VL, Jacobsen SJ, Crowson, CS, Ballman KV, et al. 
The risk of congestive heart failure in rheumatoid arthritis: a population-based study over 46 
years. Arthritis Rheum 2005;52:412–20. 
7. 
Nicola PJ, Crowson CS, Maradit-Kremers H, Ballman KV, Roger VL, Jacobsen SJ, et al. 
Contribution of congestive heart failure and ischemic heart disease to excess mortality in 
rheumatoid arthritis. Arthritis Rheum 2006;54:60. 
8. 
Wolfe F, Michaud K. Heart failure in rheumatoid arthritis: rates, predictors, and the effect 
of anti-tumor necrosis factor therapy. Am J Med 2004;116:305–11. 
9. 
Lebowitz WB. Heart in Rheumatoid Arthritis (Rheumatoid Disease) - A Clinical and 
 
Pathological Study of 62 Cases. Ann Intern Med. 1963; 58(1):102. 
 
10. 
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. 266: p. 959-64. 
11. 
Sokoloff L. Cardiac Involvement in Rheumatoid Arthritis and Allied Disorders: Current 
 
Concepts. Mod Concepts Cardiovasc Dis, 1964. 33: p. 847-50. 
 
12.       Grundtman C, et al., Cardiovascular disease in patients with inflammatory rheumatic 
disease is associated with up-regulation of markers of inflammation in cardiac microvessels and 
cardiomyocytes. Arthritis and rheumatism, 2010. 62(3): p. 667-673. 
13. 
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