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Methotrexate

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Etanercept

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Golimumab

Patients will receive a TNF inhibitor in addition to their current treatment in an open label protocol for increased disease activity and in the context of standard of care.

Patients will receive their current treatment in an open label protocol in the context of standard of care.

Subjects without RA who will function as controls.

TNF inhibitors are an FDA approved class of medications indicated for the treatment of RA when initial treatment (usually with methotrexate) has failed to achieve remission of RA disease activity. TNF inhibitors are part of the standard of care management of RA.

The possible TNF inhibitors are: Remicade, Humira, Enbrel, Cimzia, Simponi.

TNF inhibitors

Standard of care treatment for RA, such as Methotrexate or other disease-modifying antirheumatic drugs.

DMARDs

Joan M Bathon, MD

For aim 1, the proposed studies will be performed in 150 patients with RA and 25 subjects without RA (healthy volunteers) who will function as controls.

For aim 2, 25 of the patients enrolled in aim 1 (who are in need for further treatment due to increased RA activity despite their current treatment) will be recruited to continue in the study for an additional 24 (+/- 2) weeks (or 6 months). These patient will receive a TNF inhibitor in addition to their current treatment in an open label protocol for increased disease activity and in the context of standard of care.

The investigators hypothesize that anti-TNF agents in RA patients without heart disease will not adversely affect the heart (will not cause a detrimental change in heart structure or its function).

Patients with Rheumatoid Arthritis (RA) have a shortened life expectancy compared to the general population. Cardiovascular disease (CVD), including heart failure (HF), is the primary cause of the extra deaths in RA. HF, in general, results from failure of the heart muscle to pump adequately. In other words the heart muscle in HF becomes "weak". In patients without RA, the heart muscle gets larger before symptoms of HF appear. Contrary to that, patients with RA have reduced heart size and reduced heart strength. This may mean that in RA the pathway to heart failure may be different compared to what happens in patients without RA. It is possible - for example - that in RA the heart muscle becomes smaller before it becomes weak (while in non-RA patients the heart muscle becomes larger before it becomes weak). It is possible that cells that create inflammation in the joints may also do the same in the heart muscle making it smaller, thinner and eventually weaker.

Patients with RA nowadays can be treated with a variety of medications for their joint inflammation. These medications are powerful and have reduced the risk of permanent joint damage and disability. However it is unknown what is the effect of these medications on the heart size and strength and whether they increase or decrease the risk for cardiovascular disease and heart failure.

Among the medications used for RA are medications called TNF inhibitors. They are usually prescribed to patients who have joint inflammation that has not responded to treatment with the first line medication Methotrexate. Data in non-RA patients with advanced heart failure suggest that anti-TNF agents may not help heart failure and may even be harmful. However, the effect of these agents on the hearts of RA patients has never been directly studied. Some observational studies suggest that RA patients treated with TNF inhibitors have a lower risk of developing heart disease. Overall the knowledge regarding the effect of TNF inhibitors on RA patients heart function is limited.

RHYTHM (Formerly Escape II Myocardium)

RHYTHM (RHeumatoid Arthritis studY of THe Myocardium): How Rheumatoid Arthritis (RA) and Tumor Necrosis Factor (TNF) Inhibitors Affect the Myocardial Structure and Function.

This is designed to evaluate the baseline characteristics of the cross sectional RA cohort to understand the correlation of disease activity measured by the Clinical Disease Activity Index (CDAI) with myocardial inflammation measured by fluorodeoxyglucose (FDG) uptake in positron emission tomography (PET) scan at the baseline visit. Myocardial FDG uptake is classified as "diffuse" or "focal."

This is designed to measure the myocardial inflammation, and its association with change in CDAI, after ramp-up of RA therapy over 6 months. Measurements are taken at baseline and 6-months post treatment escalation. Myocardial FDG uptake is classified as "diffuse" or "focal."

This is designed to evaluate the baseline characteristics of the entire RA cohort to understand the association of myocardial inflammation measure by FDG uptake with measures of left ventricular (LV) structure measured by 2D/3D echocardiogram at the baseline visit.

This is designed to evaluate the baseline characteristics of the entire RA cohort to understand the association of myocardial inflammation measure by FDG uptake with measures of left ventricular (LV) function measured by 2D/3D echocardiogram at the baseline visit.

National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)

Columbia University

Professor Medicine, Rheumatology

An adverse event (AE) is any undesirable sign, symptom or medical condition occurring after starting study drug (or therapy). Medical conditions/diseases present before starting study treatment are only considered adverse events if they worsen after starting study therapy. In addition all adverse events regardless of whether they constitute unanticipated problems as well as AEs thought to be possibly related to study procedures will also be reported to IRB, safety officer, SMC, and NIH/NIAMS.

Participants were randomized to TNFi or DMARD therapy. Patients will receive their current treatment in an open label protocol in the context of standard of care.

TNFi: biologic treatment for RA, such as Humira, Enbrel, Remicade,

RA Patients - Pharmacotherapy Escalation (TNFi)

Participants were randomized to TNFi or DMARD therapy. Patients will receive their current treatment in an open label protocol in the context of standard of care.

DMARDs: Standard of care treatment for RA, such as Methotrexate or other disease-modifying antirheumatic drugs.

RA Patients - Pharmacotherapy Escalation (DMARD)

Healthy Volunteers

A cohort of patients with Rheumatoid Arthritis will undergo the baseline study visit only (no randomization to treatment). Note, that those who were randomized, their data will be utilized in the full cross sectional analysis.

Patients - Cross Sectional (RA)

Patients will receive a TNF inhibitor in addition to their current treatment in an open label protocol for increased disease activity and in the context of standard of care.

TNF inhibitors: TNF inhibitors are an FDA approved class of medications indicated for the treatment of RA when initial treatment (usually with methotrexate) has failed to achieve remission of RA disease activity. TNF inhibitors are part of the standard of care management of RA.

The possible TNF inhibitors are: Remicade, Humira, Enbrel, Cimzia, Simponi.

DMARDs: Standard of care treatment for RA, such as Methotrexate or other disease-modifying antirheumatic drugs.

Patients - DMARDs + TNF Inhibitors

Patients will receive their current treatment in an open label protocol in the context of standard of care.

DMARDs: Standard of care treatment for RA, such as Methotrexate or other disease-modifying antirheumatic drugs.

Patients - DMARDs Only

Total

Age, Categorical

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

RA participants=133, Healthy Volunteers=16

Dr. Joan Bathon, MD

Diffuse FDG Uptake

Focal FDG Uptake

No FDG Uptake

A cohort of patients with Rheumatoid Arthritis who underwent the baseline visit analysis and completed the visit in the full cross sectional analysis.

A cohort of healthy volunteers (those without an autoimmune or history of cardiac illness) was utilized. n=16 were recruited directly, while n=11 were recruited via the CUIMC Nuclear Cardiology archive.

2 RA patients and 1 healthy volunteer (control subject) were not included in this analysis population because the subjects withdrew study participation prior to scan (no data were collected).

Number of Participants With Myocardial FDG Uptake

Focal Baseline FDG Uptake

Focal Follow-up FDG Uptake

Diffuse Baseline FDG Uptake

Diffuse Follow-up FDG Uptake

Participants were randomized to TNFi or DMARD therapy.

Patients will receive their current treatment in an open label protocol in the context of standard of care.

TNFi: biologic treatment for RA, such as Humira, Enbrel, Remicade,

Participants were randomized to TNFi or DMARD therapy.

Patients will receive their current treatment in an open label protocol in the context of standard of care.

DMARDs: Standard of care treatment for RA, such as Methotrexate or other disease-modifying antirheumatic drugs.

2 TNFi, and 2 DMARDs and 1 healthy volunteer (control subject) were not included in this analysis population because the subjects withdrew participation prior to study completion or scan (no data were collected).

Number of Participants With Myocardial FDG Uptake After Escalation of RA Pharmacotherapy

A cohort of healthy volunteers (those without an autoimmune or history of cardiac illness) was utilized. n=16 were recruited directly, while n=11 were recruited via the CUIMC Nuclear Cardiology archive

Only 119 out of 121 subjects had data analyzed due to 2 subject withdrawals prior to scan.

LV Structure (Mean EDVI) in Association With Myocardial FDG Uptake

LV Function (Mean Stroke Volume Index) in Association With Myocardial FDG Uptake

Overall Study

Janus Kinase Inhibitors

Patients newly diagnosed with active Rheumatoid Arthritis and receiving lowest effective dosage of Methotrexate as initial therapy.

Patients diagnosed with active Rheumatoid Arthritis and have shown intolerance or inadequate response to Methotrexate so JAK Inhibitor (Barcitinib) was added at 4mg/day orally to their therapy.

Patients diagnosed with active rheumatoid arthritis and have shown intolerance or inadequate response to Methotrexate so TNF Inhibitor was added to their therapy (either Golimumab at 50mg subcutaneous injection/m, or Etanercept at 50mg subcutaneous injection/wk)

Observation of Rheumatoid arthritis disease response to JAK inhibitors and TNF inhibitors after definite timepoints from the initialization of treatment in comparison to the current standard of care of therapy with conventional DMARDs.

Observation

Esraa Mahmoud, MBBCh

Rheumatoid arthritis is a systemic autoimmune disease characterized by inflammatory synovitis and progressive joint destruction, which are associated with severe disability and increased mortality. It occurs at an incidence of 5 per 1000 with Women being 2 times more likely to be affected by Rheumatoid Arthritis than men. The peak incidence in both groups is in the sixth decade of life.

Management of RA has improved substantially in recent years. In addition to the reduction of signs and symptoms, improvement of physical function, and inhibition of structural damage, better patient outcomes, and clinical remission are now considered achievable goals. Therefore, the current recommended primary target for the treatment of RA should be a state of clinical remission.

Methotrexate (MTX) should be initiated, typically as monotherapy. If treatment response is inadequate, other Disease-modifying antirheumatic drugs (DMARDs) may be added to (rather than replacing) methotrexate to enhance efficacy and reduce the potential for the formation of anti-drug antibodies. TNF inhibitors are the first-line biologic therapies used in the event of incomplete response or adverse reaction to conventional DMARDs as TNF alpha is an important proinflammatory cytokine produced by macrophages and other cells, with myriad actions relevant to the pathogenesis of RA, including stimulation of other proinflammatory cytokine production, expression of endothelial cell adhesion molecules, production of metalloproteinases, and stimulation of osteoclasts. Activated Janus kinases (JAKs) play pivotal roles in intracellular signaling from cell-surface receptors for multiple cytokines implicated in the pathologic processes of rheumatoid arthritis. Baricitinib, an orally available small molecule, provides reversible inhibition of Janus Kinase 1 (JAK1) and Janus Kinase 2 (JAK2) and has shown clinical efficacy in studies involving patients with moderate to severely active Rheumatoid Arthritis who are either intolerant to MTX treatment or who have had an inadequate response to DMARDs, either conventional or biologic.

Aims of the Study:

* To determine the outcome of patients with moderate to severely active rheumatoid arthritis (RA) - despite methotrexate treatment - on JAK inhibitors (Baricitinib).
* To determine the outcome of patients with moderate to severely active rheumatoid arthritis (RA) - despite methotrexate treatment- on TNF inhibitors (Golimumab and Etanercept).
* To compare the outcome between these 2 groups of patients in terms of improvements in signs and symptoms, physical function, patient-reported outcomes, and progression of structural joint damage.
* Detection of any adverse effects that may emerge during the course of treatment.

Patients will be classified into 3 groups:

group (1): patients receiving Methotrexate group (2): patients receiving Methotrexate in addition to JAK inhibitors (Baricitinib at 4 mg once daily by oral route) group (3): patients receiving Methotrexate in addition to TNF inhibitors (Golimumab at 50 mg/month or Etanercept at 50mg/ week by subcutaneous injections)

Comparative Study of Janus Kinase (JAK) Inhibitors Vs Tumor Necrosis Factor (TNF) Inhibitors in Rheumatoid Arthritis

Comparative Study of JAK Inhibitors Vs TNF Inhibitors in Patients With Rheumatoid Arthritis

Individual Participant Data (IPD) will not be shared with anyone as per consent

Assessment of Tender Joints Count (TJC) and Swollen Joints Count (SJC), both are parameters to describe disease severity.

A patient is asked to indicate his/her perceived pain intensity along a 100 mm horizontal line, and this rating is then measured from the left edge. Minimum score is zero indicating no pain, while maximum score is 100 indicating severe pain.

DAS28 (Disease Activity Score for 28 Joints) is a widely used scoring system for assessment of disease activity in Rheumatoid Arthritis patients. Minimum value is zero, which indicates disease remission while maximum value is 9.4, which indicates highest disease activity.

CDAI score is used in routine assessment of disease activity in RA patients. Minimum score is 0 indicating disease remission , while maximum score is 600 indicating highest disease activity.

measured by the modified Larsen scoring system using plain x-rays (AP view) on both hands and feet. Minimum score is zero indicating normal joint, while maximum score is 5 indicating complete joint deformation.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
RHYTHM (Formerly Escape II Myocardium)	NCT01548768	Rheumatoid Arth...	TNF inhibitors DMARDs	18 Years -	Columbia University
Comparative Study of Janus Kinase (JAK) Inhibitors Vs Tumor Necrosis Factor (TNF) Inhibitors in Rheumatoid Arthritis	NCT05567380	Rheumatoid Arth...	Observation	18 Years -	Sohag University
Comparative Study of Janus Kinase (JAK) Inhibitors Vs Tumor Necrosis Factor (TNF) Inhibitors in Rheumatoid Arthritis	NCT05567380	Rheumatoid Arth...	Observation	18 Years -	Sohag University
RHYTHM (Formerly Escape II Myocardium)	NCT01548768	Rheumatoid Arth...	TNF inhibitors DMARDs	18 Years -	Columbia University

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