Efficacy and safety of tumor necrosis factor inhibitors (TNFi) in seronegative rheumatoid arthritis patients who are inadequate responders to conventional synthetic disease modifying anti-rheumatic drugs (csDMARDs). A systematic literature review with meta-analysis.

Lead Investigator: Carl Turesson, Lund University
Title of Proposal Research: Efficacy and safety of tumor necrosis factor inhibitors (TNFi) in seronegative rheumatoid arthritis patients who are inadequate responders to conventional synthetic disease modifying anti-rheumatic drugs (csDMARDs). A systematic literature review with meta-analysis
Vivli Data Request: 9731, 7826
Funding Source: None
Potential Conflicts of Interest: Consulting fees from Roche, speaker fees from Abbvie, Bristol Myers-Squibb, Nordic Drugs, Pfizer and Roche, and an unrestricted research grant from Bristol Myers-Squibb.
The present study is not funded by the above reported pharmaceutical companies.

Summary of the Proposed Research:

Rheumatoid arthritis (RA) is a chronic autoimmune disease that is characterised by the presence of special antibodies in the blood, that are directed against one or more of the patient´s own proteins. These kind of antibodies are called autoantibodies. Autoantibodies that are usually found in RA patients are rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPA). The former are autoantibodies that target a specific portion of normal antibodies, whereas the latter are antibodies directed against proteins that have undergone a particular biochemical process, which is called “citrullination.” However, about 20% of patients with RA do not have RF and ACPA in their blood. Therefore, RA is classified as seropositive or seronegative according to the presence or absence of RF and ACPA, respectively. Seropositive and seronegative RA are not exactly the same disease: for example, seropositive RA is more severe than seronegative RA. Immunosuppressants are a group of drugs that modulate the patient´s immune-system and are used for the treatment of autoimmune diseases like RA. In particular, a special group of immunosuppressants, called disease modifying anti-rheumatic drugs (DMARD), are used against RA. DMARDs are grouped into three categories: conventional synthetic DMARDs (csDMARDs), biologic DMARDs (bDMARDs), targeted synthetic DMARDs (tsDMARDs). CsDMARDs represent the first-line treatment. When the latter are not effective, bDMARDs and tsDMARDs may be prescribed. Tumor necrosis factor (TNF) is a body protein involved in the inflammatory process of RA. TNF inhibitors (TNFi) are drugs that target TNF and represent the most commonly prescribed bDMARDs for the treatment of RA, since many randomised clinical trials (RCTs) have showed their efficacy and safety in patients with this condition. However, the great majority of patients that are included in RCTs have seropositive RA and therefore we do not know whether TNFi are effective in seronegative RA as well. We would like to fill this knowledge gap by performing a systematic literature review with meta-analysis of RCTs, since this is the best way to assess such clinical question. We have already performed a literature search showing that there are no RCTs investigating only patients with seronegative RA. Moreover, the published RA trials do not break down results according to autoantibody status. Therefore, we will proceed by requesting disaggregated data of seronegative patients from the existing RCTs on RA. Afterwards, we will pool the data in a meta-analysis to assess RA related clinical outcomes. The generated evidence will be summarised and qualitatively judged according to Cochrane methodology.

Requested Studies:

A Placebo-Controlled, Double-Blinded, Randomized Clinical Trial of Anti-TNF Chimeric Monoclonal Antibody (cA2) in Patients With Active Rheumatoid Arthritis Despite Methotrexate Treatment
Data Contributor: Johnson & Johnson
Study ID: NCT00269867
Sponsor ID: CR006259

A Randomized, Double-Blind, Placebo- and Active-Controlled, Phase 3 Study Evaluating the Efficacy and Safety of Baricitinib in Patients With Moderately to Severely Active Rheumatoid Arthritis Who Have Had an Inadequate Response to Methotrexate Therapy
Data Contributor: Lilly
Study ID: NCT01710358
Sponsor ID: 13978

A Multi-center Randomized, Phase 2/3, Double-blind, Parallel-group, Placebo-controlled Study to Assess the Safety and Efficacy of Adalimumab Administered as Subcutaneous Injections in Adult Chinese Rheumatoid Arthritis Subjects Treated With Methotrexate
Data Contributor: AbbVie
Study ID: NCT00538902
Sponsor ID: M04-705

A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study of the Human Anti-TNF Monoclonal Antibody Adalimumab in Rheumatoid Arthritis Patients Currently Receiving Treatment With Methotrexate
Data Contributor: AbbVie
Study ID: NCT00195702
Sponsor ID: DE019

A Phase III Multicentre, Double Blind, Placebo-controlled, Parallel Group 52-week Study to Assess the Efficacy and Safety of 2 Dose Regimens of Lyophilised CDP870 as Additional Medication to Methotrexate in the Treatment of Signs and Symptoms and Preventing Structural Damage in Patients With Active Rheumatoid Arthritis Who Have an Incomplete Response to Methotrexate
Data Contributor: UCB
Study ID: NCT00152386
Sponsor ID: C87027

A Study of Adalimumab in Adult Japanese Subjects With Rheumatoid Arthritis
Data Contributor: AbbVie
Study ID: NCT00647491
Sponsor ID: M02-575

Study of the Human Anti-TNF-Antibody Adalimumab
Data Contributor: AbbVie
Study ID: NCT00647920
Sponsor ID: M02-573

A Multicenter, Randomized, Double-blind, Placebo-controlledTrial of Golimumab, a Fully Human Anti-TNFa MonoclonalAntibody, Administered Subcutaneously, in Subjects With ActiveRheumatoid Arthritis Despite Methotrexate Therapy
Data Contributor: Johnson & Johnson
Study ID: NCT00264550
Sponsor ID: CR006343

A Phase 3 Study Comparing 2 Doses Of CP-690,550 And The Active Comparator, Humira (Adalimumab) Vs. Placebo For Treatment Of Rheumatoid Arthritis
Data Contributor: Pfizer Inc.
Study ID: NCT00853385
Sponsor ID: NCT00853385

A Randomized, Double-Blind, Placebo-Controlled, Phase III Study of the Human Anti-TNF Antibody Adalimumab Administered as Subcutaneous Injections in Korean Rheumatoid Arthritis Subjects Treated With Methotrexate
Data Contributor: AbbVie
Study ID: NCT00235859
Sponsor ID: M02-556

A Randomized, Double-blind, Dose-ranging Trial of CNTO 148 Subcutaneous Injection Compared With Placebo in Subjects With Active Rheumatoid Arthritis Despite Treatment With Methotrexate
Data Contributor: Johnson & Johnson
Study ID: NCT00207714
Sponsor ID: CR005263

A Phase II, Randomized, Double-Blind, Parallel-Group Study to Evaluate the Efficacy and Safety of MLTA3698A in Combination With a Disease-Modifying Anti-Rheumatic Drug (DMARD) Compared With Adalimumab in Combination With a DMARD in Patient With Active Rheumatoid Arthritis
Data Contributor: Roche
Study ID: NCT01225393
Sponsor ID: ALT4864g