Lead Investigator: Diane van der Woude, Leiden University Medical Center
Title of Proposal Research: Effect of rheumatoid factor and anticitrullinated peptide antibody on the efficacy of biological disease-modifying antirheumatic drugs in patients with rheumatoid arthritis
Vivli Research Request: 4922, 3274
Funding Source: None
Potential Conflicts of Interest: None
Summary of the Proposed Research:
Biological disease-modifying antirheumatic drugs (bDMARDs) have significantly improved clinical outcomes of rheumatoid arthritis (RA) patients. However, the association between the presence of autoantibodies and efficacy of bDMARDs has not yet been thoroughly studied.
The purpose of this study is to investigate the role of autoantibodies in the response to bDMARDs. More specifically we aim at understanding whether there is a different efficacy of bDMARDs in seropositive patients compared to seronegative patients.
We are conducting a systematic literature review, if possible complemented by a meta-analysis. Randomized controlled trials (RCTs) have been identified through previous systematic literature reviews addressing the efficacy of bDMARDs to inform the EULAR recommendations for the management of RA. Data will be collected into a standardized data extraction sheet.
Studies that included both autoantibody-positive and negative patients (with the percentage of seropositive patients being ≤80%) fulfilling the 1987 or 2010 RA criteria will be eligible. Interventions considered will be on-label dose of bDMARDs and any comparator. Strategy trials will not be included.
The primary endpoint is the American College of Rheumatology 20% improvement criteria (ACR20) response at 6 months. Secondary endpoints are the change in the Disease Activity Score 28-joint count with erythrocyte sedimentation rate (DAS28-ESR), American College of Rheumatology 50% improvement criteria (ACR50) response, American College of Rheumatology 70% improvement criteria (ACR70) response, achievement of remission, change in the Health Assessment Questionnaire (HAQ), and progression in total Sharp (van der Heijde) score, at 6 months. All endpoints will be analyzed in subgroups of patients according to baseline auto-antibody status. This amounts to 1 primary and 6 secondary endpoints, which is much more limited and reasonable. We will also look at the outcomes at 12 and 24 months, but not statistically test them as those outcomes are assessed in the long-term extension period, i.e. without a formal comparator, as there is no placebo.
The first step is to collect the above-mentioned endpoints stratified for baseline auto-antibody status. We are also requesting the data of other RCTs addressing the efficacy of bDMARDs. Having all data, we will conduct a meta-analysis of RCTs.
Statistical Analysis Plan:
Randomized controlled trials (RCTs) were identified through the previous systematic literature reviews addressing the efficacy of bDMARDs to inform the EULAR recommendations for the management of RA [6-8]. The following trials were selected: (1) trials evaluating one of the eight bDMARDs: infliximab (IFX), etanercept (ETN), adalimumab (ADA), certolizumab-pegol (CZP), golimumab (GLM), abatacept (ABT), rituximab (RTX) and tocilizumab (TCZ); (2) patients with RA (1987 ACR  or 2010 ACR/EULAR  RA classification criteria); (3) trials of ≥6 months’ duration; and (4) publications in English.
Trials that included both autoantibody-positive and negative patients (with a percentage of seropositive patients ≤80%) were included. Interventions were considered as on-label dose of bDMARDs and any comparator.
Strategy trials such as treat-to-target strategy approach were not included, as due to their complex design they do not allow to properly investigate the effect of bDMARDs in subgroups of patients (seropositive vs seronegative) without the confounding effect of the steered-treatment. Trials evaluating IL-1 blocker and anakinra (ANA) were excluded, because these drugs are not really being used for RA.
After independent screening, articles still regarded as candidates by at least one investigator were scrutinized independently through full-text reading.
The first step is to collect the endpoints on disease activity, function and radiographic progression, stratified for baseline auto-antibody status. Subgroup analyses based on the following subgroups will be performed: double seronegative (ACPA-negative and RF-negative) vs double seropositive (ACPA-positive and RF-positive). Additionally, patients will also be grouped according to ACPA status: positive vs negative, and according to RF status: positive vs negative. A standardized data extraction sheet is provided for the collection of these data.
For each trial meeting our inclusion criteria, we sent a group-level data request to the first or corresponding author of the trial, or both, or to the trial sponsor. We will use the following data: ACR20 (n), ACR50 (n), ACR70 (n), DAS28-ESR (mean, SD), DAS28-CRP (mean, SD), delta DAS28-ESR (mean, SD), delta DAS28-CRP (mean, SD), DAS28-ESR remission (n), DAS28-CRP remission (n), HAQ (mean, SD), delta HAQ (mean, SD), HAQ response rate ≥0.22 (n), total Sharp score (mean, SD), delta Sharp score (mean, SD), delta total Sharp score ≤0 (n), and delta total Sharp score ≤0.5 (n) at 6, 12, and 24 months. If we receive the specific results in patient-level data, the data on the above-mentioned aggregated means and proportions will be first extracted using an excel spreadsheet.
All analyses will be performed on complete cases. However, missing data imputation methods may have been used in some of the trials. For dichotomous outcomes, missing data will be imputed using Non-responder imputation (NRI), which assigns a subject with a missing binary or categorical outcome as if they are a non-responder. For continuous variables, the average value of the outcome variable among those in that treatment group with complete data will be imputed.
Patients with RA will be grouped and analyzed separately as follows: (1) DMARD-naive or methotrexate (MTX)-naive, (2) MTX-inadequate response (IR) or conventional synthetic (cs)DMARD-IR and (3) tumor necrosis factor inhibitor (TNFi) TNFi-IR. Overall serotype effects will be obtained for bDMARDs and control groups.
The primary analysis will be a mixed-effect meta-regression of relative risk ratios (RRRs). Further secondary analyses are planned to include head-to-head trials, explore the influence of reported covariates on the outcome (such as geographic location, patient characteristics) and by aggregating data in different ways (different time points).
The Cochrane risk of bias assessment tool will be used to assess the risk of bias of each of the trials.
- Nam JL, Takase-Minegishi K, Ramiro S, Chatzidionysiou K, Smolen JS, van der Heijde D, et al. Efficacy of biological disease-modifying antirheumatic drugs: a systematic literature review informing the 2016 update of the EULAR recommendations for the management of rheumatoid arthritis. Ann Rheum Dis. 2017 Jun;76(6):1113-1136.
- Nam JL, Ramiro S, Gaujoux-Viala C, Takase K, Leon-Garcia M, Emery P, et al. Efficacy of biological disease-modifying antirheumatic drugs: a systematic literature review informing the 2013 update of the EULAR recommendations for the management of rheumatoid arthritis. Ann Rheum Dis. 2014 Mar; 73(3):516-528.
- Nam JL, Winthrop KL, van Vollenhoven RF, Pavelka K, Valesini G, Hensor EM, et al. Current evidence for the management of rheumatoid arthritis with biological disease-modifying antirheumatic drugs: a systematic literature review informing the EULAR recommendations for the management of RA. Ann Rheum Dis. 2010 Jun; 69(6):976-986.
- Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 1988 Mar;31(3):315-24.
- Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham CO 3rd, et al. 2010 rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Ann Rheum Dis. 2010 Sep;69(9):1580-8.
Safety Trial of Adalimumab in Rheumatoid Arthritis (Abbott STAR trial)
Sponsor ID: DE031
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
Study ID: NCT00235859
Sponsor ID: M02-556
(Note: Additional studies added as part of Data Request 4922)
A DOUBLE-BLIND STUDY EVALUATING THE EFFICACY AND SAFETY OF THE COMBINATION OF ETANERCEPT AND METHOTREXATE IN COMPARISON TO ETANERCEPT ALONE OR METHOTREXATE ALONE IN RHEUMATOID ARTHRITIS PATIENTS (TEMPO)
Data Contributor: Pfizer Inc.
Study ID: NCT00393471 (Pfizer Protocol ID: B1801240)
A 24-MONTH, RANDOMIZED, DOUBLE-BLIND, TWO-PERIOD STUDY TO EVALUATE THE EFFICACY AND SAFETY OF THE COMBINATION OF ETANERCEPT AND METHOTREXATE AND METHOTREXATE ALONE IN SUBJECTS WITH ACTIVE EARLY RHEUMATOID ARTHRITIS (COMET)
Data Contributor: Pfizer Inc.
Study ID: NCT00195494 (Pfizer ID: B1801325)
A-6-MONTH, DOUBLE-BLIND COMPARISON OF ETANERCEPT, SULPHASALAZINE, AND THE COMBINATION OF ETANERCEPT (COMBE)
Data Contributor: Pfizer Inc.
Study ID: Legacy Wyeth Study 0881A1-309- No NCT# (Pfizer ID: B1801241)
STUDY EVALUATING THE EFFICACY AND SAFETY OF ETANERCEPT AND METHOTREXATE IN JAPANESE SUBJECTS WITH RHEUMATOID ARTHRITIS (TAKEUCHI)
Data Contributor: Pfizer Inc.
Study ID: NCT00445770 (Pfizer Protocol ID: B1801002)
Takase-Minegishi K, Böhringer S, Nam J, Kaneko Y, Behrens F, Saevarsdottir S, Detert J, Leirisalo-Repo M, van der Heijde D, Landewé R, Ramiro S, van der Woude D. The Impact of Autoantibodies (RF and ACPA) on the Efficacy of Biological Disease-modifying Antirheumatic Drugs in Rheumatoid Arthritis: Meta-analysis of Randomized Controlled Trials [abstract]. Arthritis Rheumatol. 2022; 74 (suppl 9). https://acrabstracts.org/abstract/the-impact-of-autoantibodies-rf-and-acpa-on-the-efficacy-of-biological-disease-modifying-antirheumatic-drugs-in-rheumatoid-arthritis-meta-analysis-of-randomized-controlled-trials/.