Effect of baseline rheumatoid factor and anticitrullinated peptide antibody serotype on rituximab clinical response: a meta-analysis
- John D Isaacs1,
- Stanley B Cohen2,
- Paul Emery3,
- Paul P Tak4,5,
- Jianmei Wang6,
- Guiyuan Lei6,
- Sarah Williams6,
- Preeti Lal7,
- Simon J Read6
- 1Newcastle University and Newcastle upon Tyne Hospitals NHS Foundation Trust, Institute of Cellular Medicine, Newcastle upon Tyne, UK
- 2Metroplex Clinical Research Center, Dallas, Texas, USA
- 3Leeds General Infirmary, Leeds, UK
- 4Department of Clinical Immunology and Rheumatology, F4-105, AMC/University of Amsterdam, Amsterdam, Netherlands
- 5GlaxoSmithKline, Stockley Park, UK
- 6Roche Products Ltd, Welwyn Garden City, UK
- 7Genentech Inc, South San Francisco, California, USA
- Correspondence to John D Isaacs, Institute of Cellular Medicine, Newcastle University and Newcastle upon Tyne Hospitals NHS Foundation Trust, Freeman Road, Newcastle upon Tyne NE7 7DN, UK;
Contributors JDI, JW, GL, SW and SJR contributed to the design of the study and analysis of the data. All authors contributed to the interpretation of the data, drafted and/or revised the manuscript for intellectual content and approved the final version of the manuscript.
- Accepted 25 March 2012
- Published Online First 11 June 2012
Background Studies examining the relationship between serological status (rheumatoid factor and/or anticitrullinated antibody) and rituximab treatment outcome in rheumatoid arthritis (RA) have been hampered by limited numbers of seronegative patients.
Objective To carry out a meta-analysis of trials from the rituximab RA clinical programme to investigate this relationship further.
Methods This was a meta-analysis of four placebo-controlled, phase II or III clinical trials. The efficacy end point in all analyses was change from baseline in Disease Activity Score in 28 joints-erythrocyte sedimentation rate (DAS28-ESR) at 24 weeks. Assay of serotype and missing data imputation methods were consistent across all studies.
Results The population analysed comprised 2177 patients (rituximab, n=1416; placebo, n=761). Demographics and baseline disease characteristics were well balanced. When a fixed-effects meta-analysis approach was used, the overall-effect model indicated evidence of additional treatment benefit with rituximab in seropositive patients: reduction in DAS28-ESR at week 24 was on average 0.35 units (95% CI 0.12 to 0.84; n=1394) greater than in seronegative patients; this effect was not seen in placebo patients. Heterogeneity indices indicated significant uncertainty in the overall-effect model (Q=8.8, I=0.77; p=0.03 (χ2 test)). Baseline Health Assessment Questionnaire score, pain visual analogue scale, swollen joint counts of 28 joints and race were significant contributors to this heterogeneity, with additional analysis indicating that these effects may predominate in early RA (methotrexate-naïve) populations. A dominant effect was seen in patients for whom one or more tumour necrosis factor inhibitors had failed.
Conclusion Although the difference was modest, the overall-effect model indicates that seropositive patients respond better to rituximab than seronegative patients.
Funding Roche Products Ltd.
Competing interests JDI has received consulting fees and speaker fees from Roche Products. SBC has acted as clinical investigator and/or has received consultancy fees from Amgen, Biogen-Idec, Bristol-Myers Squibb, Centocor, Flexxion Therapeutics, Genentech, Johnson & Johnson, Pfizer, Merck, Proctor & Gamble, and Roche Products. PE has provided expert advice and has acted as clinical investigator for Abbott, Bristol-Myers Squibb, Merck, Pfizer, and Roche Products. PPT has received consulting fees, speaker fees and honoraria from Genentech and Roche Products, and is an employee of, and owns stock or stock options in, GlaxoSmithKline. JW, GL, SW and SJR are employees of Roche Products. PL is an employee of Genentech and owns stock or stock options in Roche.
Provenance and peer review Not commissioned; externally peer reviewed.