Rituximab versus tocilizumab and B-cell status in TNF-alpha inadequate-responder rheumatoid arthritis patients: the R4-RA RCT
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Published:2022-08
Issue:7
Volume:9
Page:1-58
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ISSN:2050-4365
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Container-title:Efficacy and Mechanism Evaluation
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language:en
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Short-container-title:Efficacy Mech Eval
Author:
Humby Frances1ORCID, Durez Patrick2ORCID, Buch Maya H3ORCID, Lewis Myles J1ORCID, Bombardieri Michele1ORCID, John Christopher1ORCID, Rizvi Hasan4ORCID, Warren Louise1ORCID, Peel Joanna1ORCID, Fossati-Jimack Liliane1ORCID, Hands Rebecca E1ORCID, Giorli Giovanni1ORCID, Rivellese Felice1ORCID, Cañete Juan D5ORCID, Taylor Peter C6ORCID, Sasieni Peter7ORCID, Fonseca João E8ORCID, Choy Ernest9ORCID, Pitzalis Costantino1ORCID
Affiliation:
1. Centre for Experimental Medicine and Rheumatology, Queen Mary University of London, London, UK 2. Institute of Experimental and Clinical Research, Université Catholique de Louvain, Louvain, Belgium 3. Clinical Trials Research Unit, University of Leeds, Leeds, UK 4. Blizard Institute, Barts Health NHS Trust, London, UK 5. Arthritis Unit, L’Institut d’Investigacions Biomèdiques, Barcelona, Spain 6. Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK 7. King’s Clinical Trial Unit, King’s College London, London, UK 8. Instituto de Medicina Molecular, University of Lisbon, Lisbon, Portugal 9. Section of Rheumatology, Cardiff University School of Medicine, Cardiff University, Cardiff, UK
Abstract
Background
Although biological therapies have transformed the outlook for those with rheumatoid arthritis, there is a lack of any meaningful response in approximately 40% of patients. The role of B cells in rheumatoid arthritis pathogenesis is well recognised and is supported by the clinical efficacy of the B-cell-depleting agent rituximab (MabThera, F. Hoffman La-Roche Ltd, Basel, Switzerland). Rituximab is licensed for use in rheumatoid arthritis following failure of conventional synthetic disease-modifying antirheumatic drugs and tumour necrosis factor inhibitor therapy. However, over 50% of patients show low/absent synovial B-cell infiltration, suggesting that, in these patients, inflammation is driven by alternative cell types. This prompted us to test the hypothesis that, in synovial biopsy B-cell-poor patients, tocilizumab (RoActemra, F. Hoffman La-Roche Ltd, Basel, Switzerland) (targeting interleukin 6) is superior to rituximab (targeting CD20+/B cells).
Design
The R4–RA (A Randomised, open-labelled study in anti-TNFalpha inadequate responders to investigate the mechanisms for Response, Resistance to Rituximab versus Tocilizumab in Rheumatoid Arthritis patients) trial is a 48-week Phase IV, open-label, randomised controlled trial conducted in 19 European centres that recruited patients failing on or intolerant to conventional synthetic disease-modifying antirheumatic drug therapy and at least one tumour necrosis factor inhibitor.
Participants
Synovial tissue was obtained at trial entry and classified histologically as B-cell rich or B-cell poor to inform balanced stratification. Patients were randomised on a 1 : 1 basis to receive standard therapy with rituximab or tocilizumab. B-cell-poor/-rich molecular classification was also carried out. The study was powered to test the superiority of tocilizumab over rituximab at 16 weeks in the B-cell-poor population.
Main outcome measures
The primary end point was defined as an improvement in the Clinical Disease Activity Index (CDAI) score of ≥ 50% from baseline. In addition, patients were considered to be non-responders if they did not reach an improvement in CDAI score of ≥ 50% and a CDAI score of < 10.1, defined for simplicity as CDAI major treatment response (CDAI-MTR). Secondary outcomes included the assessment of CDAI response in the B-cell-rich cohort, in which the non-inferiority of rituximab compared with tocilizumab was evaluated. Safety data up to week 48 are reported.
Results
In total, 164 patients were randomised: 83 patients received rituximab and 81 received tocilizumab. Eighty-one out of 83 rituximab patients and 73 out of 81 tocilizumab patients completed treatment up to week 16 (primary end point). Baseline characteristics were comparable between the treatment groups. In the histologically classified B-cell-poor population (n = 79), no significant difference was observed in the primary outcome, an improvement in CDAI score of ≥ 50% from baseline (risk ratio 1.25, 95% confidence interval 0.80 to 1.96). A supplementary analysis of the CDAI-MTR, however, did reach statistical significance (risk ratio 1.96, 95% confidence interval 1.01 to 3.78). In addition, when B-cell-poor classification was determined molecularly, both the primary end point and the CDAI-MTR were statistically significant (risk ratio 1.72, 95% confidence interval 1.02 to 2.91, and risk ratio 4.12, 95% confidence interval 1.55 to 11.01, respectively). Moreover, a larger number of secondary end points achieved significance when classified molecularly than when classified histologically. In the B-cell-rich population, there was no significant difference between treatments in the majority of both primary and secondary end points. There were more adverse events and serious adverse events, such as infections, in the tocilizumab group than in the rituximab group.
Conclusion
To our knowledge, this is the first biopsy-based, multicentre, randomised controlled trial of rheumatoid arthritis. We were unable to demonstrate that tocilizumab was more effective than rituximab in patients with a B-cell-poor pathotype in our primary analysis. However, superiority was shown in most of the supplementary and secondary analyses using a molecular classification. These analyses overcame possible unavoidable weaknesses in our original study plan, in which the histological method of determining B-cell status may have misclassified some participants and our chosen primary outcome was insufficiently sensitive. Given the significant results observed using the molecular classification, future research will focus on refining this stratification method and evaluating its clinical utility.
Trial registration
Current Controlled Trials ISRCTN97443826.
Funding
This project was funded by the Efficacy and Mechanism Evaluation (EME) programme, a Medical Research Council and National Institute for Health and Care Research (NIHR) partnership. This will be published in full in Efficacy and Mechanism Evaluation; Vol. 9, No. 7. See the NIHR Journals Library website for further project information.
Funder
Efficacy and Mechanism Evaluation programme Medical Research Council
Publisher
National Institute for Health and Care Research (NIHR)
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