Stratification of biological therapies by pathobiology in biologic-naive patients with rheumatoid arthritis (STRAP and STRAP-EU): two parallel, open-label, biopsy-driven, randomised trials.

BACKGROUND

Despite highly effective targeted therapies for rheumatoid arthritis, about 40% of patients respond poorly, and predictive biomarkers for treatment choices are lacking. We did a biopsy-driven trial to compare the response to rituximab, etanercept, and tocilizumab in biologic-naive patients with rheumatoid arthritis stratified for synovial B cell status.

METHODS

STRAP and STRAP-EU were two parallel, open-label, biopsy-driven, stratified, randomised, phase 3 trials done across 26 university centres in the UK and Europe. Biologic-naive patients aged 18 years or older with rheumatoid arthritis based on American College of Rheumatology (ACR)-European League Against Rheumatism classification criteria and an inadequate response to conventional synthetic disease-modifying antirheumatic drugs (DMARDs) were included. Following ultrasound-guided synovial biopsy, patients were classified as B cell poor or B cell rich according to synovial B cell signatures and randomly assigned (1:1:1) to intravenous rituximab (1000 mg at week 0 and week 2), subcutaneous tocilizumab (162 mg per week), or subcutaneous etanercept (50 mg per week). The primary outcome was the 16-week ACR20 response in the B cell-poor, intention-to-treat population (defined as all randomly assigned patients), with data pooled from the two trials, comparing etanercept and tocilizumab (grouped) versus rituximab. Safety was assessed in all patients who received at least one dose of study drug. These trials are registered with the EU Clinical Trials Register, 2014-003529-16 (STRAP) and 2017-004079-30 (STRAP-EU).

FINDINGS

Between June 8, 2015, and July 4, 2019, 226 patients were randomly assigned to etanercept (n=73), tocilizumab (n=74), and rituximab (n=79). Three patients (one in each group) were excluded after randomisation because they received parenteral steroids in the 4 weeks before recruitment. 168 (75%) of 223 patients in the intention-to-treat population were women and 170 (76%) were White. In the B cell-poor population, ACR20 response at 16 weeks (primary endpoint) showed no significant differences between etanercept and tocilizumab grouped together and rituximab (46 [60%] of 77 patients vs 26 [59%] of 44; odds ratio 1·02 [95% CI 0·47-2·17], p=0·97). No differences were observed for adverse events, including serious adverse events, which occurred in six (6%) of 102 patients in the rituximab group, nine (6%) of 108 patients in the etanercept group, and three (4%) of 73 patients in the tocilizumab group (p=0·53).

INTERPRETATION

In this biologic-naive population of patients with rheumatoid arthrtitis, the dichotomic classification into synovial B cell poor versus rich did not predict treatment response to B cell depletion with rituximab compared with alternative treatment strategies. However, the lack of response to rituximab in patients with a pauci-immune pathotype and the higher risk of structural damage progression in B cell-rich patients treated with rituximab warrant further investigations into the ability of synovial tissue analyses to inform disease pathogenesis and treatment response.

FUNDING

UK Medical Research Council and Versus Arthritis.

Informations de copyright

Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of interests AF reports grants or contracts from Janssen, GSK, Mestag, Nascient, Bristol Myers Squibb (BMS), Roche, and UCB, and consulting fees from Janssen and Sonoma. AGP reports grants or contracts from GSK, Pfizer, and Gilead, and consulting fees from Inflection Biosciences. CJE reports payment or honoraria for lectures, presentations, speaker's bureaus, manuscript writing, or educational events from Pfizer, Gilead, Galapagos, AbbVie, Eli Lilly, BMS, Biogen, Celgene, Roche, Sanofi, and UCB Pharma; consulting fees from Gilead, Galapagos, AbbVie, and Eli Lilly; and support for attending meetings or travel from Eli Lilly. CP reports grants or contracts from GSK, Pfizer, BMS, Sanofi, Novartis, Janssen, Exagen, Genentech, and Navidea; trial funding from the UK Medical Research Council and Versus Arthritis; provision of investigational medicinal products for the trial from Pfizer and Roche; consulting fees from AbbVie, Janssen, Exagen, and Kinikska; and support for attending meetings or travel from EULAR, British Society for Rheumatology, and ACR. DvdH reports consulting fees from GSK, Pfizer, Gilead, Galapagos, AbbVie, Eli Lilly, BMS, UCB Pharma, Novartis, Janssen, Argenx, Bayer, and Takeda; is an associate editor for Annals of the Rheumatic Diseases, an editorial board member for the Journal of Rheumatology and RMD Open, an adviser for Axial Spondyloarthritis International Society, and Director of Imaging Rheumatology. EC reports grants or contracts from Pfizer, Biogen, Sanofi, and Bio-Cancer; consulting fees from Gilead, AbbVie, Biogen, Sanofi, UCB Pharma, Janssen, Fresenius Kabi, and R-Pharm; payment or honoraria for lectures, presentations, speaker's bureaus, manuscript writing, or educational events from Galapagos, AbbVie, Eli Lilly, Sanofi, Fresenius Kabi, and Chugai Pharma; support for attending meetings or travel from Galapagos and UCB Pharma. EG reports payment or honoraria for lectures, presentations, speaker's bureaus, manuscript writing, or educational events from Pfizer, Galapagos, AbbVie, Eli Lilly, BMS, Novartis, and Janssen. FR reports consulting fees from Ono Pharmaceutical. HC reports payment or honoraria for lectures, presentations, speaker's bureaus, manuscript writing, or educational events from GSK and UCB Pharma; consulting fees from Pfizer, Galapagos, and Argenx; and participation on a Data Safety Monitoring Board or Advisory Board for AstraZeneca. IM reports grants or contracts from Pfizer, Gilead, AbbVie, Eli Lilly, BMS, UCB Pharma, Novartis, Janssen, AstraZeneca, Amgen, Causeway Therapeutics, Cabaletta, Sanofi Regeneron, Evelo, Compugen, and Moonlake, and is a trustee for Versus Arthritis. JG reports payment or honoraria for lectures, presentations, speaker's bureaus, manuscript writing, or educational events from Pfizer, Galapagos, AbbVie, Eli Lilly, UCB Pharma, Janssen, and Vifor. JPP reports payment or honoraria for lectures, presentations, speaker's bureaus, manuscript writing, or educational events from Pfizer, AbbVie, Eli Lilly; consulting fees from AbbVie; support for attending meetings or travel from AbbVie and Eli Lilly; and participation on a Data Safety Monitoring Board or Advisory Board for AbbVie. MRE reports payment or honoraria for lectures, presentations, speaker's bureaus, manuscript writing, or educational events from GSK, Galapagos, and AbbVie; support for attending meetings or travel from Eli Lilly, AbbVie, and Janssen; and consulting fees from GSK, Fresenius Kabi, and AstraZeneca. MHB reports grants or contracts from Gilead, and payment or honoraria for lectures, presentations, speaker's bureaus, manuscript writing, or educational events from Galapagos, AbbVie, and Boehringer Ingelheim. NN reports support for attending meetings or travel from Janssen. PD reports payment or honoraria for lectures, presentations, speaker's bureaus, manuscript writing, or educational events from Pfizer, Galapagos, AbbVie, and Eli Lilly, and support for attending meetings or travel from Galapagos, AbbVie, and Fresenius Kabi. PCT reports consulting fees from GSK, Pfizer, Gilead, Galapagos, AbbVie, Eli Lilly, Biogen, Sanofi, UCB Pharma, Janssen, Fresenius Kabi, and Nordic Pharma; grants or contracts from Galapagos; payment or honoraria for lectures, presentations, speaker's bureaus, manuscript writing, or educational events from AbbVie; support for attending meetings or travel from Eli Lilly; participation on a Data Safety Monitoring Board or Advisory Board from Moonlake, Kymab, and Immunovant. All other authors declare no competing interests.