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

Rivellese, Felice, Nerviani, Alessandra, Giorli, Giovanni, Warren, Louise, Jaworska, Edyta, Bombardieri, Michele, Lewis, Myles J, Humby, Frances, Pratt, Arthur G, Filer, Andrew, Gendi, Nagui, Cauli, Alberto, Choy, Ernest ORCID: https://orcid.org/0000-0003-4459-8609, McInnes, Iain, Durez, Patrick, Edwards, Christopher J, Buch, Maya H, Gremese, Elisa, Taylor, Peter C, Ng, Nora, Cañete, Juan D, Raizada, Sabrina, McKay, Neil D, Jadon, Deepak, Sainaghi, Pier Paolo, Stratton, Richard, Ehrenstein, Michael R, Ho, Pauline, Pereira, Joaquim P, Dasgupta, Bhaskar, Gorman, Claire, Galloway, James, Chinoy, Hector, van der Heijde, Désirée, Sasieni, Peter, Barton, Anne, Pitzalis, Costantino, Zayat, Ahmed, Machado, Ana Rita, Cuervo, Andrea, Mahto, Arti, Cubuk, Cankut, Rawlings, Charlotte, Mosanya, Chijioke, Buckley, Chris, Holroyd, Chris, Maskall, Debbie, Carlucci, Francesco, Thorborn, Georgina, Tan, Gina, Lliso-Ribera, Gloria, Rizvi, Hasan, Peel, Joanna, Fonseca, João Eurico, Isaacs, John, Ramírez, Julio, Meric de Bellefon, Laurent, Fossati-Jimak, Liliane, Githinji, Mary, Congia, Mattia, Millar, Neal, Purkayastha, Nirupam, Celis, Raquel, Seth, Rakhi, Hands-Greenwood, Rebecca, Landewé, Robert, Perniola, Simone, Alivernini, Stefano, Marcia, Stefano, Marini, Stefano, Kelly, Stephen and Romão, Vasco 2023. 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. The Lancet Rheumatology 5 (11) , e648-e659. 10.1016/S2665-9913(23)00241-2

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Abstract

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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Publisher:	Elsevier
ISSN:	2665-9913
Date of First Compliant Deposit:	21 March 2024
Last Modified:	21 Mar 2024 16:13
URI:	https://orca.cardiff.ac.uk/id/eprint/167273

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