Journal article
Rituximab versus tocilizumab in rheumatoid arthritis: synovial biopsy-based biomarker analysis of the phase 4 R4RA randomized trial
- Abstract:
- Patients with rheumatoid arthritis (RA) receive highly targeted biologic therapies without previous knowledge of target expression levels in the diseased tissue. Approximately 40% of patients do not respond to individual biologic therapies and 5–20% are refractory to all. In a biopsy-based, precision-medicine, randomized clinical trial in RA (R4RA; n = 164), patients with low/absent synovial B cell molecular signature had a lower response to rituximab (anti-CD20 monoclonal antibody) compared with that to tocilizumab (anti-IL6R monoclonal antibody) although the exact mechanisms of response/nonresponse remain to be established. Here, in-depth histological/molecular analyses of R4RA synovial biopsies identify humoral immune response gene signatures associated with response to rituximab and tocilizumab, and a stromal/fibroblast signature in patients refractory to all medications. Post-treatment changes in synovial gene expression and cell infiltration highlighted divergent effects of rituximab and tocilizumab relating to differing response/nonresponse mechanisms. Using ten-by-tenfold nested cross-validation, we developed machine learning algorithms predictive of response to rituximab (area under the curve (AUC) = 0.74), tocilizumab (AUC = 0.68) and, notably, multidrug resistance (AUC = 0.69). This study supports the notion that disease endotypes, driven by diverse molecular pathology pathways in the diseased tissue, determine diverse clinical and treatment–response phenotypes. It also highlights the importance of integration of molecular pathology signatures into clinical algorithms to optimize the future use of existing medications and inform the development of new drugs for refractory patients.
- Publication status:
- Published
- Peer review status:
- Peer reviewed
Actions
Access Document
- Files:
-
-
(Preview, Version of record, pdf, 15.0MB, Terms of use)
-
- Publisher copy:
- 10.1038/s41591-022-01789-0
Authors
Contributors
+ Taylor, PC
- Institution:
- University of Oxford
- Division:
- MSD
- Department:
- NDORMS
- Sub department:
- Botnar Research Centre
- Oxford college:
- St Peter's College
- Role:
- Contributor
- ORCID:
- 0000-0001-7766-6167
+ R4RA collaborative group
- Role:
- Contributor
- Publisher:
- Springer Nature
- Journal:
- Nature Medicine More from this journal
- Volume:
- 28
- Pages:
- 1256-1268
- Publication date:
- 2022-05-19
- Acceptance date:
- 2022-03-21
- DOI:
- EISSN:
-
1546-170X
- ISSN:
-
1078-8956
- Language:
-
English
- Keywords:
- Pubs id:
-
1262418
- Local pid:
-
pubs:1262418
- Deposit date:
-
2022-06-06
Terms of use
- Copyright holder:
- Crown copyright
- Copyright date:
- 2022
- Rights statement:
- © Crown 2022. Open Access: This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
- Licence:
- CC Attribution (CC BY)
If you are the owner of this record, you can report an update to it here: Report update to this record