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.

Biomarker analysis of the phase 4 R4RA trial identifies pretreatment synovial biopsy features selectively associated with response to rituximab or tocilizumab, and leads to the development of models that might predict treatment benefit in patients with rheumatoid arthritis

Details

Title
Rituximab versus tocilizumab in rheumatoid arthritis: synovial biopsy-based biomarker analysis of the phase 4 R4RA randomized trial
Author
Rivellese, Felice 1   VIAFID ORCID Logo  ; Surace, Anna E. A. 1   VIAFID ORCID Logo  ; Goldmann, Katriona 1 ; Sciacca, Elisabetta 1   VIAFID ORCID Logo  ; Çubuk, Cankut 1   VIAFID ORCID Logo  ; Giorli, Giovanni 1 ; John, Christopher R. 1 ; Nerviani, Alessandra 2   VIAFID ORCID Logo  ; Fossati-Jimack, Liliane 2   VIAFID ORCID Logo  ; Thorborn, Georgina 2 ; Ahmed, Manzoor 2 ; Prediletto, Edoardo 2   VIAFID ORCID Logo  ; Church, Sarah E. 3   VIAFID ORCID Logo  ; Hudson, Briana M. 3 ; Warren, Sarah E. 3 ; McKeigue, Paul M. 4 ; Humby, Frances 2   VIAFID ORCID Logo  ; Bombardieri, Michele 2 ; Barnes, Michael R. 5   VIAFID ORCID Logo  ; Lewis, Myles J. 1   VIAFID ORCID Logo  ; Pitzalis, Costantino 2   VIAFID ORCID Logo  ; Durez, Patrick 6 ; Buch, Maya H. 7 ; Rizvi, Hasan 8 ; Mahto, Arti 9 ; Montecucco, Carlomaurizio 10 ; Lauwerys, Bernard 6 ; Ng, Nora 11 ; Ho, Pauline 12 ; Romão, Vasco C. 13 ; da Fonseca, João Eurico Cabral 14 ; Verschueren, Patrick 15 ; Kelly, Stephen 5 ; Sainaghi, Pier Paolo 16 ; Gendi, Nagui 17 ; Dasgupta, Bhaskar 18 ; Cauli, Alberto 19 ; Reynolds, Piero 20 ; Cañete, Juan D. 21 ; Ramirez, Julio 22 ; Celis, Raquel 22 ; Moots, Robert 23 ; Taylor, Peter C. 24 ; Edwards, Chris J. 25 ; Isaacs, John 26 ; Sasieni, Peter 27 ; Choy, Ernest 28 ; Thompson, Charlotte 29 ; Bugatti, Serena 10 ; Bellan, Mattia 16 ; Congia, Mattia 19 ; Holroyd, Christopher 30 ; Pratt, Arthur 26 ; White, Laura 31 ; Warren, Louise 2 ; Peel, Joanna 2 ; Hands, Rebecca 2 ; Hadfield, Gaye 2 

1  Queen Mary University of London, Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, London, UK (GRID:grid.4868.2) (ISNI:0000 0001 2171 1133); Queen Mary University of London, Centre for Translational Bioinformatics, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, London, UK (GRID:grid.4868.2) (ISNI:0000 0001 2171 1133) 
2  Queen Mary University of London, Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, London, UK (GRID:grid.4868.2) (ISNI:0000 0001 2171 1133) 
3  NanoString Technologies Inc., Seattle, USA (GRID:grid.510973.9) (ISNI:0000 0004 5375 2863) 
4  University of Edinburgh, Usher Institute, College of Medicine and Veterinary Medicine, Edinburgh, UK (GRID:grid.4305.2) (ISNI:0000 0004 1936 7988) 
5  Queen Mary University of London, Centre for Translational Bioinformatics, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, London, UK (GRID:grid.4868.2) (ISNI:0000 0001 2171 1133) 
6  Cliniques Universitaires Saint-Luc, Department of Rheumatology, Brussels, Belgium (GRID:grid.48769.34) (ISNI:0000 0004 0461 6320); Université catholique de Louvain, Institute of Experimental and Clinical Research, Brussels, Belgium (GRID:grid.7942.8) (ISNI:0000 0001 2294 713X) 
7  The University of Manchester, Centre for Musculoskeletal Research, Division of Musculoskeletal & Dermatological Sciences, Manchester, UK (GRID:grid.5379.8) (ISNI:0000000121662407); NIHR Manchester Biomedical Research Centre, Manchester, UK (GRID:grid.454377.6) (ISNI:0000 0004 7784 683X) 
8  Barts Health NHS Trust, Department of Cellular Pathology, London, UK (GRID:grid.139534.9) (ISNI:0000 0001 0372 5777); Queen Mary University of London, Institute of Health Sciences Education, London, UK (GRID:grid.4868.2) (ISNI:0000 0001 2171 1133) 
9  Kings College Hospital NHS Foundation Trust, Department of Rheumatology, London, UK (GRID:grid.429705.d) (ISNI:0000 0004 0489 4320) 
10  University of Pavia, Department of Rheumatology, Fondazione I.R.C.C.S. Policlinico San Matteo, Pavia, Italy (GRID:grid.8982.b) (ISNI:0000 0004 1762 5736) 
11  Guy’s and St Thomas’ NHS Foundation Trust, Rheumatology Department, London, UK (GRID:grid.420545.2) (ISNI:0000 0004 0489 3985) 
12  The Kellgren Centre for Rheumatology, Manchester Royal Infirmary, Manchester University NHS Foundation Trust, Manchester, UK (GRID:grid.419319.7) (ISNI:0000 0004 0641 2823) 
13  Hospital De Santa Maria Centro Hospitalar Universitário Lisboa Norte, Rheumatology Department, Lisbon, Portugal (GRID:grid.411265.5) (ISNI:0000 0001 2295 9747); Universidade de Lisboa, Rheumatology Research Unit, Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Lisbon, Portugal (GRID:grid.9983.b) (ISNI:0000 0001 2181 4263) 
14  Universidade de Lisboa, Rheumatology Research Unit, Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Lisbon, Portugal (GRID:grid.9983.b) (ISNI:0000 0001 2181 4263) 
15  KU Leuven, Skeletal Biology and Engineering Research Centre, Department of Development and Regeneration, Leuven, Belgium (GRID:grid.5596.f) (ISNI:0000 0001 0668 7884); University Hospital Leuven, Division of Rheumatology, Leuven, Belgium (GRID:grid.410569.f) (ISNI:0000 0004 0626 3338) 
16  University of Eastern Piedmont and Maggiore della Carita Hospital, Department of Rheumatology, Novara, Italy (GRID:grid.412824.9) (ISNI:0000 0004 1756 8161) 
17  Basildon Hospital, Rheumatology Department, Basildon, UK (GRID:grid.439462.e) (ISNI:0000 0004 0399 6800) 
18  Mid & South Essex University Hospitals NHS Foundation Trust, Southend University Hospital, Rheumatology Department, Westcliff-on-Sea, UK (GRID:grid.412711.0) (ISNI:0000 0004 0417 1042) 
19  AOU and University of Cagliari, Rheumatology Unit, Department of Medicine and Public Health, Monserrato, Italy (GRID:grid.7763.5) (ISNI:0000 0004 1755 3242) 
20  Homerton University Hospital, Department of Rheumatology, London, UK (GRID:grid.439591.3) (ISNI:0000 0004 0399 2770) 
21  Hospital Clínic de Barcelona, Rheumatology Department, Barcelona, Spain (GRID:grid.410458.c) (ISNI:0000 0000 9635 9413); Institut d’Investigacions Biomèdiques August Pí I Sunyer, Barcelona, Spain (GRID:grid.10403.36) (ISNI:0000000091771775) 
22  Hospital Clínic de Barcelona, Rheumatology Department, Barcelona, Spain (GRID:grid.410458.c) (ISNI:0000 0000 9635 9413) 
23  Aintree University Hospital, Academic Rheumatology Unit, Liverpool, UK (GRID:grid.411255.6) (ISNI:0000 0000 8948 3192); Edge Hill University, Faculty of Health, Social Care and Medicine, Ormskirk, UK (GRID:grid.255434.1) (ISNI:0000 0000 8794 7109) 
24  University of Oxford, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Botnar Research Centre, Oxford, UK (GRID:grid.4991.5) (ISNI:0000 0004 1936 8948) 
25  University Hospital Southampton, NIHR Clinical Research Facility, Southampton, UK (GRID:grid.123047.3) (ISNI:0000000103590315); University of Southampton, Faculty of Medicine, Southampton, UK (GRID:grid.5491.9) (ISNI:0000 0004 1936 9297) 
26  Newcastle University, Translational and Clinical Research Institute, Newcastle upon Tyne, UK (GRID:grid.1006.7) (ISNI:0000 0001 0462 7212); Newcastle upon Tyne hospitals NHS Foundation Trust, Musculoskeletal Unit, Newcastle upon Tyne, UK (GRID:grid.420004.2) (ISNI:0000 0004 0444 2244) 
27  Kings College London, King’s Clinical Trials Unit, London, UK (GRID:grid.13097.3c) (ISNI:0000 0001 2322 6764) 
28  Cardiff University, CREATE Centre, Cardiff, UK (GRID:grid.5600.3) (ISNI:0000 0001 0807 5670); University Hospital of Wales, Department of Rheumatology, Cardiff, UK (GRID:grid.241103.5) (ISNI:0000 0001 0169 7725) 
29  University of Sussex, Brighton and Sussex Medical School, Brighton, UK (GRID:grid.12082.39) (ISNI:0000 0004 1936 7590) 
30  University Hospital Southampton NHS Foundation Trust, Southampton General Hospital, Southampton, UK (GRID:grid.430506.4) (ISNI:0000 0004 0465 4079) 
31  University College London, Cancer Research UK & UCL Cancer Trials Centre, London, UK (GRID:grid.83440.3b) (ISNI:0000000121901201) 
Pages
1256-1268
Publication year
2022
Publication date
Jun 2022
Publisher
Nature Publishing Group
ISSN
10788956
e-ISSN
1546170X
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41591-022-01789-0
ProQuest document ID
2677954123
Copyright
© Crown 2022. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.