Evidence map›Paper›PMID 35589854›Full record

Trial reportNature medicine2022

Rituximab versus tocilizumab in rheumatoid arthritis: synovial biopsy-based biomarker analysis of the phase 4 R4RA randomized trial.

Felice Rivellese, Anna E A Surace, Katriona Goldmann, Elisabetta Sciacca, Cankut Çubuk, Giovanni Giorli, Christopher R John, Alessandra Nerviani, Liliane Fossati-Jimack, Georgina Thorborn and 12 more

Open access · hybridAbstract readClinical Trial, Phase IVRandomized Controlled Trial
PubMed Full text at PMC Publisher
In one paragraph

Trial report in Nature medicine, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 181 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
181citing papers in PubMed, 1 pooled it
39.2field-weighted citation impact, top 1% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

181 citing papers in PubMed, 1 synthesis or guideline pooled it, 252 citations in OpenAlex.

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  15. Science translational medicine · 2026
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  17. Targeting FcRn for immunomodulation: a promising therapy in autoimmune inflammatory rheumatic diseases.Inflammation research : official journal of the European Histamine Research Society ... [et al.] · 2026
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121 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

22 authors at 20 institutions in 6 countries.

Felice Rivellese *Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.ORCID http://orcid.org/0000-0002-6759-7521
Anna E A Surace *Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.ORCID http://orcid.org/0000-0001-9589-3005
Katriona GoldmannCentre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
Elisabetta SciaccaCentre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.ORCID http://orcid.org/0000-0001-7525-1558
Cankut ÇubukCentre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.ORCID http://orcid.org/0000-0003-4646-0849
Giovanni GiorliCentre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
Christopher R JohnCentre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
Alessandra NervianiCentre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.ORCID http://orcid.org/0000-0003-4064-4014
Liliane Fossati-JimackCentre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.ORCID http://orcid.org/0000-0003-3757-3999
Georgina ThorbornCentre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
Manzoor AhmedCentre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
Edoardo PredilettoCentre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.ORCID http://orcid.org/0000-0001-6830-0614
Sarah E ChurchNanoString Technologies Inc., Seattle, WA, USA.ORCID http://orcid.org/0000-0002-7194-4282
Briana M HudsonNanoString Technologies Inc., Seattle, WA, USA.
Sarah E WarrenNanoString Technologies Inc., Seattle, WA, USA.
Paul M McKeigueUsher Institute, College of Medicine and Veterinary Medicine, University of Edinburgh, Edinburgh, UK.
Frances HumbyCentre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.ORCID http://orcid.org/0000-0003-1280-9133
Michele BombardieriCentre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
Michael R BarnesCentre for Translational Bioinformatics, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.ORCID http://orcid.org/0000-0001-9097-7381
Myles J LewisCentre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK. myles.lewis@qmul.ac.uk.ORCID http://orcid.org/0000-0001-9365-5345
Costantino PitzalisCentre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK. c.pitzalis@qmul.ac.uk.ORCID http://orcid.org/0000-0003-1326-5051
R4RA collaborative group
Queen Mary University of London · GBCliniques Universitaires Saint-Luc · BEUniversità degli Studi del Piemonte Orientale “Amedeo Avogadro” · ITNanostring Technologies (United States) · USUniversity of Cagliari · ITBrighton and Sussex Medical School · GBHospital Clínic de Barcelona · ESKing's College London · GBUniversity of Lisbon · PTUniversity of Liverpool · GBBarts Health NHS Trust · GBCancer Research UK · GBGuy's and St Thomas' NHS Foundation Trust · GBHomerton University Hospital · GBManchester Royal Infirmary · GBNuffield Orthopaedic Centre · GBSouthampton General Hospital · GBSouthend University Hospital NHS Foundation Trust · GBUniversity Hospital Southampton NHS Foundation Trust · GBUniversity of Edinburgh · GB

Funding

Cancer Research UK 16893Cancer Research UK 25356Department of Health 11/100/76Department of Health 131575Department of Health TRF-2018-11-ST2-002Medical Research Council G1001518Medical Research Council MR/V012509/1Versus Arthritis 20022Versus Arthritis 21890
6 · The paper itself

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.

Indexed as

Antirheumatic AgentsArthritis, RheumatoidAntibodies, MonoclonalAntibodies, Monoclonal, HumanizedBiomarkersBiopsyHumansRituximabAntibodies, MonoclonalAntibodies, Monoclonal, HumanizedAntirheumatic AgentsBiomarkersRituximabtocilizumab

Identifiers

PMID35589854
PMCPMC9205785
OpenAlexW4280528160

What OpenQuestion holds

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.