O07 Randomised, open labelled clinical trial to investigate synovial mechanisms determining response: resistance to rituximab versus tocilizumab in RA patients failing TNF inhibitor therapy
Bibliographic record
Abstract
Abstract Background Biologic therapies have transformed the outlook for RA but the significant health economic impact of these therapies has highlighted the need to define predictive markers of response. Rituximab (RTX) is licensed for use following failure of csDMARDs and TNF inhibitor (TNFi) therapy. However, in this increasing therapeutically resistant cohort only 30% of patients achieve an ACR50 response. The observation in early RA that 50% of patients show low/absence of synovial B-cells prompted us to test the hypothesis that in these patients a biologic agent targeting alternative pathways maybe more effective. We report results from the first pathobiology-driven randomised controlled trial (RCT) in RA (R4RA) evaluating whether patient stratification according to the synovial B-cell rich/poor status enriches for response/non response to RTX. Methods R4RA is a phase IV open-label RCT conducted in 19 European centres recruiting patients failing or intolerant to csDMARD therapy and at least one TNFi. Synovial tissue was obtained at trial entry and used to classify patients as B-cell rich or poor using both histological and RNA-seq classification criteria. Patients were randomised to receive RTX or tocilizumab (TCZ). The study was powered to test in the B cell poor population superiority of TCZ over RTX at 16 weeks. The primary and co-primary end-points were defined respectively as Clinical Disease Activity Index (CDAI) ≥50% improvement from baseline and Major Treatment response (MTR)= CDAI improvement ≥ 50% and CDAI ≤10.1. Results The trial recruited to target (n = 164) with a power of 89.5%. In the B cell poor cohort a numerically higher number of patients achieved the primary endpoint and a significantly higher number of patients achieved co-primary endpoint (MTR). Classification of patients as B cell poor/rich according to RNA-seq criteria enhanced the difference between TCZ and RTX, with a significantly higher number of TCZ treated patients reaching both CDAI 50% improvement and CDAI MTR in the B-cell poor group. Conclusion In a RA B cell poor population failing csDMARDs and TNFi therapy, TCZ is more effective than RTX. This first biopsy-driven RCT suggests clinical utility for integrating molecular pathology profiling into treatment algorithms to allocate targeted therapies. Disclosures F. Humby: Honoraria; Roche, Pfizer. Grants/research support; Pfizer. P. Durez: BMS,Bristol-Myers Squibb, Celltrion, Eli Lilly, Hospira, Mundipharma, Pfizer, Samsung, Sanofi, UCB. M. Buch: Consultancies; Pfizer, Roche, UCB, AbbVie, Eli Lilly, Sandoz, and Sanofi. Grants/research support; Pfizer, Roche, UCB, AbbVie, Eli Lilly, Sandoz, and Sanofi. M. Lewis: None. M. Bombardieri: None. H. Rizvi: None. S. Kelly: None. L. Fossati: None. R. Hands: None. G. Giorli: None. A. Mahto: None. C. Montecucco: None. B. Lauwerys: None. V.C. Romao: None. A.G. Pratt: Member of speakers’ bureau; Eli Lilly and Janssen-Cilag Ltd. Grants/research support; Pfizer. S. Bugatti: None. N. Ng: None. F. Rivellese: None. P. Ho: None. M. Bellan: None. P. Sainaghi: None. P. Verschueren: None. N. Gendi: None. B. Dasgupta: Abbvie, BMS, GSK, Roche, Roche Chugai, Sanofi, Sanofi Aventis, Sanofi-Aventis. A. Cauli: BMS, Celgene, Lilly, Lilly MSD, MSD, Novartis, Pfizer, Sanofi, Sigma Wesseumen, UCB. C. John: None. A. Nerviani: None. G. Thornborn: None. D. Holroyd: None. M. Congia: None. C. Thompson: None. P. Reynolds: None. J. Cañete: None. R. J. Moots: Biogen, Bristol-Myers Squibb, Chugai, Novartis, Pfizer Inc, Roche, Sandoz, UCB. P.C. Taylor: AbbVie, Biogen, Celgene, Eli Lilly and Company, Fresenius, Fresenius SE & Co, Galapagos, Gilead. GlaxoSmithKline, Janssen, Lilly, Nordic Pharma, Pfizer, Pfizer Inc, Roche, Sanofi, UCB. C. Edwards: Abbvie, Biogen, BMS, Fresenius, Janssen, Lilly, MSD, Novartis, Pfizer, Roche, UCB. J. Isaacs: None. P. Sasieni: None. J. E. Fonesca: None. E. Choy: AbbVie, Abbvie, Roche, Chugai, Amgen, Eli Lilly, Janssen, Novartis, Regeneron, R-Pharm and Sanofi, Amgen, Amgen, Roche, Chugai, Bristol-Myers Squibb, Eli-Lilly Janssen, Pfizer, Regeneron, Sanofi and UCB., AstraZeneca, Bio-Cancer, Bio-Cancer, Biogen, Novartis, Sanofi, Roche, Pfizer and UCB ,Biogen, BMS, Boehringer Ingelheim, Celgene, Chugai Pharma, Eli Lilly, Ferring Pharmaceuticals, GSK, Hospira, Janssen, Jazz Pharmaceuticals, Merck Sharp & Dohme, Merrimack Pharmaceutical, Napp, Novartis, Novimmune, ObsEva, Pfizer, Regeneron, Roche, R-Pharm, Sanofi, SynAct Pharma, Tonix, Union Chimique Belge. C. Pitzalis: None. NIHR have funded the study.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.003 | 0.006 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".