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Extended report
Predicting and managing primary and secondary non-response to rituximab using B-cell biomarkers in systemic lupus erythematosus
  1. Md Yuzaiful Md Yusof1,2,
  2. Daniel Shaw1,
  3. Yasser M El-Sherbiny1,2,3,
  4. Emma Dunn4,
  5. Andy C Rawstron5,
  6. Paul Emery1,2,
  7. Edward M Vital1,2
  1. 1Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Chapel Allerton Hospital, Chapeltown Road, Leeds, UK
  2. 2NIHR Leeds Biomedical Research Centre, Leeds Teaching Hospitals NHS Trust, Leeds, UK
  3. 3Department of Clinical Pathology, Faculty of Medicine, Mansoura University, Egypt
  4. 4Department of Nephrology, St James’ University Hospital, Leeds Teaching Hospitals NHS Trust, Leeds, UK
  5. 5Haematological Malignancy Diagnostic Service, Leeds Teaching Hospitals NHS Trust, Leeds, UK
  1. Correspondence to Dr Edward M Vital, Chapel Allerton Hospital, Leeds LS7 4SA, UK; e.m.j.vital{at}leeds.ac.uk, edvital{at}gmail.com

Abstract

Objective To assess factors associated with primary and secondary non-response to rituximab in systemic lupus erythematosus (SLE) and evaluate management of secondary non-depletion non-response (2NDNR).

Methods 125 patients with SLE treated with rituximab over 12 years were studied prospectively. A major clinical response was defined as improvement of all active British Isles Lupus Assessment Group (BILAG)-2004 domains to grade C/better and no A/B flare. Partial responders were defined by one persistent BILAG B. B-cell subsets were measured using highly sensitive flow cytometry. Patients with 2NDNR, defined by infusion reaction and defective depletion, were treated with ocrelizumab or ofatumumab.

Results 117 patients had evaluable data. In cycle 1 (C1), 96/117 (82%) achieved BILAG response (major=50%, partial=32%). In multivariable analysis, younger age (OR 0.97, 95% CI 0.94 to 1.00) and B-cell depletion at 6 weeks (OR 3.22, 95% CI 1.24 to 8.33) increased the odds of major response. Complete depletion was predicted by normal complement and lower pre-rituximab plasmablasts and was not associated with increased serious infection post-rituximab. Seventy-seven (with data on 72) C1 responders were retreated on clinical relapse. Of these, 61/72 (85%) responded in cycle 2 (C2). Of the 11 C2 non-responders, nine met 2NDNR criteria (incidence=12%) and tested positive for anti-rituximab antibodies. Lack of concomitant immunosuppressant and higher pre-rituximab plasmablasts predicted 2NDNR. Five were switched to ocrelizumab/ofatumumab, and all depleted and responded.

Conclusion Treatment with anti-CD20 agents can be guided by B-cell monitoring and should aim to achieve complete depletion. 2NDNR is associated with anti-rituximab antibodies, and switching to humanised agents restores depletion and response. In SLE, alternative anti-CD20 antibodies may be more consistently effective.

  • treatment
  • B-cells
  • DMARDs (biologic)
  • systemic lupus erythematosus

This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/4.0/

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Footnotes

  • Contributors MYMY, PE and EMV: substantial contributions to the conception or design of the work, or the acquisition, analysis or interpretation of data, drafting the work or revising it critically for important intellectual content, final approval of the version published and agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. DS, YME-S, ED and ACR: substantial contributions to the conception or design of the work, or the acquisition, analysis or interpretation of data, drafting the work or revising it critically for important intellectual content and final approval of the version published.

  • Funding This research was funded/supported by the National Institute for Health Research (NIHR) and NIHR Leeds Biomedical Research Centre based at Leeds Teaching Hospitals NHS Trust; and NIHR Research Grants (DRF-2014-07-155) and (CS-2013-13-032). The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health.

  • Competing interests EMV is an NIHR Clinician Scientist. He has received honoraria and research grant support from Roche, GSK and AstraZeneca. PE has received consultant fees from BMS, Abbott, Pfizer, MSD, Novartis, Roche and UCB. He has received research grants paid to his employer from AstraZeneca, Abbott, BMS, Pfizer, MSD and Roche.

  • Patient consent The study does not contain any personal medical information about an identifiable living individual, thus patient consent is not required.

  • Ethics approval The use of rituximab, ofatumumab and ocrelizumab were all approved by Leeds Teaching Hospitals NHS Trust Drug and Therapeutic Committee. Analysis of samples for antirituximabantibody was approved by the Leeds (East) Research Ethics Committee (REC), 10/H1306/88, and the committee confirmed that other aspects of the study did not require ethical approval in accordance with the UK National Health Service REC guidelines.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Correction notice This article has been corrected since it published Online First. The abstract has been corrected.

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