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Original Research
26 October 2021

Effectiveness of Belimumab After Rituximab in Systemic Lupus Erythematosus: A Randomized Controlled Trial

Authors: Muhammad Shipa, MBBS https://orcid.org/0000-0001-5590-9498, Andrew Embleton-Thirsk, PhD https://orcid.org/0000-0001-9402-8132, Mariea Parvaz, MSc, Liliana Ribeiro Santos, MD https://orcid.org/0000-0001-6396-2002, Patrick Muller, MSc https://orcid.org/0000-0002-6824-578X, Kashfia Chowdhury, MSc https://orcid.org/0000-0002-8185-5152, David A. Isenberg, MD, Caroline J. Doré, BSc https://orcid.org/0000-0001-9796-4970, Caroline Gordon, MA, MD https://orcid.org/0000-0002-1244-6443, and Michael R. Ehrenstein, MBBS, PhD https://orcid.org/0000-0003-1673-743X ; on behalf of theBEAT-LUPUS InvestigatorsAuthor, Article, & Disclosure Information
Publication: Annals of Internal Medicine
Volume 174, Number 12
https://doi.org/10.7326/M21-2078
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Visual Abstract. Effectiveness of Belimumab After Rituximab in Systemic Lupus Erythematosus.
Rituximab is commonly used for patients with systemic lupus erythematosus (SLE) that is refractory to conventional therapy, but it yields variable responses. This phase 2 clinical trial sought to obtain preliminary evidence for the efficacy of belimumab after rituximab in patients with SLE.

Abstract

Background:

B-cell depletion with rituximab is commonly used for patients with systemic lupus erythematosus (SLE) that is refractory to conventional therapy, but it yields variable responses. We hypothesized that high B-cell activating factor (BAFF) levels after rituximab can cause disease flares, thereby limiting its effectiveness.

Objective:

To obtain preliminary evidence for efficacy of the anti-BAFF therapeutic belimumab after rituximab in SLE.

Design:

Phase 2, randomized, double-blind (patients, assessors, researchers, care providers), placebo-controlled, parallel-group, superiority trial. (ISRCTN: 47873003)

Setting:

England.

Participants:

Fifty-two patients who had SLE that was refractory to conventional treatment and whose physicians had recommended rituximab therapy were recruited between 2 February 2017 and 28 March 2019.

Intervention:

Participants were treated with rituximab and 4 to 8 weeks later were randomly assigned (1:1) to receive intravenous belimumab or placebo for 52 weeks.

Measurements:

The prespecified primary end point was serum IgG anti–double-stranded DNA (anti-dsDNA) antibody levels at 52 weeks. Secondary outcomes included incidence of disease flares and adverse events.

Results:

At 52 weeks, IgG anti-dsDNA antibody levels were lower in patients treated with belimumab compared with placebo (geometric mean, 47 [95% CI, 25 to 88] vs. 103 [CI, 49 to 213] IU/mL; 70% greater reduction from baseline [CI, 46% to 84%]; P < 0.001). Belimumab reduced risk for severe flare (BILAG-2004 grade A) compared with placebo (hazard ratio, 0.27 [CI, 0.07 to 0.98]; log-rank P = 0.033), with 10 severe flares in the placebo group and 3 in the belimumab group. Belimumab did not increase incidence of serious adverse events. Belimumab significantly suppressed B-cell repopulation compared with placebo (geometric mean, 0.012 [CI, 0.006 to 0.014] vs. 0.037 [CI, 0.021 to 0.081] × 109/L) at 52 weeks in a subset of patients (n = 25) with available data.

Limitations:

Small sample size; biomarker primary end point.

Conclusion:

Belimumab after rituximab significantly reduced serum IgG anti-dsDNA antibody levels and reduced risk for severe flare in patients with SLE that was refractory to conventional therapy. The results suggest that this combination could be developed as a therapeutic strategy.

Primary Funding Source:

Versus Arthritis.

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Supplemental Material

BEAT-LUPUS Study Protocol
Supplementary Materials

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Information & Authors

Information

Published In

cover image Annals of Internal Medicine
Annals of Internal Medicine
Volume 174 • Number 12 • December 2021
Pages: 1647 - 1657

History

Published online: 26 October 2021
Published in issue: December 2021

Keywords

  1. Adverse events
  2. Arthritis
  3. Clinical trials
  4. Hospital medicine
  5. Immunosuppressives
  6. Intent to treat analysis
  7. Rheumatology
  8. Safety
  9. Systemic lupus erythematosus

Copyright

© 2021 American College of Physicians.

Authors

Affiliations

Muhammad Shipa, MBBS https://orcid.org/0000-0001-5590-9498
University College London, London, United Kingdom (M.S., A.E., M.P., L.R.S., P.M., K.C., D.A.I., C.J.D., M.R.E.)
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Andrew Embleton-Thirsk, PhD https://orcid.org/0000-0001-9402-8132
University College London, London, United Kingdom (M.S., A.E., M.P., L.R.S., P.M., K.C., D.A.I., C.J.D., M.R.E.)
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Mariea Parvaz, MSc
University College London, London, United Kingdom (M.S., A.E., M.P., L.R.S., P.M., K.C., D.A.I., C.J.D., M.R.E.)
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Liliana Ribeiro Santos, MD https://orcid.org/0000-0001-6396-2002
University College London, London, United Kingdom (M.S., A.E., M.P., L.R.S., P.M., K.C., D.A.I., C.J.D., M.R.E.)
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Patrick Muller, MSc https://orcid.org/0000-0002-6824-578X
University College London, London, United Kingdom (M.S., A.E., M.P., L.R.S., P.M., K.C., D.A.I., C.J.D., M.R.E.)
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Kashfia Chowdhury, MSc https://orcid.org/0000-0002-8185-5152
University College London, London, United Kingdom (M.S., A.E., M.P., L.R.S., P.M., K.C., D.A.I., C.J.D., M.R.E.)
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David A. Isenberg, MD
University College London, London, United Kingdom (M.S., A.E., M.P., L.R.S., P.M., K.C., D.A.I., C.J.D., M.R.E.)
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Caroline J. Doré, BSc https://orcid.org/0000-0001-9796-4970
University College London, London, United Kingdom (M.S., A.E., M.P., L.R.S., P.M., K.C., D.A.I., C.J.D., M.R.E.)
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Caroline Gordon, MA, MD https://orcid.org/0000-0002-1244-6443
University of Birmingham, Birmingham, United Kingdom (C.G.).
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Michael R. Ehrenstein, MBBS, PhD https://orcid.org/0000-0003-1673-743X
University College London, London, United Kingdom (M.S., A.E., M.P., L.R.S., P.M., K.C., D.A.I., C.J.D., M.R.E.)
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BEAT-LUPUS Investigators*
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Note: All authors reviewed and edited the draft version of the manuscript and approved the final version that was submitted.
Acknowledgment: The authors thank the patients and their families for their participation in this trial. They acknowledge the important contribution of the BEAT-LUPUS Trial Steering Committee, the Data Monitoring Committee, and all of the patients involved in trial development. The authors are also indebted to the National Institute of Health Research Local Clinical Research Networks; the National Institute of Health Research Biomedical Research Centres where present at the participating sites; all of the physicians, nurses, and trial coordinators at the clinical research facilities at the participating centers (see Appendix 1); the National Institute of Health Research Musculoskeletal Translational Research Collaboration; the British Isles Lupus Assessment Group; NHS England Specialised Rheumatology Clinical Reference Group; and Lupus UK.
Financial Support: The trial was supported by Versus Arthritis (grant 20873) and by the University College London Hospitals Biomedical Research Centre, which is funded through a grant from the National Institute of Health Research. GlaxoSmithKline provided belimumab free of charge, as well as additional funding. Ms. Parvaz was supported in part by the Medical Research Council through the MASTERPLANS (MAximizing Sle ThERapeutic PotentiaL by Application of Novel and Stratified approaches) Consortium and by Versus Arthritis. Lupus UK provided additional funding.
Data Sharing Statement: The complete deidentified patient data set will be made available upon publication to researchers whose proposed use of the data has been approved. Requests should be sent to [email protected].
Corresponding Author: Michael Ehrenstein, MBBS, PhD, Department of Rheumatology, University College London, 5 University Street, London, WC1E 6JF, United Kingdom; e-mail, [email protected].
Current Author Addresses: Drs. Shipa and Santos, Ms. Parvaz, and Profs. Isenberg and Ehrenstein: Department of Rheumatology, University College London, 5 University Street, London, WC1E 6JF, United Kingdom.
Dr. Embleton-Thirsk, Mr. Muller, Ms. Chowdhury, and Prof. Doré: Comprehensive Clinical Trials Unit, University College London, 90 High Holborn, 2nd Floor, London, WC1V 6LJ, United Kingdom.
Prof. Gordon: Rheumatology Department, City Hospital, Sandwell and West Birmingham NHS Trust, Dudley Road, Birmingham, B18 7QH, United Kingdom.
Author Contributions: Conception and design: P. Muller, K. Chowdhury, D.A. Isenberg, C.J. Doré, C. Gordon, M.R. Ehrenstein, N. Jordan, B. Griffiths.
Analysis and interpretation of the data: M. Shipa, A. Embleton-Thirsk, M. Parvaz, L.R. Santos, P. Muller, K. Chowdhury, C.J. Doré, C. Gordon, M.R. Ehrenstein.
Drafting of the article: M. Shipa, A. Embleton-Thirsk, K. Chowdhury, D.A. Isenberg, C.J. Doré, C. Gordon, M.R. Ehrenstein, N. Jordan, B. Griffiths, C. Yee.
Critical revision of the article for important intellectual content: M. Shipa, A. Embleton-Thirsk, L.R. Santos, K. Chowdhury, C.J. Doré, C. Gordon, M.R. Ehrenstein, C.J. Edwards.
Final approval of the article: M. Shipa, A. Embleton-Thirsk, M. Parvaz, L.R. Santos, P. Muller, K. Chowdhury, D.A. Isenberg, C.J. Doré, C. Gordon, M.R. Ehrenstein, D.P. D’Cruz, N. Jordan, B. Parker, L. Lightstone, A. Salama, D. Pyne, C.J. Edwards, B. Griffiths, E.M. Vital, B. Rhodes, C. Yee, M. Akil, P. Topham, N.J. Gullick.
Provision of study materials or patients: L.R. Santos, C. Gordon, M.R. Ehrenstein, N. Jordan, B. Parker, L. Lightstone, A. Salama, D. Pyne, C.J. Edwards, B. Griffiths, E.M. Vital, M. Akil, P. Topham, N.J. Gullick.
Statistical expertise: M. Shipa, A. Embleton-Thirsk, P. Muller, K. Chowdhury, C.J. Doré.
Obtaining of funding: D.A. Isenberg, C.J. Doré, M.R. Ehrenstein.
Administrative, technical, or logistic support: D.A. Isenberg, M. Akil.
Collection and assembly of data: M. Shipa, M. Parvaz, L.R. Santos, D.A. Isenberg, C. Gordon, M.R. Ehrenstein, D.P. D’Cruz, B. Parker, A. Salama, D. Pyne, C.J. Edwards, B. Griffiths, E.M. Vital, B. Rhodes, C. Yee, M. Akil, N.J. Gullick.
This article was published at Annals.org on 26 October 2021.
*
For a list of the BEAT-LUPUS Investigators, see Appendix 1.

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Muhammad Shipa, Andrew Embleton-Thirsk, Mariea Parvaz, et al. Effectiveness of Belimumab After Rituximab in Systemic Lupus Erythematosus: A Randomized Controlled Trial. Ann Intern Med.2021;174:1647-1657. [Epub 26 October 2021]. doi:10.7326/M21-2078

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