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  • Review Article
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Opportunities and limitations of B cell depletion approaches in SLE

Nature Reviews Rheumatology volume 21, pages 111–126 (2025)Cite this article

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Abstract

B cell depletion with rituximab, a chimeric monoclonal antibody that selectively targets B cells by binding CD20, has been used off label in severe and resistant systemic lupus erythematosus (SLE) for over two decades. Several biological mechanisms limit the efficacy of rituximab, including immunological reactions towards the chimeric molecule, increased numbers of residual B cells, including plasmablasts and plasma cells, and a post-treatment surge in B cell-activating factor (BAFF) levels. Consequently, rituximab induces remission in only a proportion of patients, and safety issues limit its use. However, the use of rituximab has established the value of B cell depletion strategies in SLE and has guided the development of several improved B cell depletion therapies for SLE. These include enhanced monoclonal antibodies, modalities that redirect the specificity of patient T cells using chimeric antigen receptor T cells or bispecific T cell engagers, and combination treatment that simultaneously inhibits the BAFF pathway. In this Review, we consider evidence gathered from over two decades of using rituximab in SLE and examine how B cell depletion therapies could be further optimized to achieve immunological and clinical efficacy. In addition, we discuss the prospects of B cell depletion strategies for personalized treatment in SLE based on genetic research and studies in pre-symptomatic individuals.

Key points

  • Although the B cell depletion agent rituximab failed to reach its primary end points in randomized controlled trials in systemic lupus erythematosus (SLE), favourable clinical experience has led to its frequent off-label use in patients with SLE.

  • Deep B cell depletion of prolonged duration has been associated with improved clinical response to rituximab.

  • Additional B cell depletion therapies that enhance B cell depletion, reduce immunogenicity, delay relapse of B cell numbers or target memory B cells and plasma cells are under development, although trials comparing these therapies head to head are lacking.

  • Innate and non-immune mechanisms that lead to B cell activation, as well as B cell-independent inflammation, might underlie resistance to B cell depletion therapy.

  • Although enhanced B cell depletion improves clinical responses in patients with SLE, both B cell-driven mechanisms and innate or non-immune mechanisms might need to be targeted to achieve cure.

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Fig. 1: Mechanisms of B cell depletion by rituximab.
Fig. 2: No evidence for increased risk of infections by B cell depletion across multiple trials.
Fig. 3: Emergent B lineage depletion therapies in SLE.
Fig. 4: Options after B cell depletion failure with rituximab with currently licensed or off-label drugs.
Fig. 5: B cell-intrinsic and B cell-extrinsic mechanisms in SLE pathogenesis.

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Authors and Affiliations

  1. Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden

    Marit Stockfelt

  2. Rheumatology, Sahlgrenska University Hospital, Gothenburg, Sweden

    Marit Stockfelt

  3. Center of Expertise for Lupus, Vasculitis and Complement-mediated Systemic disease (LuVaCs), Department of Nephrology, Leiden University Medical Center, Leiden, the Netherlands

    Y. K. Onno Teng

  4. Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, UK

    Edward M. Vital

  5. NIHR Leeds Biomedical Research Centre, Leeds Teaching Hospitals NHS Trust, Leeds, UK

    Edward M. Vital

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All authors researched data for the article. All authors contributed substantially to discussion of the content. M.S. wrote the article. All authors reviewed and/or edited the manuscript before submission.

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M.S. declares no competing interests. E.M.V. has received consultancy fees from Roche, GSK, AstraZeneca, UCB, Otsuka, BMS, Pfizer, Abbvie, Pfizer, Alpine, Alumis, Merck, BMS, Aurinia Pharmaceuticals, Lilly and Novartis, and has also received research grants paid to his employer from AstraZeneca and Sandoz. Y.K.O.T. has received grants/research support from the Dutch Arthritis Foundation, Autoimmune Research & Collaboration (ARCH) Foundation, Dutch Kidney Foundation, Netherlands Organization for Scientific Research, GSK, CSL Vifor and LUMC, and has received consulting fees from AstraZeneca, Alexion, GSK, Novartis, Otsuka Pharmaceuticals and Vifor Pharma.

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Glossary

B cell-activating factor

Also called B lymphocyte stimulator; a potent B cell activator and survival factor that promotes B cell maturation.

Double-negative B cells

B cells that have class switched and lack expression of IgD but also the memory marker CD27. Of these, DN2 cells have higher expression of CD11c and T-BET and are increased in the circulation in patients with SLE.

Fcγ receptor III

Activating Fc receptor that mediates interaction between the Fc ___domain of antibodies and FcγR-bearing effector cells.

Plasmablasts

A heterogeneous subset of short-lived circulating antibody-producing cells that might lie outside a CD19+ lymphocyte gate in flow cytometry and can be defined as CD3−CD14−CD19+/−CD38++CD27++ mononuclear cells.

Transitional B cells

B cells that have successfully recombined their surface receptor and exited the bone marrow but are not yet fully mature. Depending on their stage of transition, they can be CD24hiCD38hi.

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Stockfelt, M., Teng, Y.K.O. & Vital, E.M. Opportunities and limitations of B cell depletion approaches in SLE. Nat Rev Rheumatol 21, 111–126 (2025). https://doi.org/10.1038/s41584-024-01210-9

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