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Advances in the treatment of systemic lupus erythematosus

Nature Reviews Drug Discovery (2025)Cite this article

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Abstract

Systemic lupus erythematous is a clinically and pathogenetically heterogeneous disease that has long challenged researchers and clinicians aiming to improve its treatment. Advances over the past 75 years have revealed a number of key immune mechanisms that drive clinical manifestations, paving the way for the development of therapies that go beyond broad immunosuppression to improve clinical efficacy and reduce side effects. These include approaches aimed at specific immune pathways, and emerging efforts to restore immune homeostasis, such as chimeric antigen receptor T cell therapies to eliminate pathogenic B cells, low-dose interleukin 2 or regulatory T cell therapies. Although hopes for durable remissions or cure are rising, major obstacles remain owing to the complex nature of the disease. In this Review, we discuss emerging therapeutic strategies designed to address these challenges.

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Fig. 1: Overview of SLE pathogenesis.
Fig. 2: Overview of treatment approaches in SLE.
Fig. 3: Overview of targets in immune and non-immune cells targeted by SLE therapies.
Fig. 4: Current and future strategies for the use of CAR-based therapies in systemic lupus.

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Acknowledgements

M.S. is supported by the Bettencourt-Schueller Foundation, the INSERM (ATIP-Avenir), Ecole de l’INSERM Bettencourt-Schueller, the FOREUM foundation and the Arthritis Pierre Coubertin foundation. Work in the Tsokos Lab was supported by grants from NIAID, NIH.

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Author notes

  1. These authors contributed equally: Marc Scherlinger, Antonios G. A. Kolios.

Authors and Affiliations

  1. Rheumatology department, National reference center for rare autoimmune systemic diseases, RESO; Strasbourg University Hospital, Strasbourg, France

    Marc Scherlinger

  2. UMR_S INSERM 1109, Immunorhumatologie Moléculaire, Strasbourg, France

    Marc Scherlinger

  3. Department of Dermatology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland

    Antonios G. A. Kolios

  4. Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA

    Antonios G. A. Kolios, Vasileios C. Kyttaris & George C. Tsokos

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  1. Marc Scherlinger
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  2. Antonios G. A. Kolios
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  4. George C. Tsokos
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Contributions

G.C.T., M.S., A.G.K. and V.C.K. researched data for the article and provided substantial contribution to discussion of the content. All authors contributed to writing the article and reviewed and edited it before submission.

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Correspondence to Marc Scherlinger or George C. Tsokos.

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Competing interests

M.S. is a consultant for Abbvie, Amgen, AstraZeneca, Biogen, BMS, Fresenius, Galapagos, GSK, Innate Pharma, Nordic Pharma, Novartis, Roche, Sandoz. G.C.T. is on the scientific advisory boards of CUGENE, A2 Biotherapeutics, Biolojic and CorEvitas. The other authors declare no additional competing interests.

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Glossary

British Islands Lupus Assessment Group-based Combined Lupus Assessment (BICLA)

A composite SLE trial end point relying on the absence on new severe BILAG organ involvement and improvement of disease base on the physician evaluation.

Cytapheresis

A procedure similar to haemodialysis during which circulating cells are collected from a patient often to use them as a therapeutic compound.

Cytokine release syndrome (CRS)

A condition during which a large amount of inflammatory cytokines are released, often following T cell activation. Its severity ranges from isolated fever to hypotension and multi-organ failure.

Definition of remission in SLE (DORIS)

A disease state characterized by the absence of clinical symptoms and a daily prednisone dose of ≤5 mg. Sustained DORIS remission is associated with improved outcomes and is now a key end point in clinical trials.

IgG4-related disease

An inflammatory and fibrotic disorder characterized by a non-clonal expansion of IgG4 + B cells in various tissues.

Lupus low disease activity state (LLDAS)

A disease state characterized by minimal clinical activity and a daily prednisone dose of ≤7.5 mg. It is less stringent than DORIS remission, associated with better SLE outcome, and an important end point in trials.

Lymphodepletion

A cytotoxic chemotherapy (cyclophosphamide ± fludarabine), which allows a better cellular graft expansion and efficacy.

Molecular mimicry

The structural proximity between an exogenous antigen (for instance, viral) and an autoantigen, which may result in the induction of autoimmunity.

NETosis

Immunogenic programmed neutrophil death during which neutrophils release a net of DNA, histones and other molecules in the extracellular milieu to trap pathogens and elicit an immune response.

Organic brain syndrome

A general term referring to the impairment of brain function.

Self-tolerance

Mechanisms underlying the prevention of immune system activation against oneself.

Sjögren disease

A systemic autoimmune disease characterized by salivary glands immune infiltration along with B cell activation, which may lead to complications such as cryoglobulinemia and lymphoma.

SLE disease activity index (SLEDAI-2K)

SLE disease activity index 2000: an imperfect but easy tool to measure SLE disease activity in clinical settings and in trials.

SLE responder index 4 (SRI-4)

A composite clinical end point that encompass a decrease ≥4 points in the SLE disease activity (SLEDAI) index, the absence of new severe organ involvement (BILAG score A/B) and no disease worsening in the physician global assessment.

Type I interferon (IFN-I) signature

A transcriptomic signature of circulating cell exposed to IFN-I characterized by the upregulation of IFN-stimulated genes. The IFN-I signature is used in the clinics because its measurement is easier and cheaper than IFN-I level evaluation.

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Scherlinger, M., Kolios, A.G.A., Kyttaris, V.C. et al. Advances in the treatment of systemic lupus erythematosus. Nat Rev Drug Discov (2025). https://doi.org/10.1038/s41573-025-01242-0

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