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Update on the pathophysiology and treatment of primary Sjögren syndrome

Nature Reviews Rheumatology volume 20, pages 473–491 (2024)Cite this article

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Abstract

Sjögren syndrome or Sjögren disease is a chronic form of autoimmune epithelitis characterized by lymphocytic infiltration of the exocrine glands, particularly the salivary and lacrimal glands, leading to progressive glandular dysfunction and subsequent xerostomia and xerophthalmia. Other common manifestations include pain and fatigue, various systemic manifestations and non-Hodgkin’s lymphoma. Sjögren syndrome is therefore a complex and disabling disease associated with a reduced quality of life and with considerable long-term damage. Most of the available treatments are merely symptomatic with limited efficacy in both preventing glandular damage and suppressing systemic disease activity. In the past 10 years, great progress has been made in understanding the pathophysiology of Sjögren syndrome, opening new avenues towards a more targeted and individualized therapeutic approach to the disease. Indeed, several randomized controlled trials have just been completed or are poised to commence evaluating the effectiveness of novel drugs targeting both innate and adaptive immune pathways, including pro-inflammatory cytokines, the type I interferon system, B cell activation, B cell and T cell co-stimulation pathway, and ectopic germinal centre formation. Novel clinical trials are also ongoing exploring various targeted approaches (that is, IgG recycling inhibition, nuclease therapy and CAR-T cell therapy) for Sjögren syndrome.

Key points

  • New insights into Sjögren syndrome pathophysiology are opening new avenues in the treatment of Sjögren syndrome, with novel molecules in the pipeline.

  • Different therapeutic strategies are under investigation that interfere with activation of interferon pathways including agents that degrade circulating RNA, agents that interfere with Toll-like receptor activation and inhibitors of downstream signalling.

  • Novel strategies that target B cell hyperactivity have shown promising results, including anti-BAFF antibodies, agents that target B cell receptor signalling and antibody-depleting drugs.

  • Targeting B cell and/or T cell co-stimulation pathways, including targeting the CD40–CD40 ligand axis and the ICOS–ICOS ligand axis, have also shown promise.

  • A miscellanea of additional novel agents, including drugs that target T cells and pro-inflammatory cytokines, are in the pipeline and could offer novel therapeutic possibilities in the near future.

  • Novel insights into clinical, molecular and histopathological stratification, based on multiomics techniques, emerging imaging biomarkers and new composite outcome measures, are paving new avenues for personalized medicine in Sjögren syndrome.

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Fig. 1: Sjögren syndrome pathogenetic model.
Fig. 2: Novel agents targeting the main pathways involved in Sjögren syndrome pathophysiology.
Fig. 3: Biological and synthetic DMARDs that target type I, II and III interferon signalling.
Fig. 4: Biological and synthetic DMARDs that target BCR signalling.
Fig. 5: Mechanism of action of FcRn inhibitors.

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Authors and Affiliations

  1. Rheumatology Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy

    Chiara Baldini, Giovanni Fulvio, Gaetano La Rocca & Francesco Ferro

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  1. Chiara Baldini
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The authors contributed equally to all aspects of the article.

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Competing interests

C.B. and F.F. have participated in randomized clinical trials of deucravacitinib (for BMS), belimumab plus rituximab (for GSK), anti-CD40L therapy (for Horizon Therapeutics), anti-CD40 therapy (for Novartis) and anti-CD20 therapy (for Novartis). G.F. and G.L.R. have participated in randomized clinical trials of deucravacitinib (for BMS), anti-CD40L therapy (for Horizon Therapeutics), anti-CD40 therapy (for Novartis) and anti-CD20 therapy (for Novartis). C.B. has served as adviser or consultant for Aurina, GSK, Horizon Therapeutics/AMGEN, Johnson and Johnson and Sanofi.

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Baldini, C., Fulvio, G., La Rocca, G. et al. Update on the pathophysiology and treatment of primary Sjögren syndrome. Nat Rev Rheumatol 20, 473–491 (2024). https://doi.org/10.1038/s41584-024-01135-3

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