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Recent advances and evolving concepts in Still’s disease

Nature Reviews Rheumatology volume 20, pages 116–132 (2024)Cite this article

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Abstract

Still’s disease is a rare inflammatory syndrome that encompasses systemic juvenile idiopathic arthritis and adult-onset Still’s disease, both of which can exhibit life-threatening complications, including macrophage activation syndrome (MAS), a secondary form of haemophagocytic lymphohistiocytosis. Genetic insights into Still’s disease involve both HLA and non-HLA susceptibility genes, suggesting the involvement of adaptive immune cell-mediated immunity. At the same time, phenotypic evidence indicates the involvement of autoinflammatory processes. Evidence also implicates the type I interferon signature, mechanistic target of rapamycin complex 1 signalling and ferritin in the pathogenesis of Still’s disease and MAS. Pathological entities associated with Still’s disease include lung disease that could be associated with biologic DMARDs and with the occurrence of MAS. Historically, monophasic, recurrent and persistent Still’s disease courses were recognized. Newer proposals of alternative Still’s disease clusters could enable better dissection of clinical heterogeneity on the basis of immune cell profiles that could represent diverse endotypes or phases of disease activity. Therapeutically, data on IL-1 and IL-6 antagonism and Janus kinase inhibition suggest the importance of early administration in Still’s disease. Furthermore, there is evidence that patients who develop MAS can be treated with IFNγ antagonism. Despite these developments, unmet needs remain that can form the basis for the design of future studies leading to improvement of disease management.

Key points

  • Still’s disease, a rare inflammatory syndrome that encompasses systemic juvenile idiopathic arthritis and adult-onset Still’s disease, can exhibit life-threatening macrophage activation syndrome (MAS), a secondary form of haemophagocytic lymphohistiocytosis.

  • Genetic insights into Still’s disease involve both HLA and non-HLA susceptibility genes, suggesting autoimmune involvement, whereas phenotypic evidence suggests the involvement of an autoinflammatory process.

  • Evidence indicates that pathogenic mechanisms involving the type I interferon signature, mechanistic target of rapamycin complex 1 and pro-inflammatory properties of ferritin contribute to the development of Still’s disease and MAS.

  • Pathological conditions now associated with Still’s disease include Still’s disease-related lung involvement, which is potentially associated with the use of biologic DMARDs and the occurrence of MAS.

  • Clusters of patients with Still’s disease have been identified by the characterization of immune cell populations, which might represent diverse endotypes or different phases of disease activity.

  • Therapeutically, evidence is available in relation to IL-1 antagonism and Janus kinase inhibition, including early administration, suggesting that MAS in Still’s disease might be tractable with IFNγ antagonism.

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Fig. 1: Still’s disease in the context of autoinflammatory and autoimmune disorders.
Fig. 2: Main pathogenic mechanisms that underlie the development of Still’s disease and its life-threatening evolution.
Fig. 3: Inflammatory mediators and targeted therapies in Still’s disease.
Fig. 4: Therapeutic management of Still’s disease and MAS.
Fig. 5: The ‘window of opportunity’ in Still’s disease.

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Acknowledgements

The authors thank M. Vomero for her assistance in creating the figures. P.A.N. was funded by NIH grants R01AR073201 and P30AR070253.

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Authors and Affiliations

  1. Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, L’Aquila, Italy

    Piero Ruscitti

  2. Department of Medical Sciences, Surgery and Neurosciences, Research Center of Systemic Autoinflammatory Diseases and Behçet’s Disease Clinic, University of Siena, Siena, Italy

    Luca Cantarini

  3. Division of Immunology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA

    Peter A. Nigrovic

  4. Division of Rheumatology, Inflammation, and Immunity, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    Peter A. Nigrovic

  5. Leeds Institute of Rheumatic and Musculoskeletal Medicine (LIRMM), University of Leeds, Leeds, UK

    Dennis McGonagle

  6. National Institute for Health Research (NIHR) Leeds Biomedical Research Centre (BRC), Leeds Teaching Hospitals, Leeds, UK

    Dennis McGonagle

  7. Clinical and research section of Rheumatology and Clinical Immunology, Fondazione Policlinico Campus Bio-Medico, Rome, Italy

    Roberto Giacomelli

  8. Rheumatology and Clinical Immunology, Department of Medicine, University of Rome “Campus Biomedico”, School of Medicine, Rome, Italy

    Roberto Giacomelli

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The authors contributed equally to all aspects of the article.

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Competing interests

P.A.N. discloses consulting for Apollo, BMS, Exo Therapeutics, Fresh Tracks Therapeutics, Merck, Novartis, Pfizer, Qiagen and Sobi; investigator-initiated research grants from BMS and Pfizer; and authorship royalties from UpToDate, the American Academy of Paediatrics and Arthritis & Rheumatology. The remaining authors declare no competing interests.

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Ruscitti, P., Cantarini, L., Nigrovic, P.A. et al. Recent advances and evolving concepts in Still’s disease. Nat Rev Rheumatol 20, 116–132 (2024). https://doi.org/10.1038/s41584-023-01065-6

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