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Distinct mucosal endotypes as initiators and drivers of rheumatoid arthritis

Nature Reviews Rheumatology volume 20, pages 601–613 (2024)Cite this article

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Abstract

Rheumatoid arthritis (RA) is a potentially devastating autoimmune disease. The great majority of patients with RA are seropositive for anti-citrullinated protein antibodies (ACPAs), rheumatoid factors, or other autoantibodies. The onset of clinically apparent inflammatory arthritis meeting classification criteria (clinical RA) is preceded by ACPA seropositivity for an average of 3–5 years, a period that is designated as ‘at-risk’ of RA for ACPA-positive individuals who do not display signs of arthritis, or ‘pre-RA’ for individuals who are known to have progressed to developing clinical RA. Prior studies of individuals at-risk of RA have associated pulmonary mucosal inflammation with local production of ACPAs and rheumatoid factors, leading to development of the ‘mucosal origins hypothesis’. Recent work now suggests the presence of multiple distinct mucosal site-specific mechanisms that drive RA evolution. Indicatively, subsets of individuals at-risk of RA and patients with RA harbour a faecal bacterial strain that has exhibited arthritogenic activity in animal models and that favours T helper 17 (TH17) cell responses in patients. Periodontal inflammation and oral microbiota have also been suggested to promote the development of arthritis through breaches in the mucosal barrier. Herein, we argue that mucosal sites and their associated microbial strains can contribute to RA evolution via distinct pathogenic mechanisms, which can be considered causal mucosal endotypes. Future therapies instituted for prevention in the at-risk period, or, perhaps, during clinical RA as therapeutics for active arthritis, will possibly have to address these individual mechanisms as part of precision medicine approaches.

Key points

  • The onset of seropositive rheumatoid arthritis (RA) is typically preceded by the presence of RA-related autoantibodies (ACPAs, rheumatoid factors, AMPAs) in the peripheral blood for 3–5 years prior to the onset of symptoms and histologically or imaging-identified joint inflammation.

  • The period of time prior to clinical RA onset can be designated a period ‘at-risk of RA’ prospectively, or a ‘pre-RA’ period retrospectively.

  • An increasing number of studies have identified immune and microbial alterations at mucosal sites in subsets of individuals at-risk of RA or with pre-RA. The primary sites studied include the lung, gut and oral or periodontal regions.

  • Each of the mucosal sites seems to elaborate unique phenotypes and mechanisms that might drive the development of pre-RA and generation of local or systemic autoantibodies. These apparent mechanistic differences underlie the causal mucosal endotype hypothesis.

  • The inter-relationships and relative timing of changes at each of these mucosal sites is not yet understood but is the object of ongoing studies in conjunction with work to understand the underlying mechanisms of loss of tolerance.

  • If confirmed, the presence of distinct causal mucosal endotypes is likely to influence the design of RA prevention trials as well as potentially underlie differences in therapeutic responses in patients with clinical RA.

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Fig. 1: Transitions from pre-RA to clinical RA during the natural history of rheumatoid arthritis.
Fig. 2: Mechanisms potentially involved in the lung mucosal endotype of rheumatoid arthritis.
Fig. 3: Mechanisms linking dysbiosis and the gut mucosal endotype to the systemic spread of autoimmunity.
Fig. 4: Mechanisms involved in the oral and periodontal endotype.

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Acknowledgements

V.M.H.’s work is supported by grants U01 AI101981, T32 AR07534, P30 AR079369, UM1 AI110503, R01 AR051394, U19 AI50864 and Rheumatology Research Foundation; K.D.D.’s work is supported by NIH P30 AR079369; K.A.K.’s work is supported by Pfizer ASPIRE, K08 DK107905 and R01 AR075033; J.M.N.’s work is supported by R01 AR081812.

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Authors and Affiliations

  1. Division of Rheumatology, University of Colorado Denver, Aurora, CO, USA

    V. Michael Holers, Kristen M. Demoruelle, Fan Zhang, Kristine A. Kuhn & Kevin D. Deane

  2. Benaroya Research Institute, Seattle, WA, USA

    Jane H. Buckner & Eddie A. James

  3. Division of Rheumatology, Allergy and Immunology, University of California San Diego, La Jolla, CA, USA

    Gary S. Firestein

  4. Division of Immunology and Rheumatology, Stanford University, Stanford, CA, USA

    William H. Robinson

  5. VA Palo Alto Health Care System, Palo Alto, CA, USA

    William H. Robinson

  6. Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA

    Allen C. Steere

  7. Department of Epidemiology, Colorado School of Public Health, Aurora, CO, USA

    Jill M. Norris

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  1. V. Michael Holers
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Contributions

V.M.H. wrote the first draft of the manuscript based on concepts devised through years of interactions and discussions with all the other authors, who also all then reviewed, revised and contributed substantially to its content.

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Correspondence to V. Michael Holers.

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Nature Reviews Rheumatology thanks Axel Finckh, Vanessa Kronzer, Renuka Nayak and Mario Zaiss for their contribution to the peer review of this work.

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Glossary

Chronic obstructive pulmonary disease

Lung alveolar and airway disease characterized by tissue destruction and defective oxygenation often associated with cigarette and other deleterious environmental exposures141.

Dysbiosis

Alterations of the normal composition of the microbiome at any specific site142.

Inducible bronchus-associated lymphatic tissue

Immune aggregates found in the lung in the interstitial and peri-bronchial sites of patients with clinical rheumatoid arthritis, as well as other immune lung diseases49.

Non-specific interstitial pneumonitis

Form of interstitial lung disease in patients with clinical rheumatoid arthritis that is characterized radiographically by predominant traction bronchiectasis and extensive ground-glass opacities with sub-pleural sparing143.

Usual interstitial pneumonia

Form of interstitial lung disease rheumatoid arthritis characterized by basal predominant reticular opacities in the sub-pleural site, as well as honeycombing, sites of ground-glass opacity, and evidence of traction bronchiectasis143.

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Holers, V.M., Demoruelle, K.M., Buckner, J.H. et al. Distinct mucosal endotypes as initiators and drivers of rheumatoid arthritis. Nat Rev Rheumatol 20, 601–613 (2024). https://doi.org/10.1038/s41584-024-01154-0

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