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Persistent inflammatory and non-inflammatory mechanisms in refractory rheumatoid arthritis

Nature Reviews Rheumatology volume 17, pages 17–33 (2021)Cite this article

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Abstract

Despite nearly three decades of advances in the management of rheumatoid arthritis (RA), a substantial minority of patients are exposed to multiple DMARDs without necessarily benefitting from them; a group of patients variously designated as having ‘difficult to treat’, ‘treatment-resistant’ or ‘refractory’ RA. This Review of refractory RA focuses on two types of patients: those for whom multiple targeted therapies lack efficacy and who have persistent inflammatory pathology, which we designate as persistent inflammatory refractory RA (PIRRA); and those with supposed refractory RA who have continued disease activity that is predominantly independent of objective evidence of inflammation, which we designate as non-inflammatory refractory RA (NIRRA). These two types of disease are not mutually exclusive, but identifying those individuals with predominant PIRRA or NIRRA is important, as it informs distinct treatment and management approaches. This Review outlines the clinical differences between PIRRA and NIRRA, the genetic and epigenetic mechanisms and immune pathways that might contribute to the immunopathogenesis of recalcitrant synovitis in PIRRA, and a possible basis for non-inflammatory symptomatology in NIRRA. Future approaches towards the definition of refractory RA and the application of single-cell and integrated omics technologies to the identification of refractory RA endotypes are also discussed.

Key points

  • The term refractory rheumatoid arthritis (RA) implies treatment-resistant persistent joint and/or systemic inflammation; however, it is often used interchangeably with broader definitions such as ‘difficult to treat’ RA.

  • Refractory RA could be stratified into two major categories; persistent inflammatory refractory RA (PIRRA), in which unabated inflammation is evident, and non-inflammatory refractory RA (NIRRA), which lacks discernible inflammation.

  • Within the category of PIRRA, serological status and HLA associations can provide meaningful stratification that can inform potential therapeutic avenues.

  • Epigenetic modifiers, including methylation, microRNAs and long non-coding RNAs, can influence the course of RA and could provide a basis for the emergence of refractory RA.

  • NIRRA is typically mediated by ongoing pain and patient-reported outcomes; pain mechanisms might include autoimmune and neuroinflammatory pathways that are independent of joint synovitis.

  • The classification of RA and other diseases along an innate-to-adaptive immunological axis can be applied to refractory RA to help discover targets that might be of therapeutic benefit.

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Fig. 1: Refractory RA subgroups within the wider context of ‘difficult-to-treat’ RA.
Fig. 2: Proposed trajectory and distribution of joint involvement in refractory RA.
Fig. 3: Speculative pain mechanisms in non-inflammatory refractory RA.
Fig. 4: A first step in the stratification of refractory RA.
Fig. 5: Therapeutic approaches to targeting inflammation in refractory RA.

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Authors and Affiliations

  1. Centre for Musculoskeletal Research, School of Biological Sciences, Faculty of Biology, Medicine & Health, University of Manchester, Manchester, UK

    Maya H. Buch & Stephen Eyre

  2. NIHR Manchester Biomedical Research Centre, Manchester Academic Health Science Centre, Manchester University Foundation Trust, Manchester, UK

    Maya H. Buch & Stephen Eyre

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

    Maya H. Buch & Dennis McGonagle

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

    Dennis McGonagle

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M.H.B. and D.M. researched data for the article. All authors provided substantial contributions to discussions of content, wrote the article and reviewed or edited the manuscript before submission.

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A search for original articles was performed in PubMed. The search terms used were “refractory” and “rheumatoid arthritis” in combination. We also searched the reference lists of identified articles for further relevant papers.

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Buch, M.H., Eyre, S. & McGonagle, D. Persistent inflammatory and non-inflammatory mechanisms in refractory rheumatoid arthritis. Nat Rev Rheumatol 17, 17–33 (2021). https://doi.org/10.1038/s41584-020-00541-7

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