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Understanding Refractory Rheumatoid Arthritis: Implications for a Therapeutic Approach

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Abstract

Refractory rheumatoid arthritis (RA) has emerged as an area of unmet need in a landscape of generally well-controlled disease. Whilst most patients are adequately treated on methotrexate and other first-line disease-modifying anti-rheumatic drugs (DMARDs), a proportion requires biologic (b) and targeted synthetic (ts) DMARDs, with a further subsection failing multiple agents. Recent observational studies have adopted working definitions of refractory RA based on number of failed DMARDs, with prevalence estimates of 6–21% depending on threshold and study population. Risk factors include treatment delay, baseline disease activity and function, female gender, smoking, obesity and lower socioeconomic status. Practical and conceptual challenges in defining refractory RA arise from limitations of disease activity scores used to assess response, with attendant misclassification risk of co-existent non-inflammatory pathology, and failure to capture additional outcomes, such as fatigue, that have variable treatment response. Time is an important factor in defining refractory disease; registry studies show that growing treatment options have resulted in rapid b/tsDMARD cycling and earlier refractory status, and refractory RA is itself a dynamic concept, evolving with each new therapeutic class. Whilst the biology underpinning refractory RA remains largely unknown, a general overview of biomarker studies and clinical trials old and new offers insights into prediction of response and treatment failure. Whilst the future holds promise, current data are insufficient to personalise or meaningfully sequence b/tsDMARDs. Therefore, avoidance of a refractory course is best achieved by following proven management paradigms (e.g. early diagnosis and treat-to-target), addressing modifiable risk factors, and considering enrolment in novel trials.

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Author notes

  1. Andrew R. Melville and Lianne Kearsley-Fleet contributed equally to this review.

Authors and Affiliations

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

    Andrew R. Melville

  2. Centre for Epidemiology Versus Arthritis, Centre for Musculoskeletal Research, Manchester Academic Health Science Centre, The University of Manchester, Manchester, UK

    Lianne Kearsley-Fleet, Maya H. Buch & Kimme L. Hyrich

  3. National Institute of Health Research Manchester Biomedical Research Centre, Manchester Academic Health Science Centre, Manchester University NHS Foundation Trust, Manchester, UK

    Maya H. Buch & Kimme L. Hyrich

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  1. Andrew R. Melville
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  3. Maya H. Buch
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  4. Kimme L. Hyrich
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Correspondence to Kimme L. Hyrich.

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No external funding was used in the preparation of this article.

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AM and LKF declare no conflicts of interest. MB has received research grants paid to her employer from Pfizer, Bristol-Myers Squibb, Roche and UCB, and provided expert advice and received consultant fees from AbbVie, Bristol-Myers Squibb, Eli Lilly, EMD Serono, Pfizer, Roche, Sandoz, Sanofi and UCB. KH has received honoraria from AbbVie (paid to institution) and grant income from Pfizer, BMS and UCB (paid to institution).

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Melville, A.R., Kearsley-Fleet, L., Buch, M.H. et al. Understanding Refractory Rheumatoid Arthritis: Implications for a Therapeutic Approach. Drugs 80, 849–857 (2020). https://doi.org/10.1007/s40265-020-01309-9

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