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Understanding Refractory Rheumatoid Arthritis: Implications for a Therapeutic Approach

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Understanding Refractory Rheumatoid Arthritis: Implications for a Therapeutic Approach Drugs https://doi.org/10.1007/s40265-020-01309-9 LEADING ARTICLE Understanding Refractory Rheumatoid Arthritis: Implications for a Therapeutic Approach Andrew R. Melville1 · Lianne Kearsley‑Fleet2 · Maya H. Buch2,3 · Kimme L. Hyrich2,3 © Springer Nature Switzerland AG 2020 Abstract Refractory rheumatoid arthritis (RA) has emerged as an area of unmet need in a landscape of generally well-controlled dis- ease. Whilst most patients are adequately treated on methotrexate and other frst-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 defnitions 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, base- line disease activity and function, female gender, smoking, obesity and lower socioeconomic status. Practical and conceptual challenges in defning refractory RA arise from limitations of disease activity scores used to assess response, with attendant misclassifcation risk of co-existent non-infammatory pathology, and failure to capture additional outcomes, such as fatigue, that have variable treatment response. Time is an important factor in defning 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 ofers insights into prediction of response and treatment failure. Whilst the future holds promise, current data are insufcient 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 modifable risk factors, and considering enrolment in novel trials. 1 Introduction: Rheumatoid Arthritis methotrexate and other conventional synthetic (cs) disease- and Biologic Therapy modifying anti-rheumatic drugs (DMARDs), an estimated two-ffths of patients fail to respond to these frst-line treat- Rheumatoid arthritis (RA) is an autoimmune disease with ments and require a biologic (b) or targeted synthetic (ts) a prevalence of approximately 1% of the adult popula- DMARD [2]. tion [1]. Whilst many patients are adequately treated with Since the success of the frst tumour necrosis factor (TNF) inhibitors in the late 1990s, b/tsDMARDS have played a major role in transforming outcomes in RA, with positive Andrew R. Melville and Lianne Kearsley-Fleet contributed equally efects on remission rates, joint damage/radiographic pro- to this review. gression, function, quality of life and co-morbidities. The * Kimme L. Hyrich therapeutic options have exploded in recent years, with fve [email protected] diferent TNF inhibitors now available as well as therapies 1 that modify other immune pathways, including interleukin Leeds Institute of Rheumatic and Musculoskeletal Medicine, inhibitors (IL6, IL1), anti-CD20 B-cell depleting agents and University of Leeds, Leeds, UK 2 T-cell co-stimulation (CTLA4) inhibitors. Most recently, Centre for Epidemiology Versus Arthritis, Centre intracellular-acting small-molecule therapies have further for Musculoskeletal Research, Manchester Academic Health Science Centre, The University of Manchester, Manchester, expanded the treatment armamentarium, with the arrival of UK Janus kinase (JAK) inhibitors (Table 1). 3 National Institute of Health Research Manchester Biomedical International guidelines recommend b/tsDMARD therapy Research Centre, Manchester Academic Health Science after csDMARD failure (methotrexate monotherapy in most Centre, Manchester University NHS Foundation Trust, cases). In some countries, further stipulations prior to b/ Manchester, UK Vol.:(0123456789) A. R. Melville et al. essentially suggest equivalent efectiveness across agents, Key Points and latest guidelines no longer recommend any hierarchical positioning [3–5]. Despite tremendous progress in the treatment of rheuma- In this review, we aim to provide an understanding of the toid arthritis (RA) over the past two decades in the era of emerging concept of refractory RA. We summarise the fnd- targeted therapies, refractory disease has emerged as an ings of recent observational studies on this subject, includ- area of unmet clinical need. ing defnitions used, limitations thereof, and risk factors There is currently no universally accepted defnition of identifed. In the absence of a detailed understanding of the refractory RA, but various working defnitions based biology underpinning refractory RA itself, we explore the on number of failed DMARDs have permitted initial scientifc and wider clinical basis of response to therapy and insights into the scale of the problem and risk factors for treatment failure in general, ultimately outlining current and a refractory disease course. future implications for research and clinical practice. A detailed mechanistic understanding of the biology underpinning refractory RA, or indeed response/non- 2 Refractory Disease response to targeted therapies, is lacking; tailoring of therapy at an individual level (which in theory might 2.1 Extent of the Problem and Proposed Defnitions minimise the risk of sequential non-response) remains an aspiration. Whilst targeted therapies (along with infuential manage- ment paradigms including early diagnosis, early DMARD initiation, and treat to target) have led to improved outcomes tsDMARDs exist, largely for health economic reasons; in for the vast majority of patients, an important subgroup the UK, for example, failure of at least two csDMARDs and continue with inadequately controlled disease, refractory to a high disease activity score (28 joint count disease activity multiple drugs with diferent modes of action. Refractory score (DAS28) > 5.1) are required. TNF inhibitors, as the RA remains under-represented in the literature, and a full frst bDMARDs to be introduced, continue to be the most appreciation of the individual impact and health economic commonly prescribed frst-line bDMARDs. This refects burden is lacking, but it is increasingly recognised as an area clinician familiarity and abundant efectiveness and safety of unmet clinical need [6]. data; however, randomised controlled trials (RCT) and (in There is currently no consensus defnition for refractory the absence of head-to-head trials) network meta-analyses RA. Indeed, it should be noted that, as the number of tar- geted therapies increases, the defnition of what constitutes refractoriness continues to evolve. To illustrate this point, Table 1 Biologic and targeted disease-modifying anti-rheumatic studies from the fairly recent past defned refractory dis- drugs licensed by the European Medicines Agency for rheumatoid ease based on failure of methotrexate alone [7], whilst most arthritis recent studies focus on multiple DMARD failures, including Tumour necrosis factor (TNF) inhibitors one or more b/tsDMARDs. Adalimumab In a recent observational study from Vienna, refractory Certolizumab pegol RA was defned as failure to achieve low disease activity Etanercept despite three or more DMARDs, of which one must be a Infiximab bDMARD. Approximately 17% of a tertiary centre cohort Golimumab met this defnition, and 6% of a community hospital valida- Interleukin-1 receptor antagonist tion cohort [8]. Female gender, time to frst treatment, and Anakinra higher baseline disease activity predicted refractory disease Interleukin-6 pathway inhibitor in a multivariable model, with a 50% predicted probability Sarilumab (receptor antagonist) Tocilizumab (receptor antagonist) amongst the most high-risk patients. Refractory patients also Cell-targeted B-cell-depleting agents had a slightly younger age at onset (mean age 44 vs. 51 years Rituximab (anti-CD20 Ig) for treatment amenable patients). Known disease-specifc T-cell co-stimulation blockers factors associated with ‘severe’ RA (i.e. predictive of radio- Abatacept (anti-CTLA4 Ig) graphic progression), including sero-positivity for cyclic Janus kinase (JAK) inhibitors citrullinated peptide (CCP) or rheumatoid factor (RF), and Baricitinib baseline radiographic damage score, were non-signifcant Tofacitinib in the model. Understanding refractory rheumatoid arthritis: implications for therapeutic approach In work published by the British Society for Rheumatol- The use of composite scores to defne treatment response, ogy Biologics Register for RA (BSRBR-RA), among 13,502 and by extension refractory RA, has its limitations. Subjec- patients starting their frst bDMARD, 21% went on to start tive components are heavily weighted in the DAS28 for- a third [9], consistent with an estimate extrapolated from mula; indeed, the tender joint count (which may be infu- RCT data [10]. However, there is an argument for defn- enced by co-existent osteoarthritis or chronic pain) has ing (truly) refractory RA as failure of multiple b/tsDMARD double the weight of the swollen joint count. Another issue classes [10, 11], as variation in key cytokine and cellular is the (un)feasibility of achieving low disease activity scores mechanisms driving pathogenesis and persistence, and/ (particularly remission according to the strict ACR/EULAR or redundancy
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