Understanding Refractory Rheumatoid Arthritis: Implications for a Therapeutic Approach

Abstract

Refractory 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 diseasemodifying 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 is 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. Rheumatoid arthritis (RA) is a common autoimmune disease affecting 1% of the adult population. Whilst many patients are adequately treated with methotrexate and other conventional synthetic (cs) disease modifying anti-rheumatic drugs (DMARDs), an estimated two-fifths of patients do not respond to methotrexate and many will go on to require a biologic (b) or targeted synthetic (ts) DMARD. For most patients, b/ts DMARDs offer the real opportunity for disease remission, but for a small but not insignificant proportion, disease control remains elusive despite trials of multiple different b/ts DMARDs. This review discusses the concept of refractory RA and our current understanding of this potentially unmet need in rheumatology. Key Points:• Despite tremendous progress in the treatment of rheumatoid arthritis (RA) over the past two decades in the era of targeted therapies, refractory disease has emerged as an area of unmet clinical need. • There is currently no universally accepted definition of refractory RA, but various working definitions based on number of failed DMARDs have permitted initial insights into the scale of the problem and risk factors for a refractory disease course.• A detailed mechanistic understanding o...

Clinical predictors of multiple failure to biological therapy in patients with rheumatoid arthritis

“…This study is not without its limitations, mainly because there is no well-established definition of multirefractoriness [10,11,15,16,23,24] and because it is difficult to establish a comparison with other cohorts. Nevertheless, our data can provide more information for the characterization of this subgroup of patients and for definitions of multi-refractory and difficult-to-treat RA which are still pending (although this is one of the objectives of the European League Against Rheumatism (EULAR) task force) [23].…”

Mitochondria as Key Players in the Pathogenesis and Treatment of Rheumatoid Arthritis

“…Despite the array of therapeutics that are already approved for the treatment of RA, some patients fail to respond to any of these treatments, and sustained clinical remission is achieved in fewer than half of patients ( 240 , 241 ). These facts highlight the continued need for additional therapies that are tailored to an individual patient’s disease.…”

Correspondence on: ‘EULAR definition of difficult-to-treat rheumatoid arthritis’

“…2 This study was designed and conducted prior to the publication of this paper establishing the definition of difficult-to-treat RA. Based on previous works published on this concept, [3][4][5][6][7][8] we defined 'multi-refractory' patients as those who have received ≥2 biologic disease-modifying antirheumatic drugs (bDMARDs) with different mechanism of action or ≥3 bDMARDs with the same target. This definition seemed to us the most appropriate option for the classification of difficult-totreat patients in terms of drug use.…”