Comorbidities and extra-articular manifestations in difficult-to-treat rheumatoid arthritis: different sides of the same coin?

Despite the improvement in treatment for people with RA, ∼30% of patients remain symptomatic in the presence of optimized medical therapy, described as having 'difficult-to-treat' (D2T) RA. The average patient with RA has 1.6 other clinical conditions, which accumulate over time. Comorbidities are increasingly recognized as key contributors to D2T disease, and are themselves perpetuated by the D2T state. In this review, we discuss the commonest comorbidities in the context of D2T RA. We propose the need for a paradigm shift in the clinical and research agenda for comorbidities-including a need to consider and manage these prior to the development of D2T disease and not as an afterthought.