Difficult-to-treat rheumatoid arthritis: what have we learned and what do we still need to learn?

Difficult-to-treat RA (D2T RA) is an area of high unmet need. The prevalence reported in the first D2T RA cohort studies ranged from 5.5% to 27.5%. Key to the definition is a conviction by the patient and/or rheumatologist that disease management has become problematic and failure of at least two biological or targeted synthetic DMARDs. D2T RA is a multifactorial disease state which was reflected in data from D2T RA cohort studies: these pointed towards high prevalence of comorbidities and/or lower socioeconomic status in D2T RA subgroups, while others had persistent symptoms without these factors being present. A holistic approach is necessary to identify the root problems underlying D2T RA in individual patients. In this review, biological and non-biological drivers that should be considered to be optimized will be discussed in view of what we have learned from patient data emerging from the first D2T RA cohort studies.