Difficult to Treat (D2T) RA: What is the Missing Link?

Over the past several decades, the treatment of rheumatoid arthritis (RA) has advanced significantly, and clinical, structural, and functional remission are achievable therapeutic goals. However, a substantial number of patients show resistance to multiple drugs. In particular, patients whose disease activity cannot be controlled despite the use of two or more biological disease-modifying antirheumatic drugs (DMARDs) or targeted synthetic DMARDs with different mechanisms of action have recently been referred to as having difficult-to-treat RA (D2T RA). D2T RA is a heterogeneous and multifactorial disease state, and the major problems are uncontrolled disease activity and decreased quality of life, as well as the economic burden. Since the concept of D2T RA is relatively new and publication regarding D2T RA is limited, the mechanism underlying DMARD inefficacy and which factors form a “difficult-to-treat” state are not yet fully understood. It is also possible that factors contributing to D2T RA may differ by patient, sex, country, and race. The present seminar introduces the current concept and unsolved problems of D2T RA, including the definition, prevalence, and factors contributing to D2T RA. Then, the management and therapeutic strategies for D2T RA are discussed including our multicentre ANSWER cohort experience. Finally, a clinical approach to prevent patients from developing D2T RA is explored.