OUP accepted manuscript

Increased effectiveness of pharmacological treatments in early RA has led many to believe that difficult-to-treat, established RA is a condition of the past. However, there are still plenty of RA patients who continue to have signs and symptoms suggestive of inflammatory disease activity, despite consecutive treatment with multiple conventional synthetic and biological DMARDs. We argue that difficult-to-treat RA constitutes an area of unmet clinical need and propose a definition of this concept. An overview of what is known about the multiple contributory factors varying for each individual patient, and an approach towards improved patient-tailored management are presented. This management approach involves thorough assessment to determine whether persistence of signs and symptoms is based on inflammatory disease activity, and the role of comorbidities. Furthermore, it addresses medication-related issues, such as non-adherence, patient beliefs and expectations, and setting of realistic treatment goals.