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Management of rheumatoid arthritis (RA) patients has significantly improved over the past decades. However, a substantial proportion of patients is difficult-to-treat (D2T), remaining symptomatic after failing biological and/or targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs). Multiple factors can contribute to D2T RA, including treatment non-adherence, comorbidities and co-existing mimicking diseases (e.g. fibromyalgia). Additionally, currently available (b/ts)DMARDs may be truly ineffective (‘true’ refractory RA) and/or lead to unacceptable side effects. In this narrative review based on a systematic literature search, an overview of underlying (immune) mechanisms is presented. Potential scenarios are discussed including the influence of different levels of gene expression and clinical characteristics. Although the exact underlying mechanisms remain largely unknown, the heterogeneity between individual patients supports the assumption that (D2T) RA is a syndrome involving different pathogenic mechanisms.

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