Difficult-to-Treat Rheumatoid Arthritis: Diagnostic Reassessment, Clinical Scenarios and Treatment Selection—A Narrative Review

Background/Objectives: Difficult-to-treat rheumatoid arthritis (D2T RA), defined by the European Alliance of Associations for Rheumatology (EULAR) in 2020/2021, requires treatment according to the recommendations, failure of at least two biological or targeted synthetic DMARDs (b/tsDMARDs), at least one feature of active, progressive or symptomatic disease, and the perception that management is problematic. Similar treatment histories may conceal different mechanisms: persistent inflammation, non-inflammatory pain, poor adherence, and comorbidity. This review examines diagnostic reassessment and treatment selection in D2T RA. Methods: A narrative review based on targeted searches of PubMed (2015–2026), Embase, and the Cochrane Library, prioritizing randomized controlled trials, systematic reviews, meta-analyses, and EULAR recommendations. Results: The pooled prevalence of D2T RA is 11.7% (95% CI 9.5–14.3). Adherence to DMARDs is approximately 66%; non-adherence, comorbidity, and mimickers require exclusion before escalation. Persistent objective inflammation was reported in 47.1% of patients (95% CI 33.3–61.4). In Rituximab versus tocilizumab in anti-TNF inadequate responder patients with rheumatoid arthritis (R4RA), molecular stratification identified differential response to tocilizumab versus rituximab Clinical Disease Activity Index (CDAI) CDAI50: 63% vs. 36%; p = 0.035), whereas histological classification did not (56% vs. 45%; p = 0.31). Janus kinase (JAK) inhibitors retain efficacy after bDMARD failure (SELECT-BEYOND: American College of Rheumatology (ACR) ACR20 65% vs. 28%; FINCH 2: 66% vs. 31%). Most trials enrolled broader populations, and their results do not establish a universal hierarchy of drug classes. Conclusions: Management should follow a structured reassessment sequence: verification of EULAR criteria, adherence review, exclusion of mimickers, parallel assessment of inflammatory and non-inflammatory mechanisms, individualized drug selection, glucocorticoid reassessment, and shared decision-making. Synovial pathotypes and molecular models remain investigational pending prospective evaluation.