Pathogenicity and virulence of Crimean-Congo hemorrhagic fever virus: From enzootic maintenance to severe human disease.

Difficult-to-treat rheumatoid arthritis (D2T RA) is a heterogeneous, multifactorial state defined by European Alliance of Associations for Rheumatology (EULAR) (treatment failures plus active/progressive disease and problematic disease management), and the earlier evidence base informing recommendations was scarce and often indirect. This systematic literature review (searches updated to July 2025) provides a synthesis of therapeutic evidence across three D2T RA-relevant clinical scenarios, addressing patient populations who have: limited treatment options due to comorbidity or contraindication; persistent active disease after ≥2 prior biologic/targeted synthetic disease-modifying antirheumatic drug (b/tsDMARD) failures and poor health-related quality of life despite low objective inflammatory activity, considered for non-pharmacological interventions. We have provided an expanded synthesis of DMARD safety across RA patient populations with a range of comorbidities or treatment contraindications.