Rheumatoid arthritis is the most common inflammatory arthritis and has benefited from significant advances in its management in the past years. However, specific challenges persist, including the management of difficult-to-treat rheumatoid (D2TRA), which is defined by the failure of at least two biological or targeted synthetic disease-modifying antirheumatic drugs with a different mechanism of action. D2TRA reported prevalence is from 5 to 20 %. EULAR (European Alliance of Associations for Rheumatology) proposed a step-by-step approach for managing D2TRA, starting with confirmation of diagnosis, assessment of inflammatory activity, immunosuppressive treatment choice and non-pharmacological treatment.