Difficult-to-treat systemic lupus erythematosus: from refractory disease to a multidimensional clinical trajectory

Difficult-to-treat (D2T) systemic lupus erythematosus (SLE) is increasingly recognised in clinical practice but is still conceptually underdeveloped. In contrast to rheumatoid arthritis and psoriatic arthritis, for which formal D2T frameworks have been proposed, SLE still lacks a multidimensional model capable of capturing the complexity of the management of the disease. In SLE, treatment complexity extends beyond refractoriness alone and may reflect the convergence of recurrent flares, persistent inability to achieve treatment targets, glucocorticoid dependence, steadily accruing organ damage, treatment toxicity, patient-reported burden, organ-specific severity, non-adherence, and contextual barriers to care. Current literature supports the existence of a clinically meaningful subgroup with sustained high unmet need, but most published evidence remains indirect and is largely derived from studies of refractory organ disease, persistent disease activity, or failure to achieve remission or low disease activity states. In this Review, we examine current literature on the concept of D2T SLE and analyse the dimensions that may constitute it, highlighting that it is better framed as a multidimensional trajectory rather than a static condition. This perspective accommodates the possibility of a pre-D2T phase, in which progressive treatment difficulty may already be emerging. Future frameworks, beyond defining D2T SLE, should integrate dynamic biomarkers, digital phenotyping, patient co-definition, health-system determinants, and biologically meaningful endotypes, with the aim of developing a precision-oriented D2T framework. Such a framework could improve future risk stratification, inform trial design, support glucocorticoid-sparing and mechanism-based escalation strategies, and ultimately help redesign SLE care around early recognition of persistent complexity rather than late recognition of failure.