Emerging approaches to difficult-to-manage axial spondyloarthritis.

INTRODUCTION: Difficult-to-manage (D2M) axial spondyloarthritis (axSpA) is a recently published Assessment of SpondyloArthritis International Society (ASAS) consensus definition, defined by persistent symptoms despite 2 or more biological or targeted synthetic DMARD (b/tsDMARD) therapies. This affects 10-20% of patients in clinical practice, representing a substantial unmet healthcare need.

AREAS COVERED: We review the updated ASAS D2M classification and its subset classification of treatment-refractory (TR) axSpA, as well as the latest studies into axSpA cohorts characterizing the cohort of D2M patients. We will review the evidence pointing toward the multitude of pathophysiological mechanisms driving D2M disease, including structural damage, nociplastic pain, and comorbidities, before then reviewing the literature for potential strategies to best manage this D2M population. We will also highlight gaps in the literature and areas of further research that are needed.

EXPERT OPINION: Management of D2M axSpA should shift from a 'next biologic' to a 'right mechanism' paradigm, with mechanistic stratification informing treatment allocation. Patients with TR-axSpA warrant pharmacological escalation or novel therapeutic approaches; conversely, the majority of D2M patients require multidisciplinary care prioritizing evidence-based non-pharmacological interventions, which are substantially underutilized despite robust efficacy data. This must be underpinned by further research targeting D2M axSpA cohorts.