Targeted Therapies in Polymyalgia Rheumatica: From Immunopathophysiology to a Redefined Treatment Paradigm

Polymyalgia rheumatica (PMR) is a common inflammatory disorder of people aged more than 50 years, usually managed with prolonged glucocorticoid (GC) therapy despite its associated toxicity and frequent relapses. Over the past decade, major advances in understanding innate and adaptive immune mechanisms have reshaped the conceptual framework of PMR, positioning it in an autoinflammation-autoimmunity continuum. Synovial and bursal tissues exhibit macrophage-dominated inflammation driven by interleukin (IL)-6, granulocyte-macrophage colony-stimulating factor and interferon-γ, sustained by T helper (Th) 1 effector responses, senescent T cells, and dysregulated B-cell and dendritic-cell compartments. This expanding immunopathological knowledge has accelerated the development of targeted therapies that challenge traditional management paradigms. Interleukin-6 receptor blockade with tocilizumab and sarilumab has demonstrated reductions in relapse rates and cumulative GC exposure. A recent randomized controlled trial showed a significant effect of the anti-IL-17A inhibitor secukinumab in achieving sustained remission and reducing GC cumulative dose. The Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway blockade represents another promising approach to treat PMR. Novel therapeutic classes, such as GC receptor modulators and selective 11β-hydroxysteroid dehydrogenase type 1 inhibitors, further aim to optimize anti-inflammatory efficacy while mitigating steroid-associated harm. This review synthetizes current insights into the immunopathophysiology of PMR and critically appraises emerging targeted treatment strategies, highlighting how these advances may redefine the standard of care. As understanding matures and therapeutic options expand, future management of PMR is likely to shift toward more precise, mechanism-driven approaches, rendering GC-free remission an achievable target for many more patients.