Targeting Inflammation in Osteoarthritis Pain: A Phenotype-Driven Approach.

Abstract

Background: Osteoarthritis (OA) is a chronic joint disease marked by the progressive loss of articular cartilage and associated inflammatory processes, which can lead to significant pain and disability. However, the heterogeneous nature of OA has limited the effectiveness of many anti-inflammatory interventions, highlighting the need for phenotype-driven therapeutic strategies.

Methods: This narrative review was conducted by searching PubMed, Web of Science, and Google Scholar from inception to June 2025. Predefined keywords included "osteoarthritis", "inflammation", "pain", "synovitis", "effusion", "treatment", "therapy" and "clinical trials". Additional relevant publications were identified through citation tracking of the included papers.

Results: Our analysis of recent randomized clinical trials (RCTs) reveals a clear divergence in therapeutic efficacy, while targeted biologics (eg, TNF-α inhibitors like adalimumab and IL-1 blockers such as lutikizumab) have largely failed to meet primary pain endpoints in unselected populations, broad-spectrum immunomodulators like methotrexate (MTX) show significant promise, particularly in reducing pain and stiffness for the inflammatory phenotype. Furthermore, emerging evidence suggests that intra-articular (IA) treatments and phenotype-driven stratifications are essential to overcoming the current "one-size-fits-all" failure in OA drug development.

Conclusion: The central message of this review is that the inconsistent efficacy of anti-inflammatory therapies in OA reflects a patient-selection problem more than a failed target: agents tested in unselected populations, including most anti-cytokine biologics, have not relieved pain, whereas signals emerge for MTX in patients with an inflammatory phenotype. Stratifying patients by imaging-defined synovitis or effusion and inflammatory biomarkers is therefore the key unmet need, and phenotype-driven trial design-rather than new molecular targets alone-offers the most promising path to effective inflammation-targeted treatment of OA pain.