Resolution of Inflammation: A Novel Therapeutic Paradigm for Rheumatoid Arthritis and Its Comorbidities

Rheumatoid arthritis (RA) is a systemic immune-mediated disease in which persistent synovial inflammation contributes not only to joint destruction but also to cardiovascular, pulmonary, metabolic, and other extra-articular complications. This review focuses specifically on the translational potential of emerging receptor-directed pro-resolving therapeutics in targeting persistent inflammation, a common mechanism driving RA and its systemic comorbidities. Although contemporary disease-modifying antirheumatic drugs (DMARDs) have substantially improved disease control and structural outcomes, a complementary therapeutic question remains: can the endogenous biological program that terminates inflammation and restores tissue homeostasis be therapeutically engaged? Resolution pharmacology addresses this question by targeting endogenous pro-resolving pathways involving specialized pro-resolving mediators (SPMs), annexin A1 (AnxA1), melanocortin receptors, the formyl peptide receptor 2 (FPR2/ALX), and related signalling networks. This review examines the evidence linking defective resolution with RA and critically evaluates the therapeutic potential of resolution-directed interventions across articular disease and major RA-associated comorbidities. Rather than treating resolution pharmacology as a uniform therapeutic class, we distinguish anti-inflammatory effects from demonstrated pro-resolving activities and evaluate evidence ranging from in vitro and animal studies to observational human studies and clinical trials. This review particularly emphasizes receptor selectivity, biased agonism, and their use in combination with established DMARD therapies. We propose that the principal opportunity for resolution pharmacology is not to replace effective DMARD therapy but to complement it, promoting inflammatory termination and tissue recovery. Thus, resolution pharmacology should currently be considered a promising translational framework requiring future clinical validation rather than an established therapeutic paradigm for RA and its comorbidities. CHEMICAL COMPOUNDS IN THIS ARTICLE: Lipoxin A4; Resolvin D1; Resolvin D2; Resolvin D5; Maresin 1; Resomelagon (AP1189); BMS-986235.