Beyond the Prevention of Anti-drug Antibody Formation with Uricase Therapy: Mechanistic Roles of DMARDs in Modifying Gout Flare Risk

Disease-modifying antirheumatic drugs (DMARDs) are immune-modifying agents that have shown efficacy in improving response rates and reducing infusion reactions associated with uricase therapy for uncontrolled gout by inhibiting anti-drug antibody (ADA) formation. However, increased gout flare rates following initiation of uricase therapy remain a concern, impacting patient quality of life and treatment adherence. Gout flares are an acute inflammatory reaction to monosodium urate crystals, driven by inflammasome activation. As such, it is possible that DMARDs could impact gout flare risk. In this hypothesis-generating narrative review, we have synthesized mechanistic data investigating the effects of the DMARDs methotrexate, mycophenolate mofetil, azathioprine, leflunomide, and sirolimus on mechanisms involved in gout flare such as NACHT, LRR, and PYD domain-containing protein 3 (NLRP3) inflammasome activation. The mechanisms by which DMARDs inhibit ADA formation appear to be distinct from those that may affect gout flares, but these may exist in balance with one another to form a distinct pharmacological profile for each agent. Paradoxically, preclinical evidence suggests that DMARDs may sometimes induce NLRP3 inflammasome activation, particularly at higher doses. We suggest that individual DMARDs’ effect on inflammatory pathways relevant to gout flare may vary depending on the pathophysiological context and differences in their pharmacological profiles. Therefore, the inflammatory consequences of combining DMARDs with uricase therapy are likely to be specific to the individual agent. Understanding the mechanistic profile of each DMARD is key to optimizing both immunogenicity management and flare outcomes in patients receiving uricase therapy for uncontrolled gout.