The last two decades have seen a remarkable resurgence of gout in the United States. This comeback has clinicians facing increasingly complex cases in which age, comorbidities, and concomitant medications impose difficult management decisions.
Autoinflammatory Cryoprinopathies Identify Potential Therapeutic Targets
Over the last few years, mutations in NALP3 have been linked to certain autosomal dominant inherited auto-inflammatory syndromes of differing severity. These syndromes include familial cold-induced auto-inflammatory syndrome, Muckle-Wells syndrome, and neonatal onset multisystem inflammatory disease/chronic infantile neurological cutaneous and articular syndrome.15 The self-resolution of periodic flares of systemic inflammation in these autoinflammatory cryopyropathies is remarkably similar to the typical course of gouty arthritis, which reflects the shared central role of NALP3.11 Recent research on autoinflammatory syndromes has brought to light new mechanisms of action of the venerable gout anti-inflammatory therapeutic colchicine. Specifically, urate crystal–induced NALP3 inflammasome protein complex assembly is suppressed by high concentrations of colchicine, likely by interfering with internalization of urate crystals and thereby inhibiting crystal delivery to the inflammasome.11
Therapeutic studies of autoinflammatory cryopyrinopathies have already provided information of substantial potential value for developing novel and more selective molecular therapeutics for difficult gout inflammation. The responsiveness of familial cold-induced autoinflammatory syndrome, Muckle-Wells syndrome, and neonatal onset multisystem inflammatory disease/chronic infantile neurological cutaneous and articular syndrome to IL-1 receptor antagonism is particularly noteworthy because a preliminary, uncontrolled study of 10 gout patients suggested therapeutic benefit of anakinra. Significantly, experimental gouty inflammation in rodents appears more IL-1b driven than TNF-a driven.12 Further investigation for gouty arthritis is warranted for not only IL-1 inhibitors but also the caspase-1 inhibitors currently under clinical development for osteoarthritis treatment. The ATP-binding function of NALP3 is critical for inflammatory signaling, as is NALP3 leucine-rich repeat domain interaction with the heat shock protein HSP90.17,19 Hence, inflammation in difficult gout could be prime applications of novel therapeutics that selectively target the NALP3 ATP-binding domain or HSP90.17,18
Conclusion
Gout is increasingly common and has become more clinically complex in recent years, particularly in older patients. Clinical development continues for novel, effective hypourecimic agents to counter the limitations of the current generation of universally available primary uric acid–lowering agents for gout (allopurinol and probenecid) in difficult gout. The linkage of gouty inflammation to innate immunity transduced by the NALP3 inflammasome, and the definition of gouty inflammation to be caspase-1 and IL-1b driven (as in familial autoinflammatory cryopyrinopathy syndromes) augur well for novel treatment strategies for gouty inflammation in refractory patients.
