Oxidative stress via uricase-induced hydrogen peroxide generation is another potential concern with enzyme therapy use. Erythrocyte-borne catalase should theoretically be sufficient to degrade circulating hydrogen peroxide generated via typical doses of uricase. Nevertheless, latent vulnerability to oxidative stress with uricase administration is indicated by hemolysis and methemoglobinemia as classic uricase side effects in patients with G6PD deficiency. In my opinion, the primary therapeutic niche for uricase in gout will be limited duration treatment (months) as induction therapy to debulk macroscopic tophi in carefully selected patients with extensive disease refractory to other treatments.
Inflammation in Difficult Gout
Difficult gout includes patients who are intolerant of, or refractory to, standard therapeutic approaches to gouty inflammation: NSAIDs (or alternatively COX-2 selective inhibitors), systemic or intra-articular glucocorticosteroids, adrenocorticotropic hormone (ACTH), or colchicine.7 Clinicians can carefully adjust colchicine doses in line with renal function and employ combinations of low-dose colchicine with other anti-inflammatories to manage some of these subjects with renal or hepatic dysfunction, gastrointestinal comorbidity, poorly controlled diabetes mellitus, age, and post-operative state.7 However, polyarticular gout flares refractory to therapy do occur. A striking example is seen in major organ–transplant recipients receiving cyclosporine who develop severe gouty arthritis despite maintenance low-dose prednisone. Some patients have major gout flares when starting or adjusting uric acid–lowering therapies, including the intensive serum urate–lowering regimens currently under clinical development.
The primary pathologic hallmark of acute gout is neutrophil influx into the joint fluid, consistent with interleukin 1 (IL-1)–induced and tumor necrosis factor-a (TNF-a)–induced activation of endothelium and with tissue generation of neutrophil chemoattractants that drive and sustain the inflammation. Certain molecular mechanisms of action of anti-inflammatory agents used in gout could be exploited for difficult gout. For example, the rapid onset of the therapeutic action of ACTH in gout appears mediated by binding to the melanocortin receptor 3 (MR3) on phagocytes in the periphery. Stimulation of MR3 by itself can suppress experimental gouty inflammation.8 We also know that low-dose prophylactic colchicine prevents gouty inflammation in part by inhibiting redistribution the neutrophil adhesion molecule E-selectin in vascular endothelium.
Primitive Innate Immune Response
Acute gout is a prototype of the primitive innate immune “early induced” response, with the characteristic recurrent, paroxysmal nature of gouty arthritis representing failure of monosodium urate crystals to directly induce durable protective immunity.9 Uptake of both apoptotic neutrophils and urate crystals by resident and recruited “professional phagocytes” mobilizes a rapid effort to quell the inflammation.9,10 The recent elucidation of new molecular biologic mechanisms of gouty inflammation may light the way to novel therapeutics.
