Recognizing epidemiologic associations between external or biological factors and disease behavior, in this case newly diagnosed gout, poses the possibility of influencing the disease course by reducing associated risk factors. But (and it is a big but) this is likely true only if the recognized associated risk factor is causative.
There is no question in my mind that the management of gout is suboptimal, despite the fact that we have a solid understanding of its pathophysiology, as well as the tools to control hyperuricemia, the root cause, to a degree above the saturation of serum urate of approximately 6.8 mg/dL. The presence of hyperuricemia, and hence of gout, is linked to all components of the metabolic syndrome, as well as to chronic kidney disease.
As yet, there are minimal data that reducing these associated risk factors will reduce hyperuricemia and gout, although I suspect that patients undergoing successful bariatric surgery may experience benefit. At present, we have stronger suggestive data — mostly observational in nature — that treating hyperuricemia may reduce progression of CKD and affect other comorbidities.
Associated risk factors like obesity and hypertension may increase the risk for incident gout by several fold. However, for perspective, across the spectrum of serum urate levels from < 6 mg/dL to > 10 mg/dL, the incident gout rate over 10 years ranges from 0.8% to 40%; yet, for studied patients with a serum urate > 10 mg/dL, only 50% develop incident gout at 15 years. While we can identify risk factors associated with the development of gout, it is not clear to me that their identification warrants any clinical interdiction for the sole goal of preventing an initial gout attack — this would be very inefficient. That said, there are obviously many other health reasons to treat identified gout comorbidities including hypertension, obesity, sleep apnea and insulin resistance/diabetes.
We need to be mindful of the many inter-relationships between the comorbidities that associate with gout. Hypertension may be initiated or influenced in some patients by hyperuricemia, and once established, the hypertension can reduce kidney function and is often treated with a thiazide class antihypertensive — both of which can increase the serum urate. However, this should not drive clinicians to stop using thiazides in patients who are successfully responding to their use with lowered blood pressure simply for the sake of lowering the serum urate by likely 1 mg/dL or less. More to the point — and this goes back to my belief that gout is suboptimally managed — is that clinicians need to make the decision as to who with gout needs to receive urate-lowering therapy, which may be influenced by the presence of comorbidities.
Once the decision to treat with urate-lowering therapy is made, the serum urate level must be monitored to assure that urate level is reached and maintained; this should be performed in the same way that the blood pressure is monitored after initiating antihypertensive therapy: Intensely at first, then at longer intervals unless there are clinical changes that warrant the return to more intense monitoring. We know that tophi will dissolve at a rate that is inverse to the serum urate level. If the therapy is stopped and the urate is allowed to rise again to > 6.8 mg/dL, deposits and tophi will begin to form and grow again. We do not understand to the same degree the relationship between serum urate and the metabolic comorbidities.
As our understanding of the comorbidities associated with gout continues to grow, hopefully we will learn more about the nature of the associations: Which comorbidities are causative for hyperuricemia and/or gout attacks and what are the reciprocal effects of manipulating the serum urate and the comorbidities?
In the meantime, for patients with hyperuricemia who need to have their gout treated, let’s be attentive to lowering their serum urate to a level which will dissolve the uric acid deposits and ultimately cease attacks completely, even without prophylactic anti-inflammatory medication. As for those patients without gout who have comorbidities associated with incident gout and hyperuricemia, let’s hope that clinical investigation will provide us with the tools to identify which patients — if any — should leave our offices with a prescription for urate-lowering therapy as well as the hackneyed admonition to lose weight and exercise more.
Brian F. Mandell, MD, PhD
Professor and chairman of academic medicine
Cleveland Clinic Lerner College of Medicine
Department of rheumatic and immunologic disease
Center for Vasculitis Care and Research
Disclosures: Mandell reports consulting for Horizon and Ironwood pharmaceuticals; being a clinical investigator for Horizon; and being the editor of rheumatology and immunology for The Merck Manual (no product association).