Faculty Bibliography

Gout is a common rheumatic condition, with increasing prevalence in recent decades. The mainstay of treatment for gout is oral urate-lowering therapy (ULT), typically with xanthine oxidase inhibitors (XOIs). Unfortunately, a proportion of patients have persistent gout that is refractory to ULT. Pegloticase, a recombinant pegylated uricase, has been approved by the US Food and Drug Administration for the treatment of refractory gout. However, concern has been raised regarding the risk of infusion reactions, which are now understood to be largely due to the development of antipegloticase antibodies. Discontinuation of pegloticase upon failure to lower serum urate has been shown to markedly reduce infusion reaction risk, but deprives patients of what, in many cases, is a last-resort treatment. In this manuscript, we review the rationale, mechanism of action, efficacy and safety of pegloticase. Additionally, we focus on potential strategies to reduce pegloticase immunogenicity and potentially make this important agent available to a wider group of patients requiring treatment.

PURPOSE OF REVIEW: The complexity of gout continues to unravel with each new investigation. Gout sits at the intersection of multiple intrinsically complex processes, and its prevalence, impact on healthcare costs, and association with important co-morbidities make it increasingly relevant. The association between gout and type 2 diabetes, hypertension, hyperlipidemia, cardiovascular disease, renal disease, and obesity suggest that either gout, or its necessary precursor hyperuricemia, may play an important role in the manifestations of the metabolic syndrome. In this review, we analyze the complex interconnections between gout and metabolic syndrome, by reviewing gout's physiologic and epidemiologic relationships with its major co-morbidities. RECENT FINDINGS: Increasing evidence supports gout's association with metabolic syndrome. More specifically, both human studies and animal models suggest that hyperuricemia may play a role in promoting inflammation, hypertension and cardiovascular disease, adipogenesis and lipogenesis, insulin and glucose dysregulation, and liver disease. Fructose ingestion is associated with increased rates of hypertension, weight gain, impaired glucose tolerance, and dyslipidemia and is a key driver of urate biosynthesis. AMP kinase (AMPK) is a central regulator of processes that tend to mitigate against the metabolic syndrome. Within hepatocytes, leukocytes, and other cells, a fructose/urate metabolic loop drives key inhibitors of AMPK, including AMP deaminase and fructokinase, that may tilt the balance toward metabolic syndrome progression. Preliminary evidence suggests that agents that block the intracellular synthesis of urate may restore AMPK activity and help maintain metabolic homeostasis. Gout is both an inflammatory and a metabolic disease. With further investigation of urate's role, the possibility of proper gout management additionally mitigating metabolic syndrome is an evolving and important question.

Tophaceous gout is painful and impairs quality of life. The optimal modality for assessing tophus resolution in response to urate-lowering treatment remains poorly defined. Using pegloticase as a model system for resolving tophi, we compared multiple imaging and physical diagnostic strategies for assessing tophus resolution. A 32-year-old subject with chronic refractory tophaceous gout was enrolled and received 6 months of pegloticase treatment. Measurements of tophi using vernier calipers (monthly), photographs and musculoskeletal ultrasound (MSK-US; every 3 months), and dual-energy CT (DECT) were compared. Pegloticase persistently lowered the patient's sUA to <0.5 mg/dl. After 6 months, caliper measurements revealed 73, 60, and 61% reductions of three index tophi, while MSK-US revealed 47, 65, and 48% reductions. In contrast, DECT revealed 100% resolution of monosodium urate deposition in all three index tophi, and resolution or improvement of all other tophi identified. On caliper and MSK-US measurement, index tophus size fluctuated, with some lesions enlarging before ultimately contracting. Correlation between assessment modalities during tophus resolution may be poor. DECT identifies urate deposits invisible to physical exam and reveals that some urate deposits completely resolve even as their physically/sonographically measurable lesions persist. Recognition of urate resorption during the urate-lowering process may be confounded by fluctuating lesion volumes during initial tophus breakdown. While DECT was superior for identifying total (including occult) urate deposition, and assessing volume of deposits, other modalities may permit better assessment of non-urate tophus components.

Gout is the most common crystal arthropathy and the leading cause of inflammatory arthritis. It is associated with functional impairment and, for many, a diminished health-related quality of life. Numerous studies have demonstrated the impact of gout and its associated conditions on patient morbidity and mortality. Unfortunately, gout remains under-diagnosed and under-treated in the general community. Despite major advances in treatment strategies, as many as 90% of patients with gout are poorly controlled or improperly managed and their hyperuricemia and recurrent flares continue. The introduction of novel urate-lowering therapies, new imaging modalities, and a deeper understanding of the pathogenesis of gout raise the possibility of better gout care and improved patient outcomes. Here, we spotlight recent advances in the diagnosis and management of gout and discuss novel therapeutics in gout treatment.

BACKGROUND: To characterize the differences between women and men with gout. METHODS: We analyzed a US national cohort of gout patients cared for by rheumatologists. RESULTS: Compared with the 1012 men with gout, women with gout (n = 262) were older (71 vs. 61 years, p < 0.001) and had a greater burden of comorbid conditions (p < 0.001 for hypertension, diabetes, renal disease and obesity). Risk factors for gout differed with women more often taking diuretics (p < 0.001), while men more frequently had dietary triggers (p < 0.05). CONCLUSIONS: The profiles of women and men with gout are markedly different, suggesting a need to tailor treatment recommendations.

OBJECTIVE: OA pathogenesis includes both mechanical and inflammatory features. Studies have implicated synovial fluid urate (UA) as a potential OA biomarker, possibly reflecting chondrocyte damage. Whether serum urate (sUA) levels reflect/contribute to OA is unknown. We investigated whether sUA predicts OA progression in a non-gout knee OA population. METHODS: Eighty-eight subjects with medial knee OA (BMI <33) but without gout were included. Baseline sUA was measured in previously banked serum. At 0 and 24 months, subjects underwent standardized weight-bearing fixed-flexion posteroanterior knee radiographs to determine joint space width (JSW) and Kellgren-Lawrence (KL) grades. Joint space narrowing (JSN) was determined as JSW change from 0 to 24 months. Twenty-seven subjects underwent baseline contrast-enhanced 3T knee MRI for synovial volume (SV) assessment. RESULTS: sUA correlated with JSN in both univariate (r=0.40, p/=6.8; JSN of 0.31 mm for sUA<6.8, p<0.01). Baseline sUA distinguished progressors (JSN>0.2mm) and fast progressors (JSN>0.5mm) from nonprogressors (JSN