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.

Background By 2050 the worldwide incidence of hip fractures in men is projected to increase by 310%. It has been proposed that this increase will be due, in part, to the number of undiagnosed and untreated cases of osteoporosis in this population. Existing literature suggest that men may be under-screened, and screening recommendations for men lag behind those for women. The aim of this study was to identify the need for screening and appropriate follow up in this population by identifying the number of fractures that preceded screening, and assess whether these patients had appropriate treatment and follow up. Methods A retrospective chart review using the Computerized Patient Record System was performed on 1848 males aged 20-80, who had undergone DEXA scanning at the VA NY Harbor Healthcare System between 2011 and 2016. The primary endpoint for assessment was whether the DEXA scan was ordered in response to a fracture event. Among patients who suffered a fracture, a further assessment was performed to evaluate whether these patients were treated for osteoporosis and whether they suffered subsequent fractures. Time to follow up DEXA was also measured. Data was collected by three investigators using a standardized extraction algorithm. Results 1848 DEXA scans were performed on males from 2011 and 2016, including 485 individuals with a history of fracture. Average age at time of first fracture was 75. The 485 patients were assessed in two groups-those who had DEXA scans ordered in response to a fragility fracture (Group A: N=170) and those who had fractures following their first DEXA (Group B: N=315). In Group A, 30% received treatment for osteoporosis following their fracture and 40% of patients sustained another fracture (46% of the untreated patients and 23% of the treated patients). In Group B, 63% received treatment following the fracture. A further 25% sustained another fracture (13% of the treated patients, and 24% of the untreated patients). 47% of all patients had a follow up DEXA. Conclusion Given the high prevalence of fractures among males without a known history of osteoporosis, there is need for routine screening of this demographic of patients in order to prevent fractures. Fewer than half the patients had a follow up DEXA. Further, our data suggest that appropriate treatment can reduce the risk of subsequent fractures by 50%. We conclude that physicians should be educated on appropriate management of osteoporosis following fractures

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.

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.

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