Faculty Bibliography

Drug discovery and development (DDD) is an interdisciplinary enterprise that spans the translational continuum. Despite DDD's importance, formal training within medical and biomedical schools is lacking. In this tutorial, we outline the current educational landscape in DDD and the growing educational need in this area. Lastly, we describe the Health Innovations and Therapeutics concentration as an example of how to design and implement an educational program in DDD.

Colchicine is an ancient medication that is currently approved for the treatment of gout and FMF. However, colchicine has a wide range of anti-inflammatory activities, and studies indicate that it may be beneficial in a variety of other conditions. This paper reviews the evidence for the well-established use of colchicine in gout, as well as several other rheumatic diseases. In addition, we highlight the potential benefit of colchicine in cardiac disease, including coronary artery disease in patients both with and without gout.

Background: Many, but not all patients with chronic gout develop tophi, and the factors that govern tophus formation are not fully understood. Several studies have suggested impairment of renal function increases the risk for development of tophi, but others have not.
Method(s): This analysis addressed the relationship between estimated glomerular filtration rate (eGFR) and the presence of tophi in patients with chronic refractory gout, as well as effects of tophus resolution on eGFR using results from two randomized controlled trials of pegloticase in chronic gout patients.
Result(s): Overall, 73% of the 212 subjects in these trials had clinically apparent tophi at baseline and 27% did not. Subjects with tophi were significantly older than those without tophi (56.7 vs 51.9 years, P=0.034) and had a significantly longer disease duration (16.3 vs 11.7 years, P=0.0072). Subjects with tophi also had a significantly lower eGFR than those without tophi (59.8 vs 67.9 mL/min/1.73 m2, P=0.0495). Subjects with advanced renal disease were also more likely to have tophi. Persistent serum urate lowering and resolution of tophi in subjects treated with pegloticase had no significant effect on eGFR despite a significant decrease in the urinary uric acid:creatinine ratio.
Conclusion(s): These results indicate that chronic refractory gout patients may present with or without clinically apparent tophi and that there is a significant association between the presence of renal dysfunction measured by eGFR and the frequency with which chronic refractory gout patients manifested tophi. However, persistent serum urate lowering and tophus resolution had no significant effect on eGFR over the period of observation in this group of subjects

Background: Impaired renal function is a recognized comorbidity of gout and gouty tophi may be more frequent in those with renal dysfunction. It is not known however, whether the velocity of resolution of tophi in response to urate lowering therapy is affected by renal insufficiency.
Method(s): This analysis used results from two 6-month randomized controlled trials of pegloticase in patients with chronic refractory gout to address this issue. The velocity of tophus resolution was determined in 18 patients with chronic gout refractory to oral urate lowering therapy who responded to pegloticase administered at a dose of 8 mg every 2 weeks (q2w) with sustained serum urate reductions (<6 mg/dL) over 6 months. eGFR was determined at baseline and after 3 and 6 months of treatment. Tophi were photographed at baseline, 3, 4.5, and 6 months and measured using Computer-Assisted Photographic Evaluation technology. At baseline, the mean area of photographed tophi was 585.8 mm2.
Result(s): Complete resolution of all tophi photographed was achieved by 34.8% of the patients. Using linear regression analysis, the velocity of tophus resolution for all the patients was calculated to be 60.1 mm2 per month. There was no significant relationship between baseline eGFR and velocity of tophus resolution (p=0.5). In addition, there were no significant differences in the velocity of tophus resolution for patients with Stage 1 chronic kidney disease (CKD) vs Stage 2 CKD (P=0.7), Stage 3 CKD (P=0.9), or Stage 4 CKD (P=0.7).
Conclusion(s): The results from this analysis thus indicate that renal impairment does not compromise the ability of pegloticase to resolve tophi rapidly in patients who respond with sustained reductions in serum urate

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