Faculty Bibliography

To assess the impact of allopurinol on diabetes in a retrospective cohort of Veterans' Affairs patients with gout.The New York Harbor VA computerized patient record system was searched to identify patients with an ICD-9 code for gout meeting at least 4 modified 1977 American Rheumatology Association gout diagnostic criteria. Patients were divided into subgroups based on >30 continuous days of allopurinol, versus no allopurinol. New diagnoses of diabetes, defined according to American Diabetes Association diagnostic criteria or clinical documentation explicitly stating a new diagnosis of diabetes, were identified during an observation period from January 1, 2000 through December 31, 2015.Six hundred six gout patients used allopurinol >30 continuous days, and 478 patients never used allopurinol. Over an average 7.9 ± 4.8 years of follow-up, there was no significant difference in diabetes incidence between the allopurinol and non-allopurinol groups (11.7/1000 person-years vs 10.0/1000 person-years, P = .27). A lower diabetes incidence in the longest versus shortest quartiles of allopurinol use (6.3 per 1000 person-years vs 19.4 per 1000 person-years, P<.0001) was attributable to longer duration of medical follow-up.In this study, allopurinol use was not associated with decreased diabetes incidence. Prospective studies may further elucidate the relationship between hyperuricemia, gout, xanthine oxidase activity, and diabetes, and the potential impact of gout treatments on diabetes incidence.

The coronavirus disease 2019 (COVID-19) pandemic presents an unprecedented challenge and opportunity for translational investigators to rapidly develop safe and effective therapeutic interventions. Greater risk of severe disease in COVID-19 patients with comorbid diabetes mellitus, obesity, and heart disease may be attributable to synergistic activation of vascular inflammation pathways associated with both COVID-19 and cardiometabolic disease. This mechanistic link provides a scientific framework for translational studies of drugs developed for treatment of cardiometabolic disease as novel therapeutic interventions to mitigate inflammation and improve outcomes in patients with COVID-19.

BACKGROUND:Patients with gout have arterial dysfunction and systemic inflammation, even during intercritical episodes, which may be markers of future adverse cardiovascular outcomes. We conducted a prospective observational study to assess whether initiating guideline-concordant gout therapy with colchicine and a urate-lowering xanthine oxidase inhibitor (XOI) improves arterial function and reduces inflammation. METHODS:Thirty-eight untreated gout patients meeting American College of Rheumatology (ACR)/European League Against Rheumatism classification criteria for gout and ACR guidelines for initiating urate-lowering therapy (ULT) received colchicine (0.6 mg twice daily, or once daily for tolerance) and an XOI (allopurinol or febuxostat) titrated to ACR guideline-defined serum urate (sU) target. Treatment was begun during intercritical periods. The initiation of colchicine and XOI was staggered to permit assessment of a potential independent effect of colchicine. Brachial artery flow-mediated dilation (FMD) and nitrate-mediated dilation (NMD) assessed endothelium-dependent and endothelium-independent (smooth muscle) arterial responsiveness, respectively. High-sensitivity C-reactive protein (hsCRP), IL-1β, IL-6, myeloperoxidase (MPO) concentrations, and erythrocyte sedimentation rate (ESR) assessed systemic inflammation. RESULTS:Four weeks after achieving target sU concentration on colchicine plus an XOI, FMD was significantly improved (58% increase, p = 0.03). hsCRP, ESR, IL-1β, and IL-6 also all significantly improved (30%, 27%, 19.5%, and 18.8% decrease respectively; all p ≤ 0.03). Prior to addition of XOI, treatment with colchicine alone resulted in smaller numerical improvements in FMD, hsCRP, and ESR (20.7%, 8.9%, 13% reductions, respectively; all non-significant), but not IL-1β or IL-6. MPO and NMD did not change with therapy. We observed a moderate inverse correlation between hsCRP concentration and FMD responsiveness (R = - 0.41, p = 0.01). Subgroup analyses demonstrated improvement in FMD after achieving target sU concentration in patients without but not with established cardiovascular risk factors and comorbidities, particularly hypertension and hyperlipidemia. CONCLUSIONS:Initiating guideline-concordant gout treatment reduces intercritical systemic inflammation and improves endothelial-dependent arterial function, particularly in patients without established cardiovascular comorbidities.

Gout is a disease in which the metabolic condition hyperuricemia leads to the formation of monosodium urate crystals, which provoke acute and chronic inflammatory responses through activation of the innate immune system. Recent advances in our knowledge of gout pathogenesis have emphasized the role of the kidneys in urate handling, the evolutionary loss of uricase as a necessary precondition for hyperuricemia, and the central role of IL-1ß in the pathogenesis of gouty inflammation. These, and other advances, have shaped our current strategies for managing gout. Here, we review the most current, evidence-based gout management approaches, including treating acute flares, addressing gout through the long-term regulation of serum urate, and prophylaxis against gouty flares during urate lowering.

OBJECTIVE:To provide guidance for the management of gout, including indications for and optimal use of urate-lowering therapy (ULT), treatment of gout flares, and lifestyle and other medication recommendations. METHODS:Fifty-seven population, intervention, comparator, and outcomes questions were developed, followed by a systematic literature review, including network meta-analyses with ratings of the available evidence according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology, and patient input. A group consensus process was used to compose the final recommendations and grade their strength as strong or conditional. RESULTS:Forty-two recommendations (including 16 strong recommendations) were generated. Strong recommendations included initiation of ULT for all patients with tophaceous gout, radiographic damage due to gout, or frequent gout flares; allopurinol as the preferred first-line ULT, including for those with moderate-to-severe chronic kidney disease (CKD; stage >3); using a low starting dose of allopurinol (≤100 mg/day, and lower in CKD) or febuxostat (<40 mg/day); and a treat-to-target management strategy with ULT dose titration guided by serial serum urate (SU) measurements, with an SU target of <6 mg/dl. When initiating ULT, concomitant antiinflammatory prophylaxis therapy for a duration of at least 3-6 months was strongly recommended. For management of gout flares, colchicine, nonsteroidal antiinflammatory drugs, or glucocorticoids (oral, intraarticular, or intramuscular) were strongly recommended. CONCLUSION/CONCLUSIONS:Using GRADE methodology and informed by a consensus process based on evidence from the current literature and patient preferences, this guideline provides direction for clinicians and patients making decisions on the management of gout.

OBJECTIVE:To provide guidance for the management of gout, including indications for and optimal use of urate-lowering therapy (ULT), treatment of gout flares, and lifestyle and other medication recommendations. METHODS:Fifty-seven population, intervention, comparator, and outcomes questions were developed, followed by a systematic literature review, including network meta-analyses with ratings of the available evidence according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology, and patient input. A group consensus process was used to compose the final recommendations and grade their strength as strong or conditional. RESULTS:Forty-two recommendations (including 16 strong recommendations) were generated. Strong recommendations included initiation of ULT for all patients with tophaceous gout, radiographic damage due to gout, or frequent gout flares; allopurinol as the preferred first-line ULT, including for those with moderate-to-severe chronic kidney disease (CKD; stage >3); using a low starting dose of allopurinol (≤100 mg/day, and lower in CKD) or febuxostat (<40 mg/day); and a treat-to-target management strategy with ULT dose titration guided by serial serum urate (SU) measurements, with an SU target of <6 mg/dl. When initiating ULT, concomitant antiinflammatory prophylaxis therapy for a duration of at least 3-6 months was strongly recommended. For management of gout flares, colchicine, nonsteroidal antiinflammatory drugs, or glucocorticoids (oral, intraarticular, or intramuscular) were strongly recommended. CONCLUSION/CONCLUSIONS:Using GRADE methodology and informed by a consensus process based on evidence from the current literature and patient preferences, this guideline provides direction for clinicians and patients making decisions on the management of gout.

BACKGROUND:Vascular injury and inflammation during percutaneous coronary intervention (PCI) are associated with increased risk of post-PCI adverse outcomes. Colchicine decreases neutrophil recruitment to sites of vascular injury. The anti-inflammatory effects of acute colchicine administration before PCI on subsequent myocardial injury are unknown. METHODS:In a prospective, single-site trial, subjects referred for possible PCI (n=714) were randomized to acute preprocedural oral administration of colchicine 1.8 mg or placebo. RESULTS:=0.001). CONCLUSIONS:Acute preprocedural administration of colchicine attenuated the increase in interleukin-6 and high-sensitivity C-reactive protein concentrations after PCI when compared with placebo but did not lower the risk of PCI-related myocardial injury. Registration: URL: https://www.clinicaltrials.gov; Unique Identifiers: NCT02594111, NCT01709981.

Purpose: Current treatments for osteoarthritis (OA) remain inadequate. Accumulating evidence suggests that OA is an inflammatory disease, with a particular role for interleukin-1beta (IL-1beta) a product of the NLRP3 inflammasome. Additionally, both calcium and urate crystals have been suggested to play potential roles in OA and both are recognized to activate the NLRP3 inflammasome to produce IL-1beta. Colchicine is an ancient and well-tolerated anti-inflammatory agent and has recently been shown to inhibit inflammasome activation and IL-1beta generation. Several studies have examined the impact of colchicine on various aspects of OA, with varying Results. We are assessing the potential benefits of colchicine on several short-term features of knee OA.
Method(s): The CLOAK (CoLchicine for treatment of OsteoArthritis of the Knee) study is a randomized, double-blind, placebo-controlled trial of colchicine (0.8 mgs daily) for 90 days. (Figure 1). We are identifying patients as they are seen in the rheumatology clinics, as well as calling patients from our knee OA database of prior studies. The recruitment goal is to enroll 120 subjects at least 50 years of age who have symptomatic knee OA with radiographic confirmation (Kellgren-Lawrence grade 2 or 3), and who are willing to forego other anti-inflammatory therapy (i.e., topical or oral NSAID and/or intraarticular steroids or hyaluronic acid) during the trial. The primary clinical outcome is the difference between treatment and placebo groups in pain improvement by visual analog scale, along with changes in the Knee Injury and Osteoarthritis Outcome Score (KOOS) and mean doses of analgesics used. Inflammatory outcomes between the two groups include changes in plasma inflammatory markers (such as hsCRP, PGE2, and IL-1Ra) and peripheral blood leukocyte genomic studies. All patients are scanned by knee ultrasound pre- and post-treatment, with assessment for synovitis and effusion. We also aspirate synovial fluid when appropriate, and will analyze all available samples together for inflammatory markers.
Result(s): To date, 78 patients have been contacted or approached, 18 screened, and 17 enrolled. Six have completed the study, with a mean BMI of 30.3. All 6 remain blinded as to study group; however, the mean VAS pain score among the group decreased by 1.7 in the index knee (which had greater pain at baseline), while the mean KOOS scores for symptoms, pain, activities of daily living, sports activity, quality of life and KOOS global all improved. Individually, 4 of the 6 completing subjects demonstrated VAS score improvement with 2 of 6 demonstrating worsening, a pattern that was duplicated in most of the KOOS scores.
Conclusion(s): The CLOAK trial is testing the potential benefit of colchicine on pain and inflammation in knee OA, specifically in patients with moderate radiographic disease who are not taking other anti-inflammatory agents. Supported by an investigator-initiated grant from Hikma Pharmaceuticals. [Formula presented]
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OBJECTIVE:Assess clinical benefit in patients with chronic refractory gout who did not meet the protocol-defined criteria of responders to pegloticase. METHODS:This analysis used results from two randomized controlled trials (RCTs) to assess the clinical efficacy in responders and nonresponders to treatment (8 mg of pegloticase every 2 weeks [q2w]). Serum urate was measured before each infusion and the following were measured: assessment of gout flares, tophus reduction, Patient Global Assessment (PGA), tender and swollen joints (TJC and SJC), pain measured with a 100-mm visual analog scale (VAS) and a variety of patient reported outcomes (36-Item Short Form Health Survey (SF-36) Physical Component Score [PCS] and Arthritis-Specific Health Index Score [ASHIS]). RESULTS:The analysis included 36 persistent urate responders, 49 nonresponders, and 43 patients who received placebo. Results for both responders and nonresponders indicated significant reduction in tophi and improvements from baseline in PGA, TJC, SJC, pain, and ASHIS. No significant improvements were observed in the patients who received placebo. CONCLUSION/CONCLUSIONS:Chronic refractory gout patients not achieving protocol-defined persistent urate lowering still achieve significant clinical benefits with pegloticase treatment, suggesting that transient reduction in serum urate may result in sustained clinical benefit.