Faculty Bibliography

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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BACKGROUND:Patients with aortic stenosis are nearly twice as likely to have a diagnosis of gout compared with individuals without aortic valve disease. METHODS:, and/or decrease in left ventricular ejection fraction due to aortic stenosis. RESULTS:/year [-0.16, -0.01], p=0.09); annualized change in peak velocity and mean gradient did not differ between groups. CONCLUSIONS:Progression to severe aortic stenosis was more frequent in patients with gout versus those without gout supporting the hypothesis that gout is a risk factor for aortic stenosis.

Systemic lupus erythematosus (SLE) is a chronic, multiorgan, systemic autoimmune disease that is more common in women than men and is typically diagnosed during reproductive age, necessitating sex-specific considerations in care. In women there is no substantive evidence to suggest that SLE reduces fertility, but subfertility may occur as a result of active disease, immunosuppressive drugs, and age-related declines in fertility related to delays in childbearing. Although pregnancy outcomes have improved, SLE still poses risks in pregnancy that contribute to poorer maternal and fetal outcomes. Cyclophosphamide, an important agent for the treatment of severe or life-threatening lupus, may adversely affect fertility, particularly with increases in dose and patient age. Fertility preservation techniques are therefore an important consideration for women and men before cytotoxic treatment. There is mixed evidence as to whether exogenous estrogen in the form of oral contraceptive pills or hormone replacement therapy may increase the risk for the development of SLE, but among women with SLE already diagnosed, combined oral contraceptive pills and hormone replacement therapy do not confer risk for severe flare and remain important in reproductive care. The higher incidence of SLE in women may nonetheless be attributable to effects of endogenous estrogen, as well as failures in X chromosome inactivation, increased Toll-like receptor gene products, and changes in microRNA function. A greater appreciation of the biological underpinnings and consequences of sex differences in SLE may lead to more targeted treatments and improved outcomes for patients with SLE.

PURPOSE OF REVIEW/OBJECTIVE:Hyperuricemia is highly prevalent, affecting approximately 38 million individuals in the United States. However, the significance of asymptomatic hyperuricemia - hyperuricemia in the absence of gout - continues to be debated. RECENT FINDINGS/RESULTS:Asymptomatic hyperuricemia results in monosodium urate crystal deposition in tissues, which may promote chronic inflammation. Intracellularly, hyperuricemia inhibits the master regulator adenosine monophosphate (AMP)-associated protein kinase and may condition innate immune responses through durable epigenetic modifications. At the population level, asymptomatic hyperuricemia is associated with multiple comorbidities, including hypertension, chronic kidney disease, coronary artery disease, and diabetes; limitations of these studies include that most are retrospective and some do not rigorously distinguish between asymptomatic hyperuricemia and gout. Treatment studies suggest that urate lowering may reduce the risk of incidence or progression of some of these comorbidities; unfortunately, many of these treatment studies are small or flawed, and not all study results are consistent. SUMMARY/CONCLUSIONS:Accumulating evidence suggests that asymptomatic hyperuricemia contributes to the comorbidities with which it associates and that proper asymptomatic hyperuricemia treatment may reduce future risk. Additional prospective trials are needed to definitely establish causality and support decision-making as to whether, and which patients with asymptomatic hyperuricemia would warrant urate-lowering treatment.

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.

Background/Purpose : Gout is a very prevalent condition associated with many metabolic and cardiorenal comorbidities. A few studies have investigated the comorbidity subtypes of gout patients by cluster analyses; however, such analyses have not yet been performed among Blacks nor confirmed in a general population cohort. As such the generalizability of these findings remains unknown. Thus, our objective was to identify gout subtypes based on comorbidities using cluster analysis among Black adults with gout in the US general population. Furthermore, we sought to compare these findings to that of White adults with gout. Methods : We used data from 371 Black and 656 White participants in the 2007-2016 cycle of the National Health and Nutrition Examination Survey (NHANES), a nationally representative sample of adults in the US with detailed clinical and physical examination data. Diagnosis of gout was based on survey of physician-or health professionaldiagnosed gout. We employed Ward's minimum variance method of clustering to group patients with gout into clusters (i.e., subtypes) based on distinct comorbidity patterns according to 8 variables: obesity, hypertension, diabetes, dyslipidemia (i.e., hypercholesterolemia and/or hypertriglyceridemia), coronary heart disease (CHD), heart failure (HF), chronic kidney disease (CKD), and non-alcoholic fatty liver disease (NAFLD). Results : Metabolic and cardiorenal comorbidities were prevalent among both Black and White participants with gout ( Table 1 ). Cluster analysis identified 5 comorbidity subgroups among Black patients with gout ( Table 2 ). All patients in Group 1 had dyslipidemia and hypertension. Group 2 had the highest proportion of patients with diabetes (95%), and nearly all patients with NAFLD belonged to this group. Group 3 consisted of patients with gout but few other comorbidities. All patients in Group 4 had CKD. Group 5 had the highest proportion of patients with CHD and HF. Cluster analysis among Whites also identified subgroups with isolated gout (Group 2) and dyslipidemia and hypertension (Group 1) ( Table 3 ). It also identified a subgroup that combined cardiac and renal disease (Group 5). Key differences among Whites was the presence of obese (Group 3) and hypertension only (Group 4) clusters, and the lack of a diabetes group. The higher prevalence of obesity in Blacks and the smaller number of Black participants likely contributed to these differences. Conclusion : These findings from a nationally representative sample of Black US adults identified 5 subgroups of gout based on comorbidities: dyslipidemia/HTN, diabetes, isolated gout, CKD, and heart disease. Notable differences from the European population and American White cohorts included the separation of CKD and cardiac disease and the absence of a group defined by obesity among US Blacks. Overall, these subgroups could be broadly classified as i) isolated gout, ii) dyslipidemia/hypertension, iii) obese or diabetes, and iv) cardiorenal disease (separately or together). These subgroups may shed light on pathophysiologic mechanisms that contribute to gout and have implications for personalized interventions to reduce the burden of gout and its comorbidities