Faculty Bibliography

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.

BACKGROUND/OBJECTIVE/OBJECTIVE:The connection between gout and various cancers remains unclear. We assessed the relationship between gout and colorectal cancer in a population of veterans. METHODS:We reviewed the Computerized Patient Record System of the VA New York Harbor Health Care System to assess the 10-year occurrence of colorectal cancer in patients with gout undergoing colonoscopy, versus patients with osteoarthritis but no gout. RESULTS:Gout and osteoarthritis subjects were similar in age, ethnicity, body mass index, and smoking history. Among 581 gout and 598 osteoarthritis subjects with documented colonoscopies, the 10-year prevalence of colorectal cancer was significantly lower in gout (0.8%) versus osteoarthritis (3.7%) (p = 0.0008) patients. Differences in colorectal cancer rates remained significant after stratifying for nonsteroidal anti-inflammatory drug use. Among gout subjects, use of colchicine and/or allopurinol, as well as the presence/absence of concomitant osteoarthritis, did not influence colorectal cancer occurrence. On subanalysis, differences in colorectal cancer occurrence between gout and osteoarthritis subjects persisted among those who underwent diagnostic (0.5% in gout vs 4.6% in osteoarthritis subjects, p < 0.001) but not screening (0.9% in gout subjects vs 1% in osteoarthritis subjects, p = 1.0) colonoscopy. There was no significant difference in nonmalignant colorectal polyp occurrence between gout and osteoarthritis subjects. CONCLUSIONS:Subjects with gout had decreased colonoscopy-documented occurrence of colorectal cancer compared with osteoarthritis subjects, suggesting a possible protective effect.

OBJECTIVE:There is a lack of standardisation in the terminology used to describe gout. The aim of this project was to develop a consensus statement describing the recommended nomenclature for disease states of gout. METHODS:A content analysis of gout-related articles from rheumatology and general internal medicine journals published over a 5-year period identified potential disease states and the labels commonly assigned to them. Based on these findings, experts in gout were invited to participate in a Delphi exercise and face-to-face consensus meeting to reach agreement on disease state labels and definitions. RESULTS:The content analysis identified 13 unique disease states and a total of 63 unique labels. The Delphi exercise (n=76 respondents) and face-to-face meeting (n=35 attendees) established consensus agreement for eight disease state labels and definitions. The agreed labels were as follows: 'asymptomatic hyperuricaemia', 'asymptomatic monosodium urate crystal deposition', 'asymptomatic hyperuricaemia with monosodium urate crystal deposition', 'gout', 'tophaceous gout', 'erosive gout', 'first gout flare' and 'recurrent gout flares'. There was consensus agreement that the label 'gout' should be restricted to current or prior clinically evident disease caused by monosodium urate crystal deposition (gout flare, chronic gouty arthritis or subcutaneous tophus). CONCLUSION/CONCLUSIONS:Consensus agreement has been established for the labels and definitions of eight gout disease states, including 'gout' itself. The Gout, Hyperuricaemia and Crystal-Associated Disease Network recommends the use of these labels when describing disease states of gout in research and clinical practice.

Background/Purpose : Several studies implicate gout and/or xanthine oxidase activity as risk factors for type 2 diabetes. However, no studies have directly evaluated the effect of the xanthine oxidase inhibition on type 2 diabetes development. We therefore assessed the impact of allopurinol use on diabetes incidence in a retrospective cohort study of Veterans' Affairs patients with gout. Methods : The New York Harbor VA Computerized Patient Record System was searched to identify patients with an ICD-9 code for gout also meeting at least 4 1977 American Rheumatology Association gout diagnostic criteria. Pharmacy records were reviewed, and subjects divided into subgroups based on >30 continuous days of allopurinol prescription, versus no allopurinol. Incident diagnoses of diabetes, defined as first hemoglobin A1c <= 6.5% or physician documentation, were identified during an observation period from January 1, 2000 through December 31, 2015. Categorical variables, including the primary endpoint, were analyzed utilizing Fisher's exact test. Continuous variables were analyzed using binomial regression and the Student's T test. Results : 1032 subjects were allopurinol users, and 485 subjects were allopurinol never-users. The average duration of allopurinol use was 48.4 months. There were significantly more Black subjects in the allopurinol group, whereas there were significantly more Asian subjects and subjects with chronic kidney disease in the non-allopurinol group. Over a mean 94.3 months of follow-up, there was no significant difference in diabetes incidence between the allopurinol and non-allopurinol groups (8.0/1000 person-years versus 11.3/1000 person-years, p=0.64). There was also no significant difference in diabetes incidence when subjects were analyzed by baseline serum urate level, colchicine use, allopurinol dose, extent of urate lowering with allopurinol or achieving target urate level. When stratified into quartiles by duration of allopurinol use, a significant difference was observed between diabetes incidence in the longest and shortest quartiles among subjects in the allopurinol cohort (7.3 per 1000 person-years versus 21.3 per 1000 person-years, p=0.007). Conclusion : In this study, allopurinol use was overall not associated with reduced diabetes incidence, but longer durations of allopurinol use may have been associated with decreased diabetes. 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. (Figure Presented )

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

Hyperuricemia is a common condition, and in a subset of patients leads to gout, the most common inflammatory arthritis. Osteoarthritis is the most common form of arthritis overall, and gout and osteoarthritis frequently coexist in the same patient. However, the relationship between the two remains poorly defined. More particularly, the impact of osteoarthritis on the development of gout, and the impact of gout on the development of osteoarthritis, remain to be determined. Additionally, whether hyperuricemia mediates osteoarthritis in the absence of gout is uncertain. Here, we review the evidence linking gout and osteoarthritis, with a special focus on the role of hyperuricemia in the presence or absence of gout. Since disease modifying agents are currently available for hyperuricemia and gout but not for osteoarthritis, a contributory role for urate in the pathogenesis of osteoarthritis could have important clinical implications.