Investigating gout flares: beyond a definition.

PURPOSE OF REVIEW: Gout flares are a paramount component of disease burden inflicted by gout onto the patient. Furthermore, they are included in the core domain set for long-term gout studies recognized by Outcome Measures in Rheumatology. Along with a validated classification criterion for gout, gout investigators have turned their efforts into defining and characterizing the gout flare. This brief review will summarize the efforts that have been done to define and characterize a gout flare in clinical studies. RECENT FINDINGS: Recent findings include a validated definition of a gout flare that has been utilized in novel clinical studies, use of technology to monitor for gout flares and their effects on patient life, and qualitative analyses into the disease burden that a patient undergoes. SUMMARY: Although guidelines for core outcome domains have been well established, there is question in methods of measuring and reporting gout flares in long-term trials. Furthermore, there is question as to the effectiveness of the agreed upon instruments' abilities to fully capture the disease burden experienced by patients with gout. A combination of outcome measurements including binary data (gout flare present or absent) along with a comprehensive measurement of disease burden over time would theoretically provide a more accurate description of the disease and serve as a basis for intervention development.

In knee OA, PT vs. glucocorticoid injections had an incremental cost-effectiveness ratio of $35 527/QALY gained.

SOURCE CITATION: Rhon DI, Kim M, Asche CV, et al. Cost-effectiveness of physical therapy vs intra-articular glucocorticoid injection for knee osteoarthritis: a secondary analysis from a randomized clinical trial. JAMA Netw Open. 2022;5:e2142709. 35072722.

Rituximab in ANCA-Associated Vasculitis.

PURPOSE OF REVIEW: The purpose of this review is to describe the efficacy and safety of rituximab (RTX) as a remission induction and maintenance therapy in ANCA-associated vasculitis (AAV). RECENT FINDINGS: A PubMed search was carried out to track down articles published between February 2006 and February 2016. Randomized controlled trials (RCTs) that encompassed patients with AAV were included. The American College of Rheumatology (ACR) and the European League against Rheumatism (EULAR) 2014-2015 online abstracts were also reviewed whether they were RTCs or not. Ten PubMed RCTs were analyzed along with eight ACR and four EULAR abstracts. RTX was not inferior to cyclophosphamide (CYC) for remission induction in AAV; it was superior to CYC in patients with relapsing disease and superior for remission maintenance in comparison with azathioprine (AZA). Rituximab is a therapeutic option to induce and maintain remission in patients with AAV.

Vascular calcifications on hand radiographs in rheumatoid arthritis and associations with autoantibodies, cardiovascular risk factors and mortality.

OBJECTIVE: To examine whether vascular calcifications on hand films in RA might aid in determining mortality risk. METHODS: Hand radiographs from 906 RA patients were scored as positive or negative for vascular calcifications. Patient characteristics associated with vascular calcifications were assessed using multivariable logistic regression, and associations with mortality were examined using Cox proportional hazards regression. Cytokines and multiplex ACPA were measured in both groups. RESULTS: A total of 99 patients (11%) demonstrated radiographic vascular calcifications. Factors independently associated with vascular calcifications included diabetes [odds ratio (OR) 2.85; 95% CI 1.43, 5.66], cardiovascular disease at enrolment (OR 2.48; 95% CI 1.01, 6.09), prednisone use (OR 1.90; 95% CI 1.25, 2.91), current smoking (OR 0.06; 95% CI 0.01, 0.23) and former smoking (OR 0.36; 95% CI 0.27, 0.48) vs never smoking. In cytokine and ACPA subtype analysis, IL-4 and anti-citrullinated apolipoprotein E were significantly increased in patients with vascular calcifications in fully adjusted multivariable models. After multivariable adjustment, vascular calcifications were associated with an increase in all-cause mortality (hazard ratio 1.41; 95% CI 1.12, 1.78; P = 0.004). CONCLUSION: Vascular calcifications on hand radiographs were independently associated with increased all-cause mortality in RA. Mechanisms underpinning the associations of IL-4 and select ACPA with vascular calcifications and their utility as biomarkers predictive of cardiovascular disease risk in RA merit further study.

A qualitative assessment of internal medicine resident perceptions of graduate medical education following implementation of the 2011 ACGME duty hour standards.

BACKGROUND: In 2011, the Accreditation Council of Graduate Medical Education implemented updated guidelines for medical resident duty hours, further limiting continuous work hours for first-year residents. We sought to investigate the impact of these restrictions on graduate medical education among internal medicine residents. METHODS: We conducted eight focus groups with internal medicine residents at the University of Alabama at Birmingham in 06/2012-07/2012. Discussion questions included, "How do you feel the 2011 ACGME work hour restrictions have impacted your graduate medical education?" Transcripts of the focus groups were reviewed and themes identified using a deductive/inductive approach. Participants completed a survey to collect demographic information and future practice plans. RESULTS: Thirty-four residents participated in our focus groups. Five themes emerged: decreased teaching, decreased experiential learning, shift-work mentality, tension between residency classes, and benefits and opportunities. Residents reported that since implementation of the guidelines, teaching was often deferred to complete patient-care tasks. Residents voiced concern that PGY-1 s were not receiving adequate clinical experience and that procedural and clinical reasoning skills are being negatively impacted. PGY-1 s reported being well-rested and having increased time for independent study. CONCLUSIONS: Residents noted a decline in teaching and are concerned with the decrease in "hands-on" clinical education that is inevitably impacted by fewer hours in the hospital, though some benefits were also reported. Future studies are needed to further elucidate the impact of decreased resident work hours on graduate medical education.

Vitamin B12 status and hyperhomocysteinemia in patients with Rheumatoid arthritis treated with methotrexate and folic acid.

BACKGROUND: Rheumatoid arthritis (RA) is an inflammatory arthritis in which the immune system targets synovial joints. Methotrexate serves as the mainstay of treatment for RA due to its efficacy. However, patients treated with methotrexate are uniquely at risk for vitamin B12 deficiency and hyperhomocysteinemia due to coincident disease risk factors and the fact that methotrexate use is associated with malabsorption. The objective of this study was to assess for vitamin B12 deficiency among patients with RA treated with methotrexate and folic acid. METHODS: This cross-sectional study included 50 patients with RA treated with methotrexate and folic acid and 49 patients with RA treated with other therapies. Patients were matched by age, sex, race, renal function, and disease activity. We compared plasma vitamin B12, methylmalonic acid, and homocysteine levels between these two groups utilizing quantitative and categorical analyses. RESULTS: Thirty-seven (74%) RA patients on methotrexate and folic acid had elevated plasma homocysteine levels compared with only 27 (55%) RA patients receiving other therapies (P < 0.05). The proportion of patients with low vitamin B12 and high methylmalonic acid levels did not differ between the two groups. CONCLUSIONS: Our data show high plasma homocysteine levels among RA patients treated with methotrexate and folic acid. While plasma vitamin B12 levels were similar between the two groups, high plasma homocysteine is also a sensitive marker of vitamin B12 deficiency. Additional studies should evaluate for the presence of clinical features of vitamin B12 deficiency and hyperhomocysteinemia among RA patients treated with methotrexate and folic acid.

Association of functional polymorphism rs2231142 (Q141K) in the ABCG2 gene with serum uric acid and gout in 4 US populations: the PAGE Study.

A loss-of-function mutation (Q141K, rs2231142) in the ATP-binding cassette, subfamily G, member 2 gene (ABCG2) has been shown to be associated with serum uric acid levels and gout in Asians, Europeans, and European and African Americans; however, less is known about these associations in other populations. Rs2231142 was genotyped in 22,734 European Americans, 9,720 African Americans, 3,849 Mexican Americans, and 3,550 American Indians in the Population Architecture using Genomics and Epidemiology (PAGE) Study (2008-2012). Rs2231142 was significantly associated with serum uric acid levels (P = 2.37 × 10(-67), P = 3.98 × 10(-5), P = 6.97 × 10(-9), and P = 5.33 × 10(-4) in European Americans, African Americans, Mexican Americans, and American Indians, respectively) and gout (P = 2.83 × 10(-10), P = 0.01, and P = 0.01 in European Americans, African Americans, and Mexican Americans, respectively). Overall, the T allele was associated with a 0.24-mg/dL increase in serum uric acid level (P = 1.37 × 10(-80)) and a 1.75-fold increase in the odds of gout (P = 1.09 × 10(-12)). The association between rs2231142 and serum uric acid was significantly stronger in men, postmenopausal women, and hormone therapy users compared with their counterparts. The association with gout was also significantly stronger in men than in women. These results highlight a possible role of sex hormones in the regulation of ABCG2 urate transporter and its potential implications for the prevention, diagnosis, and treatment of hyperuricemia and gout.

Serum urate association with hypertension in young adults: analysis from the Coronary Artery Risk Development in Young Adults cohort.

OBJECTIVE: To determine if serum urate concentration is associated with development of hypertension in young adults. METHODS: Retrospective cohort analysis from 4752 participants with available serum urate and without hypertension at baseline from the Coronary Artery Risk Development in Young Adults (CARDIA) study; a mixed race (African-American and White) cohort established in 1985 with 20 years of follow-up data for this analysis. Associations between baseline serum urate concentration and incident hypertension (defined as a blood pressure greater or equal to 140/90 or being on antihypertensive drugs) were investigated in sex-stratified bivariate and multivariable Cox-proportional analyses. RESULTS: Mean age (SD) at baseline was 24.8 (3.6) years for men and 24.9 (3.7) years for women. Compared with the referent category, we found a greater hazard of developing hypertension starting at 345 µmol/l (5.8 mg/dl) of serum urate for men and 214 µmol/l (3.6 mg/dl) for women. There was a 25% increase in the hazard of developing hypertension in men (HR1.25 (95% CI 1.15 to 1.36)) per each mg/dl increase in serum urate but no significant increase in women (HR 1.06 (95%CI 0.97 to 1.16)). CONCLUSIONS: We found a significant independent association between higher serum urate concentrations and the subsequent hazard of incident hypertension, even at concentrations below the conventional hyperuricaemia threshold of 404 µmol/l (6.8 mg/dl).

Developing a provisional definition of flare in patients with established gout.

OBJECTIVE: Various nonvalidated criteria for disease flare have been used in studies of gout. Our objective was to develop empirical definitions for a gout flare from patient-reported features. METHODS: Possible elements for flare criteria were previously reported. Data were collected from 210 gout patients at 8 international sites to evaluate potential gout flare criteria against the gold standard of an expert rheumatologist definition. Flare definitions based on the presence of the number of criteria independently associated with the flare and classification and regression tree approaches were developed. RESULTS: The mean ± SD age of the study participants was 56.2 ± 15 years, 207 of them (98%) were men, and 54 of them (26%) had flares of gout. The presence of any patient-reported warm joint, any patient-reported swollen joint, patient-reported pain at rest score of >3 (0-10 scale), and patient-reported flare were independently associated with the study gold standard. The greatest discriminating power was noted for the presence of 3 or more of the above 4 criteria (sensitivity 91% and specificity 82%). Requiring all 4 criteria provided the highest specificity (96%) and positive predictive value (85%). A classification tree identified pain at rest with a score of >3, followed by patient self-reported flare, as the rule associated with the gold standard (sensitivity 83% and specificity 90%). CONCLUSION: We propose definitions for a disease flare based on self-reported items in patients previously diagnosed as having gout. Patient-reported flare, joint pain at rest, warm joints, and swollen joints were most strongly associated with presence of a gout flare. These provisional definitions will next be validated in clinical trials.

Emerging strategies for treating gout.

Gout is a common and potentially debilitating disease characterized by a painful inflammatory arthritis ("gout flare"), caused by the deposition of monosodium urate crystals in joints and surrounding tissues. Gout is frequently comorbid with other chronic conditions such as chronic kidney disease (CKD) and diabetes mellitus, which can make treatment complex, as traditional mainstays (such as allopurinol, colchicine, and corticosteroids) may not be preferred or could have adverse events in such patients. Understanding the pathophysiology of hyperuricemia, gout, and crystalline-driven inflammation is key for drug development and research. Consequently, new agents and new protocols with existing agents are being proposed for safe and efficacious treatment in patients with a variety of comorbid conditions. This review will discuss such strategies that may be used in the future for gout treatment.

Managing Gout in Women: Current Perspectives.

Gout is a common inflammatory arthritis that tends to affect significantly more men than women. However, female gout patients are more likely to have comorbidities such as hypertension, diabetes mellitus, and renal dysfunction. Furthermore, they experience a greater disease burden due to gout than males. While nonbiological causes may possibly contribute to this sex discrepancy in burden, this raises questions regarding whether current gout pharmacotherapies are as efficacious in females as they are in males. In this review, we examine how the clinical profile of female gout patients differs from male patients; we then survey the literature for data on outcomes for female gout patients treated with urate-lowering therapies for chronic management of gout as well as commonly used agents for acute flares. We also discuss considerations for managing gout in women during pregnancy and lactation.

Folic acid and methotrexate use and their association with COVID-19 diagnosis and mortality: a case-control analysis from the UK Biobank.

OBJECTIVE: To determine if methotrexate or folic acid prescription was associated with differential risk for COVID-19 diagnosis or mortality. DESIGN: Case-control analysis. SETTING: The population-based UK Biobank (UKBB) cohort. PARTICIPANTS: Data from 380 380 UKBB participants with general practice prescription data for 2019-2021. Updated medical information was retrieved on 13 December 2021. PRIMARY AND SECONDARY OUTCOME MEASURES: The outcomes of COVID-19 diagnosis and COVID-19-related mortality were analysed by multivariable logistic regression. Exposures evaluated were prescription of folic acid and/or methotrexate. Criteria for COVID-19 diagnosis were (1) a positive SARS-CoV-2 test or (2) ICD-10 code for confirmed COVID-19 (U07.1) or probable COVID-19 (U07.2) in hospital records, or death records. By these criteria, 26 003 individuals were identified with COVID-19 of whom 820 were known to have died from COVID-19. Logistic regression statistical models were adjusted for age sex, ethnicity, Townsend deprivation index, body mass index, smoking status, presence of rheumatoid arthritis, sickle cell disease, use of anticonvulsants, statins and iron supplements. RESULTS: Compared with people prescribed neither folic acid nor methotrexate, people prescribed folic acid supplementation had increased risk of diagnosis of COVID-19 (OR 1.51 (1.42-1.61)). The prescription of methotrexate with or without folic acid was not associated with COVID-19 diagnosis (p≥0.18). People prescribed folic acid supplementation had positive association with death after a diagnosis of COVID-19 (OR 2.64 (2.15-3.24)) in a fully adjusted model. The prescription of methotrexate in combination with folic acid was not associated with an increased risk for COVID-19-related death (1.07 (0.57-1.98)). CONCLUSIONS: We report an association of increased risk for COVID-19 diagnosis and COVID-19-related death in people prescribed folic acid supplementation. Our results also suggest that methotrexate might attenuate these associations.

Gout Flare Severity From the Patient Perspective: A Qualitative Interview Study.

OBJECTIVE: The patient experience of a gout flare is multidimensional. To establish the most appropriate methods of flare measurement, there is a need to understand the complete experience of a flare. This qualitative study aimed to examine what factors contribute to the severity of a flare from the patient perspective. METHODS: Face-to-face interviews were conducted with patients with gout. Participants were asked to share their experience with their worst gout flare and contrast it to their experience of a less severe or mild flare. Interviews were audio recorded and transcribed verbatim. Data were analyzed using a reflexive thematic approach. RESULTS: In total, 22 participants with gout (17 male participants, mean age 66.5 years) were interviewed at an academic center in Auckland, New Zealand. Four key themes were identified as contributing to the severity of a flare: 1) flare characteristics (pain intensity, joint swelling, redness and warmth, duration, and location); 2) impact on function (including walking, activities of daily living, wearing footwear, and sleep); 3) impact on family and social life (dependency on others, social connection, and work); and 4) psychological impact (depression, anxiety, irritability, and sense of control). CONCLUSION: A wide range of interconnecting factors contribute to the severity of a gout flare from the patient perspective. Capturing these domains in long-term gout studies would provide a more meaningful and accurate representation of cumulative flare burden.

Serum Urate Trajectory in Young Adulthood and Incident Cardiovascular Disease Events by Middle Age: CARDIA Study.

[Figure: see text].

Tele-monitoring flares using a smartphone app in patients with gout or suspected gout: a feasibility study.

OBJECTIVES: Gout flares are painful and disabling. We developed a smartphone application (app) for patients to tele-monitor gout flares surveyed by clinicians. The aim of this study was to assess patient acceptability and technical and clinical feasibility. METHODS: Adult patients with either established gout or high suspicion thereof were recruited if they possessed a smartphone and reported a recent arthritis attack. A smartphone application was used to identify gout flares by asking during 90 consecutive days: (1) what is your pain score (0-10); (2) are your joints warm; (3) are your joints swollen; and (4) are you currently experiencing a gout flare? The clinician was alerted via email if a flare occurred. Patient acceptability was assessed using the technology acceptance model. Technical feasibility consisted of reported technical issues and clinical feasibility of actions taken by the clinician regarding gout flare alerts. RESULTS: Twenty-nine included patients completed the study. The mean age of participants was 57 years, and all but one were male. The adherence rate was 96% (110 of 2910 queries were missed). Patients had a positive attitude toward app use, found the app very easy to use (mean usability score 81 out of 100) and were neutral to positive on its usefulness. There were four minor technical issues. A total of 100 gout flare alerts were generated that led to 18 proactive contacts with patients. CONCLUSION: A smartphone app to monitor gout flares was developed and tested, showing high adherence, good acceptability and clinical feasibility for established gout patients. TRIAL REGISTRATION: Netherlands Trial Register, https://www.trialregister.nl, NL6435.

Efficacy and safety of urate-lowering therapy in people with kidney impairment: a GCAN-initiated literature review.

OBJECTIVES: The aim was to evaluate the efficacy, defined as achieving target serum urate <6.0 mg/dl, and safety of urate-lowering therapies (ULTs) for people with gout and chronic kidney disease (CKD) stages 3-5. METHODS: PubMed, The Cochrane Library and EMBASE were searched from 1 January 1959 to 31 January 2018 for studies that enrolled people with gout, who had an estimated glomerular filtration rate (eGFR) or creatinine clearance (CrCl) of <60 ml/min and exposure to allopurinol, febuxostat, probenecid, benzbromarone, lesinurad or pegloticase. All study designs other than case reports were included, except for people on dialysis, for whom we did include case reports. RESULTS: There were 36 reports with an analysis of efficacy and/or safety based upon renal function: allopurinol (n = 12), febuxostat (n = 10), probenecid (n = 3), benzbromarone (n = 5), lesinurad (n = 5) and pegloticase (n = 1). There were 108 reports that involved people with gout and renal impairment but did not contain any analysis on efficacy and/or safety based upon renal function: allopurinol (n = 84), febuxostat (n = 14), benzbromarone (n = 1), lesinurad (n = 3) and pegloticase (n = 6). Most studies excluded people with more severe degrees of renal impairment (eGFR or CrCl of <30 ml/min). For allopurinol, in particular, there was significant variability in the dose of drug used and the efficacy in terms of urate lowering, across all levels of renal impairment. CONCLUSION: There is a lack of evidence regarding the efficacy and/or safety of currently used ULTs according to different levels of renal function. Future studies should include patients with CKD and should report study outcomes stratified by renal function.