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.

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.

The clinical benefits of sodium-glucose cotransporter type 2 inhibitors in people with gout.

Gout is the most common form of inflammatory arthritis worldwide and is characterized by painful recurrent flares of inflammatory arthritis that are associated with a transiently increased risk of adverse cardiovascular events. Furthermore, gout is associated with multiple cardiometabolic-renal comorbidities such as type 2 diabetes, chronic kidney disease and cardiovascular disease. These comorbidities, potentially combined with gout flare-related inflammation, contribute to persistent premature mortality in gout, independently of serum urate concentrations and traditional cardiovascular risk factors. Although better implementation of standard gout care could improve gout outcomes, deliberate efforts to address the cardiovascular risk in patients with gout are likely to be required to reduce mortality. Sodium-glucose cotransporter type 2 (SGLT2) inhibitors are approved for multiple indications owing to their ability to lower the risk of all-cause and cardiovascular death, hospitalizations for heart failure and chronic kidney disease progression, making them an attractive treatment option for gout. These medications have also been shown to lower serum urate concentrations, the causal culprit in gout risk, and are associated with a reduced risk of incident and recurrent gout, potentially owing to their purported anti-inflammatory effects. Thus, SGLT2 inhibition could simultaneously address both the symptoms of gout and its comorbidities.

Paget disease of bone in a southeastern Veteran population.

BACKGROUND: Paget disease of bone (PDB) is a disorder of accelerated bone remodeling resulting in bone overgrowth and impaired integrity that traditionally is described to be more frequent in individuals of European descent. Based on clinical observation, we hypothesized that among the US Southeastern Veteran population, the disease is more common among African American patients. MATERIALS AND METHODS: We conducted a cross-sectional study using the Veterans Affairs' Clinical Data Warehouse (CDW) and review of electronic medical records (EMR). Using the CDW, we identified patients from the Birmingham VA Medical Center (BVAMC) with an International Classification of Diseases code for PDB between January 2000 and December 2020. We extracted their self-reported race from the CDW and determined the proportion of African American patients, which we compared to the proportion of White patients. As a secondary goal, we extracted relevant clinical characteristics from the EMR. The statistical analysis was done using Stata/SE 14.2 for Mac. RESULTS: We identified 285 individuals from the BVAMC with PDB between January 2000 and December 2020. The proportion of African American patients was significantly higher than White patients (0.51 vs. 0.4, p = 0.0036). African American patients presented at a younger age than their peers (mean[standard deviation] age at diagnosis: 64.6[11.6] vs. 70.1[10.7] years, p = 0.0009) but did not have higher alkaline phosphatase levels, higher proportion of polyostotic disease, or of symptoms and complications. CONCLUSIONS: In the BVAMC population, PDB is more common among African American patients than White patients. Our findings and other publications hint at the existence of a cluster of PDB among the African American population in the US Southeast.

Management of Patients with Gout and Kidney Disease: A Review of Available Therapies and Common Missteps.

Gout, a common form of inflammatory arthritis, is characterized by deposition of monosodium urate crystals in articular and periarticular tissues. Repeated flares of gout cause joint damage as well as significant health care utilization and decreased quality of life. Patients with CKD have a higher prevalence of gout. Treating Patients with CKD and gout is challenging because of the lack of quality data to guide management in this specific population. This often leads to suboptimal treatment of patients with gout and impaired renal function because concerns regarding the efficacy and safety of available gout therapies in this population often result in significant interphysician variability in treatment regimens and dosages. Acute gout flares are treated with various agents, including nonsteroidal anti-inflammatory drugs, colchicine, glucocorticoids, and-more recently-IL-1 inhibitors. These medications can also be used as prophylaxis if urate-lowering therapy (ULT) is initiated. While these drugs can be used in patients with gout and CKD, there are often factors that complicate treatment, such as the numerous medication interactions involving colchicine and the effect of glucocorticoids on common comorbidities, such as diabetes and hypertension. ULT is recommended to treat recurrent flares, tophaceous deposits, and patients with moderate-to-severe CKD with a serum urate goal of <6 mg/dl recommended to prevent flares. While many misconceptions exist around the risks of using urate-lowering agents in patients with CKD, there is some evidence that these medications can be used safely in Patients with renal impairment. Additional questions exist as to whether gout treatment is indicated for Patients on RRT. Furthermore, there are conflicting data on whether ULT can affect renal function and cardiovascular disease in patients. All of these factors contribute to the unique challenges physicians face when treating patients with gout and CKD.

Empiric treatment for persistent fever from suspected autoinflammatory disease: Experience from an undiagnosed diseases program.

BACKGROUND: Patients with persistent fevers of undetermined etiology often undergo extensive evaluation without a diagnosis. Autoinflammatory syndromes may not always be considered in the differential, as these are rare entities, there are no consensus clinical criteria and genetic testing can only capture a few of these diseases. We aimed to describe the experience and value of an undiagnosed diseases program in the evaluation and management of patients who present with persistent fevers. METHODS: A retrospective analysis was performed on eleven patients who presented with persistent fevers to the Undiagnosed Diseases Program (UDP) at University of Alabama at Birmingham. All patients received extensive testing prior to referral and were seen by multiple subspecialists. The primary outcome of complete remission was resolution of episodes of fever and malaise in response to empiric biological anti-inflammatory treatment. RESULTS: All patients received genetic testing and further diagnostic evaluation by the UDP. Even without confirmed genetic testing, they were empirically started on anti-inflammatory therapies (including colchicine, IL-1 inhibitors, IL-6 inhibitors). Ten patients have achieved complete remission on empiric treatment. Three patients were given formal diagnoses. No patients have had any major adverse events from therapy. CONCLUSIONS: This is a pilot study suggesting the role for empiric treatment trials of biologics for patients with suspected autoinflammatory diseases. As the differential diagnosis of patients with persistent fevers is broad, and the diagnosis of autoinflammatory diseases often comes with some degree of uncertainty, evaluation by a center with expertise in diagnosing these conditions can help determine which patients should have empiric trials of biologics.

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.

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.

Mimicking the mimicker: Necrotizing sarcoid granulomatosis.

Necrotizing sarcoid granulomatosis (NSG) is a rare disease that shares similarities with pulmonary vasculitides and sarcoidosis. This is a report of two cases of NSG with a review of literature. The first case is a 33-year-old black female with a one-year history of malaise and cough. Lung imaging revealed scattered pulmonary nodules. Histopathology showed multiple necrotizing granulomas without prominent neutrophilic infiltrates. The second case is a 58-year-old white female with a one-year history of fatigue, dyspnea, and ophthalmoplegia on the left eye. Imaging showed multiple pulmonary nodules. Lung biopsy was consistent with NSG. The challenge of the NSG diagnosis is to distinguish it from other mimickers. Pathology often shows necrotizing granulomatous vasculitis, distinguishing it from classical sarcoid. Laboratory markers for vasculitis like neutrophil cytoplasmic antibodies and antibodies against myeloperoxidase and proteinase 3 are negative or only low titers. NSG responds well to immune-suppression, most commonly with glucocorticoids.

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.

Clinical Features of ANCA-Associated Vasculitis in African American Patients in the United States: A Single-Center Medical Records Review Study.

BACKGROUND/PURPOSE: The aim of this study was to compare the clinical features at presentation of ANCA-associated vasculitis (AAV) between African American (AA) and White patients. METHODS: This is a chart review of cases between January 2003 and December 2018. African American patients with AAV were identified and matched in a 1:2 ratio with White comparators based on the year of diagnosis (±4 years). Data on demographics, clinical, and laboratory features and outcomes at presentation were collected. Descriptive statistics were used to compare the characteristics between groups. RESULTS: Thirty-two of 56 AA patients with AAV had complete data and were included for analysis. When compared with 64 matched White patients with AAV, AA patients were younger (47.5 vs 61.0 years, p = 0.001). Compared with White patients, AA patients with granulomatosis with polyangiitis (GPA) (35 vs 55 years, p = 0.0006) and microscopic polyangiitis (MPA) (55.5 vs 65.0 years, p = 0.05) were younger. African American patients with GPA were more frequently female (p = 0.008), whereas AA patients with MPA were more frequently male (p = 0.03). No differences in disease manifestations, disease activity, and outcomes were observed between AA and White patients with AAV. CONCLUSIONS: In this single-center study, AA patients with AAV were diagnosed at a younger age than Whites; this was found in both the GPA and MPA disease phenotypes. No other significant differences were observed. Future studies are needed to confirm our findings and better describe differences of AAV in racial/ethnic minorities.

Factors Affecting Response to Anakinra in Crystalline Arthritis Flares.

BACKGROUND: Interleukin 1 inhibition with anakinra has shown efficacy in the management of crystalline-induced arthritis (CIA) flares. Gout treatment guidelines recommend its use after contraindication or intolerance to first-line therapies. The aim of this study is to identify features associated with better response to anakinra when used to treat CIA flares. METHODS: This is a medical record review study that included inpatients with acute CIA in whom anakinra was used between the years 2014 and 2019 at one tertiary center (University of Alabama at Birmingham). The primary end point was response to anakinra treatment defined as a decrease in the reported visual analog score of at least 50% within 48 hours of initiation of treatment. Demographic, clinical, and laboratory factors were compared, and factors found significant in bivariate analysis at a p value of less than 0.15 were tested in a multivariate logistic regression analysis for independent association with the response. RESULTS: A total of 55 admission encounters were analyzed. The mean age was 60.1 years, 36 (66%) were men, and 31 (56%) were African Americans. Twenty-eight of 49 (57%) met the primary end point of response at 48 hours, but 52 of 55 (94.5%) ultimately responded to anakinra during hospital stay. Factors associated with response at 48 hours were race, reason for admission related to cardiac etiologies, not having failed steroids before trial of anakinra, and hospital admission within 48 hours of initiation of flare. On a multivariable logistic regression model, we could not find significant independent associations with response to anakinra. CONCLUSIONS: Our study showed high response rates to anakinra. We could not identify factors associated with a more robust, early response. It is likely that anakinra is equally effective across a wide range of clinical scenarios.

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.

Gout and the risk of COVID-19 diagnosis and death in the UK Biobank: a population-based study.

BACKGROUND: There is a paucity of data on outcomes for people with gout and COVID-19. We aimed to assess whether gout is a risk factor for diagnosis of COVID-19 and COVID-19-related death, and to test for sex- and drug-specific differences in risk. METHODS: We used data from the UK Biobank, which included 15 871 people with gout. We used multivariable-adjusted logistic regression in the following analyses using a case-control study design: to test for an association between gout and COVID-19 diagnosis in the entire UK Biobank cohort (n=459 837); to test for an association between gout and COVID-19-related death in people who were known to have died or survived with COVID-19 (n=15 772); to test for an association between gout and COVID-19-related death in the entire UK Biobank cohort (n=459 837); and to assess risk of COVID-19-related death in a subset of patients from the UK Biobank cohort with prescription data, stratified by prescription of urate-lowering therapy and colchicine (n=341 398). Models 1 and 2 were adjusted for age group, sex, ethnicity, Townsend deprivation index, BMI, and smoking status. Model 2 was also adjusted for diagnosis of 16 other diseases that are established comorbidities of gout or established risk factors for COVID-19-related death. FINDINGS: Gout was associated with diagnosis of COVID-19 (odds ratio [OR] 1·20, 95% CI 1·11-1·29) but not with risk of COVID-19-related death in the cohort of patients diagnosed with COVID-19 (1·20, 0·96-1·51). In the entire cohort, gout was associated with COVID-19-related death (1·29, 1·06-1·56); women with gout had an increased risk of COVID-19-related death (1·98, 1·34-2·94), whereas men with gout did not (1·16, 0·93-1·45). We found no significant differences in the risk of COVID-19-related death according to prescription of urate-lowering therapy or colchicine. When patients with gout were stratified by vaccination status, the risk of diagnosis with COVID-19 was significant in the non-vaccinated group (1·21, 1·11-1·30) but not the vaccinated group (1·09, 0·65-1·85). INTERPRETATION: Gout is a risk factor for COVID-19-related death in the UK Biobank cohort, with an increased risk in women with gout, which was driven by risk factors independent of the metabolic comorbidities of gout. FUNDING: Health Research Council of New Zealand.

Racial Differences in XO (Xanthine Oxidase) and Mitochondrial DNA Damage-Associated Molecular Patterns in Resistant Hypertension.

BACKGROUND: We previously reported increased plasma XO (xanthine oxidase) activity in patients with resistant hypertension. Increased XO can cause mitochondrial DNA damage and promote release of fragments called mitochondrial DNA damage-associated molecular patterns (mtDNA DAMPs). Here, we report racial differences in XO activity and mtDNA DAMPs in Black and White adults with resistant hypertension. METHODS: This retrospective study includes 91 resistant hypertension patients (44% Black, 47% female) with blood pressure >140/90 mm Hg on ≥4 medications and 37 normotensive controls (30% Black, 54% female) with plasma XO activity, mtDNA DAMPs, and magnetic resonance imaging of left ventricular morphology and function. RESULTS: Black-resistant hypertension patients were younger (mean age 52±10 versus 59±10 years; P=0.001), with higher XO activity and left ventricular wall thickness, and worse diastolic dysfunction than White resistant hypertension patients. Urinary sodium excretion (mg/24 hour per kg) was positively related to left ventricular end-diastolic volume (r=0.527, P=0.001) and left ventricular mass (r=0.394, P=0.02) among Black but not White resistant hypertension patients. Patients with resistant hypertension had increased mtDNA DAMPs versus controls (P<0.001), with Black mtDNA DAMPS greater than Whites (P<0.001). Transmission electron microscopy of skeletal muscle biopsies in resistant hypertension patients demonstrates mitochondria cristae lysis, myofibrillar loss, large lipid droplets, and glycogen accumulation. CONCLUSIONS: These data warrant a large study to examine the role of XO and mitochondrial mtDNA DAMPs in cardiac remodeling and heart failure in Black adults with resistant hypertension.

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.

Which Attributes Are Most and Least Important to Patients When Considering Gout Flare Burden Over Time? A Best-worst Scaling Choice Study.

OBJECTIVE: Several factors contribute to the patient experience of gout flares, including pain intensity, duration, frequency, and disability. It is unknown which of these factors are most important to patients when considering flare burden over time, including those related to the cumulative experience of all flares, or the experience of a single worst flare. This study aimed to determine which flare attributes are the most and least important to the patient experience of flare burden over time. METHODS: Participants with gout completed an anonymous online survey. Questions were aimed at identifying which attributes of gout flares, representing both individual and cumulative flare burden, were the most and least important over a hypothetical 6-month period. A best-worst scaling method was used to determine the importance hierarchy of the included attributes. RESULTS: Fifty participants were included. Difficulty doing usual activities during the worst flare and pain of the worst flare were ranked as the most important, whereas average pain of all flares was considered the least important. Overall, attributes related to the single worst gout flare were considered more important than attributes related to the cumulative impact of all flares. CONCLUSION: When thinking about the burden of gout flares over time, patients rank activity limitation and pain experienced during their worst gout flare as the most important contributing factors, whereas factors related to the cumulative impact of all flares over time are relatively less important.