Expert Opinion on Pegloticase with Concomitant Immunomodulatory Therapy in the Treatment of Uncontrolled Gout to Improve Efficacy, Safety, and Durability of Response.

PURPOSE OF REVIEW: Gout is a systemic disease from which some patients develop numerous painful tophi that adversely affect quality of life and functionality. Some patients treated with oral urate-lowering therapy are unable to maintain serum urate levels below 6 mg/dL, and these patients, thus classified as having refractory or uncontrolled gout, often require therapy with pegloticase to reduce symptoms and tophaceous burden. The objective of this expert opinion review is to summarize the available evidence supporting the use of concomitant immunomodulators with pegloticase to prevent development of anti-drug antibodies (ADAs) when treating patients with uncontrolled gout. RECENT FINDINGS: Emerging evidence suggests that adding an immunomodulator to pegloticase therapy can substantially increase response rates to double those observed in phase 3 randomized controlled trials. The combination of immunomodulation with pegloticase should be considered in routine clinical practice to improve durability of response, efficacy, and safety among patients with uncontrolled gout who otherwise have limited therapeutic options.

Post-hoc analysis of pegloticase pivotal trials in chronic refractory gout: relationship between fluctuations in plasma urate levels and acute flares.

OBJECTIVES: To determine factors associated with gout flares in subjects treated with pegloticase. METHODS: Gout flares from two randomised controlled trials comparing pegloticase (8 mg every 2 weeks [q2] or monthly [q4]) versus placebo were analysed. Responders had persistent urate lowering (<6mg/dL) whereas, non-responders had transient urate lowering during the 6-month RCTs. Gout flares (self-reported) were defined as acute joint pain and swelling requiring treatment. Gout flare prophylaxis (colchicine, 0.6 mg once or twice daily, or a non-steroidal anti-inflammatory drug) was initiated 1 week before the first infusion and continued throughout the study. Plasma urate at the time of flare and the change in urate preceding a flare were analysed. RESULTS: Mean flare rates increased with pegloticase versus placebo during the first 3 months followed by marked reductions during months 4-6. The increase in flares with pegloticase during the first 3 months was most evident (p=0.0006) and the decrease during the second 3 months was least marked (p=0.0006) in subjects receiving monthly pegloticase. Fluctuation in urate levels was highest in monthly responders (p=0.002) and was associated with flare occurrence. Multivariate linear regression analysis indicated the only variables significantly associated with flares were treatment group and absolute change in plasma urate before flares. CONCLUSIONS: Pegloticase treatment increased flares during the first 3 months of treatment in all groups when plasma urate was significantly lowered and was followed by a decline in months 4-6 in patients maintaining a low plasma urate. Flares associated with pegloticase treatment were associated with decreases and fluctuations in plasma urate levels.

Patient Perceptions of Gout Management Goals: A Cross-sectional Internet Survey.

OBJECTIVE: To assess patient perceptions of gout management goals. METHODS: We conducted a cross-sectional Internet survey of people who visited the Gout and Uric Acid Education Society's website to assess patient/respondent perception of gout management goals. We used chi-square test for categorical or t-test for continuous variables. RESULTS: Among the 320 survey respondents with physician-diagnosed gout, mean age was 57 (SD, 13.4) years, 72% were male, 77% White; mean gout duration was 7.6 years (SD, 11), gout flares in the last year were 5.2 (SD, 6.1), and medical comorbidities were common, 2.7 (SD, 2.6). Two-thirds respondents each reported very severe or severe symptoms from gout and that gout ranked among the top two health conditions with a negative impact on quality of life. During a clinic visit, only one-third of respondents' physicians spent 50% of more of the time discussing gout treatment. Only 54% respondents were prescribed ULT by their healthcare provider. By patient preference, the best life-long gout treatment strategies were the lowering of the serum urate level and the control of gout symptoms (62%) followed by serum urate lowering (32%). Respondents considered the following as the most important things for making gout treatment satisfactory: (1) patient education; (2) effective physician-patient communication; (3) diet and lifestyle modification; (4) serum urate monitoring and target achievement; (5) pain management and flare prevention; and (6) medication management. CONCLUSIONS: Patient identification of gout symptom control and serum urate level monitoring as the most important treatment goals is informative for clinicians and guideline developers.

A cross-sectional internet-based patient survey of the management strategies for gout.

BACKGROUND: Almost half of the patients with gout are not prescribed urate-lowering therapy (ULT) by their health care provider and >50 % use complementary and alternative therapies. Diet modification is popular among gout patients due to known associations of certain foods with gout flares. The interplay of the use of dietary supplements, diet modification, and ULT adherence in gout patients is not known. Despite the recent interest in diet and supplements, there are limited data on their use. Our objective was to assess ULT use and adherence and patient preference for non-pharmacological interventions by patients with gout, using a cross-sectional survey. METHODS: People who self-reported physician-diagnosed gout during their visit to a gout website ( http://gouteducation.org ) were invited to participate in a brief anonymous cross-sectional Internet survey between 08/11/2014 to 04/14/2015 about the management of their gout. The survey queried ULT prescription, ULT adherence, the use of non-pharmacological interventions (cherry extract, diet modification) and the likelihood of making a lifelong diet modification for gout management. RESULTS: A total of 499 respondents with a mean age 56.3 years were included; 74% were males and 74% were White. Of these, 57% (285/499) participants were prescribed a ULT for gout, of whom 88% (251/285) were currently taking ULT. Of those using ULT, 78% (97/251) reported ULT adherence >80%. Gender, race, and age were not significantly associated with the likelihood of receiving a ULT prescription or ULT adherence >80%. Fifty-six percent of patients with gout preferred ULT as a lifelong treatment for gout, 24% preferred cherry extract and 16% preferred diet modification (4% preferred none). Men had significantly lower odds of preferring ULT as the lifelong treatment choice for gout vs. other choices (p = 0.03). We found that 38.3% participants were highly motivated to make a lifelong dietary modification to improve their gout (score of 9-10 on a 0-10 likelihood scale). Older age was significantly associated with high level of willingness to modify diet (p = 0.02). CONCLUSION: We found that only 57% of gout patients reported being prescribed ULT. 40% of gout patients preferred non- pharmacological interventions such as cherry extract and diet modification for gout management. The latter finding requires further investigation.

2015 Gout classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative.

OBJECTIVE: Existing criteria for the classification of gout have suboptimal sensitivity and/or specificity, and were developed at a time when advanced imaging was not available. The current effort was undertaken to develop new classification criteria for gout. METHODS: An international group of investigators, supported by the American College of Rheumatology and the European League Against Rheumatism, conducted a systematic review of the literature on advanced imaging of gout, a diagnostic study in which the presence of monosodium urate monohydrate (MSU) crystals in synovial fluid or tophus was the gold standard, a ranking exercise of paper patient cases, and a multi-criterion decision analysis exercise. These data formed the basis for developing the classification criteria, which were tested in an independent data set. RESULTS: The entry criterion for the new classification criteria requires the occurrence of at least one episode of peripheral joint or bursal swelling, pain, or tenderness. The presence of MSU crystals in a symptomatic joint/bursa (ie, synovial fluid) or in a tophus is a sufficient criterion for classification of the subject as having gout, and does not require further scoring. The domains of the new classification criteria include clinical (pattern of joint/bursa involvement, characteristics and time course of symptomatic episodes), laboratory (serum urate, MSU-negative synovial fluid aspirate), and imaging (double-contour sign on ultrasound or urate on dual-energy CT, radiographic gout-related erosion). The sensitivity and specificity of the criteria are high (92% and 89%, respectively). CONCLUSIONS: The new classification criteria, developed using a data-driven and decision-analytic approach, have excellent performance characteristics and incorporate current state-of-the-art evidence regarding gout.

Social Listening in Gout: Impact of Proactive vs. Reactive Management on Self-Reported Emotional States.

INTRODUCTION: This study aimed to characterize patient-reported outcomes from social media conversations in the gout community. The impact of management strategy differences on the community's emotional states was explored. METHODS: We analyzed two social media sources using a variety of natural language processing techniques. We isolated conversations with a high probability of discussing disease management (score > 0.99). These conversations were stratified by management type: proactive or reactive. The polarity (positivity/negativity) of language and emotions conveyed in statements shared by community members was assessed by management type. RESULTS: Among the statements related to management, reactive management (e.g., urgent care) was mentioned in 0.5% of statements, and proactive management (e.g., primary care) was mentioned in 0.6% of statements. Reactive management statements had a significantly larger proportion of negative words (59%) than did proactive management statements (44%); "fear" occurred more frequently with reactive statements, whereas "trust" predominated in proactive statements. Allopurinol was the most common medication in proactive management statements, whereas reactive management had significantly higher counts of prednisone/steroid mentions. CONCLUSIONS: A unique aspect of examining gout-related social media conversations is the ability to better understand the intersection of clinical management and emotional impacts in the gout community. The effect of social media statements was significantly stratified by management type for gout community members, where proactive management statements were characterized by more positive language than reactive management statements. These results suggest that proactive disease management may result in more positive mental and emotional experiences in patients with gout.

Outcome reporting in randomized trials in gout: A systematic scoping review from the OMERACT gout working group assessing the uptake of the core outcome set.

OBJECTIVE: The selection and reporting of core outcome measures in clinical trials is essential for patients, researchers, and healthcare providers for clinical research to have an impact on healthcare. In this systematic scoping review, we aimed to quantify the extent to which gout clinical trials are collecting and reporting data in accordance with the core outcome domains from Outcome Measures in Rheumatology (OMERACT) published in 2009 applicable for both acute and chronic trials and evaluate the reporting according to the core domains before and after the 2009 OMERACT endorsement. METHODS: We searched multiple databases PubMed, EMBASE, the Cochrane Library including the Cochrane Central Register of Controlled Trials (CENTRAL), and Cochrane Database of Systematic Reviews (CDSR) and www. CLINICALTRIALS: gov for randomized controlled trials (RCTs) allocating people with gout versus an active pharmacological gout treatment or a control comparator (no date limitation). We extracted the data in accordance with the core outcome sets, focusing individually on core outcome domains and the core outcome measurements for acute and chronic trials, respectively. In this study 'Acute trials' reflect studies that describe interventions for short term management of gout flares, and 'chronic trials' describe interventions for long-term urate lowering therapy in the management of gout. RESULTS: From 8,522 records identified in the database search, 134 full text papers were reviewed, and 71 trials were included, of which 36 were acute and 35 were chronic. Only 3 of 36 (8%) acute trials reported all five core domains and none of the 35 included chronic trials reported all 7 core domains. In the acute trials, twenty-seven unique measurement instruments across the 5 core domains were identified. For chronic trials there were 31 unique measurement instruments used across the 7 core domains. Serum urate was reported in 100% of the chronic trials and gout flares in 80%. However, other core domains were reported in <30% of chronic trials. In particular the patient-important domains such as HR-QOL, patient global assessment and activity limitations were rarely reported. A broad variety of different measurement instruments were used to assess each endorsed core domain, a minority of trials used the OMERACT endorsed instruments. For acute trials, the number reporting on all core domains was consistently low and no change was detected before and after the endorsement of the core domains in 2009. None of the included chronic trials reported on all 7 endorsed core domains at any time. CONCLUSION: In this study we found a low adherence with the intended endorsed (i.e., core) outcome domains for acute and chronic gout studies which represents a poor uptake of the global OMERACT efforts for the minimum of what should be measured in clinical trials. In addition, there is a significant variation in how the OMERACT endorsed outcome domains have been measured. This systematic review demonstrates the need for continuous encouragement among gout researchers to adhere to OMERACT core domains as well as further guidance on outcome measurements reporting. REGISTRATION: Prospero: CRD42019151316.

Gout management and outcomes during established COVID-19 pandemic in 2020-2021: a cross-sectional Internet survey.

Objective: To assess the management of gout in established COVID-19 pandemic. Methods: We assessed medication use, health care utilization, gout-specific health-related quality of life (HRQOL), psychological distress using Patient Health Questionnaire-4 (PHQ-4), resilience, illness perception, and health literacy in people with physician-diagnosed self-reported gout in established COVID-19 pandemic in a cross-sectional Internet survey. Results: Among the 130 survey respondents with gout, the mean age was 62.8 years, 65% were male, 83% were White, 59% were prescribed urate-lowering therapy (ULT), and health literacy was adequate in 80%. A third of survey respondents reported more difficulty with their gout management since September 2020. Gout-specific HRQOL deficits were evident. Moderate-severe psychological distress was seen in 22%, and resilience score was 6.5 [standard deviation (SD), 1.9; range, 0-8]. Adjusted for age and sex, compared with no/mild psychological distress, moderate-severe psychological distress was associated with significantly higher odds ratio (OR; 95% confidence interval) of more difficulty with (1) getting health care for gout in clinic, 3.7 (1.0, 13.2); emergency room/urgent care, 8.1 (1.4, 45.0); and in the hospital, 9.8 (1.6, 59.6); (2) getting gout flares treated, 6.6 (1.6, 26.8); (3) avoiding gout complications, 4.5 (1.2, 16.7); and (4) daily activities at home, 4.2 (1.3, 14.1), and performing work, 4.1 (1.2, 13.6). Conclusion: Respondents with gout reported health care gaps, low rates of ULT prescription, high psychological distress, and HRQOL deficits during established COVID-19 pandemic. Moderate-severe psychological distress was associated with difficulties in health care access and gout management. Interventions to address these challenges in gout management are needed.

Quality of care in patients with gout: why is management suboptimal and what can be done about it?

Gout is a common inflammatory arthritis. We know a great deal about its etiopathogenesis and have relatively safe and effective therapies for it. Gout, however, remains a poorly managed disease with mistakes made in securing an accurate diagnosis and in using appropriate therapies for acute and chronic stages of the disease. Synovial fluid analysis with polarizing microscopy is the "gold standard" for confirming the diagnosis of gout but has been used in fewer than 10% of all patients diagnosed with gout. The newly adopted European clinical guidelines offer a practical alternative to synovial fluid analysis, but primary care physicians are not well-versed in their use. Other serious errors in the management of gout are related to the use of medications to treat acute and chronic gout. Frequently, the anti-inflammatory drugs used to treat acute symptoms and urate-lowering drugs used to prevent long-term destruction are improperly dosed, leading to dissatisfaction on the part of patients and physicians. Widespread education about evidence-based diagnostic and treatment guidelines is desperately needed.

Efficacy and tolerability of pegloticase for the treatment of chronic gout in patients refractory to conventional treatment: two randomized controlled trials.

CONTEXT: Patients with chronic disabling gout refractory to conventional urate-lowering therapy need timely treatment to control disease manifestations related to tissue urate crystal deposition. Pegloticase, monomethoxypoly(ethylene glycol)-conjugated mammalian recombinant uricase, was developed to fulfill this need. OBJECTIVE: To assess the efficacy and tolerability of pegloticase in managing refractory chronic gout. DESIGN, SETTING, AND PATIENTS: Two replicate, randomized, double-blind, placebo-controlled trials (C0405 and C0406) were conducted between June 2006 and October 2007 at 56 rheumatology practices in the United States, Canada, and Mexico in patients with severe gout, allopurinol intolerance or refractoriness, and serum uric acid concentration of 8.0 mg/dL or greater. A total of 225 patients participated: 109 in trial C0405 and 116 in trial C0406. INTERVENTION: Twelve biweekly intravenous infusions containing either pegloticase 8 mg at each infusion (biweekly treatment group), pegloticase alternating with placebo at successive infusions (monthly treatment group), or placebo (placebo group). MAIN OUTCOME MEASURE: Primary end point was plasma uric acid levels of less than 6.0 mg/dL in months 3 and 6. RESULTS: In trial C0405 the primary end point was reached in 20 of 43 patients in the biweekly group (47%; 95% CI, 31%-62%), 8 of 41 patients in the monthly group (20%; 95% CI, 9%-35%), and in 0 patients treated with placebo (0/20; 95% CI, 0%-17%; P < .001 and <.04 for comparisons between biweekly and monthly groups vs placebo, respectively). Among patients treated with pegloticase in trial C0406, 16 of 42 in the biweekly group (38%; 95% CI, 24%-54%) and 21 of 43 in the monthly group (49%; 95% CI, 33%-65%) achieved the primary end point; no placebo-treated patients reached the primary end point (0/23; 95% CI, 0%-15%; P = .001 and < .001, respectively). When data in the 2 trials were pooled, the primary end point was achieved in 36 of 85 patients in the biweekly group (42%; 95% CI, 32%-54%), 29 of 84 patients in the monthly group (35%; 95% CI, 24%-46%), and 0 of 43 patients in the placebo group (0%; 95% CI, 0%-8%; P < .001 for each comparison). Seven deaths (4 in patients receiving pegloticase and 3 in the placebo group) occurred between randomization and closure of the study database (February 15, 2008). CONCLUSION: Among patients with chronic gout, elevated serum uric acid level, and allopurinol intolerance or refractoriness, the use of pegloticase 8 mg either every 2 weeks or every 4 weeks for 6 months resulted in lower uric acid levels compared with placebo. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00325195.

2011 recommendations for the diagnosis and management of gout and hyperuricemia.

Gout is a major health problem in the United States; it affects 8.3 million people, which is approximately 4% of the adult population. Gout is most often diagnosed and managed in primary care practices; thus, primary care physicians have a significant opportunity to improve patient outcomes. Following publication of the 2006 European League Against Rheumatism (EULAR) gout guidelines, significant new evidence has accumulated, and new treatments for patients with gout have become available. It is the objective of these 2011 recommendations to update the 2006 EULAR guidelines, paying special attention to the needs of primary care physicians. The revised 2011 recommendations are based on the Grading of Recommendations Assessment, Development, and Evaluation approach as an evidence-based strategy for rating quality of evidence and grading the strength of recommendation formulated for use in clinical practice. A total of 26 key recommendations, 10 for diagnosis and 16 for management, of patients with gout were evaluated, resulting in important updates for patient care. The presence of monosodium urate crystals and/or tophus and response to colchicine have the highest clinical diagnostic value. The key aspect of effective management of an acute gout attack is initiation of treatment within hours of symptom onset. Low-dose colchicine is better tolerated and is as effective as a high dose. When urate-lowering therapy (ULT) is indicated, the xanthine oxidase inhibitors allopurinol and febuxostat are the options of choice. Febuxostat can be prescribed at unchanged doses for patients with mild-to-moderate renal or hepatic impairment. The target of ULT should be a serum uric acid level that is ≤ 6 mg/dL. For patients with refractory and tophaceous gout, intravenous pegloticase is a new treatment option. This article is a summary of the 2011 clinical guidelines published in Postgraduate Medicine. This article provides a streamlined, accessible overview intended for quick review by primary care physicians, with the full guidelines being a resource for those seeking additional background information and expanded discussion.

Towards development of core domain sets for short term and long term studies of calcium pyrophosphate crystal deposition (CPPD) disease: A framework paper by the OMERACT CPPD working group.

INTRODUCTION: Although calcium pyrophosphate deposition (CPPD) is common, there are no published outcome domains or validated measurement instruments for CPPD studies. In this paper, we describe the framework for development of the Outcome Measures in Rheumatology (OMERACT) CPPD Core Domain Sets. METHODS: The OMERACT CPPD working group performed a scoping literature review and qualitative interview study. Generated outcomes were presented at the 2020 OMERACT CPPD virtual Special Interest Group (SIG) meeting with discussion focused on whether different core domain sets should be developed for different calcium pyrophosphate deposition (CPPD) clinical presentations and how the future CPPD Core Domain Set may overlap with already established osteoarthritis (OA) domains. These discussions informed development of a future work plan for development of the OMERACT CPPD Core Domain Sets. FINDINGS: Domains identified from a scoping review of 112 studies and a qualitative interview study of 36 people (28 patients with CPPD, 7 health care professionals, one stakeholder) were mapped to core areas of OMERACT Filter 2.1. The majority of SIG participants agreed there was need to develop separate core domain sets for "short term" and "long term" studies of CPPD. Although CPPD + OA is common and core domain sets for OA have been established, participants agreed that existing OA core domain sets should not influence the development of OMERACT core domain sets for CPPD. Prioritization exercises (using Delphi methodology) will consider 40 potential domains for short term studies of CPPD and 47 potential domains for long term studies of CPPD. CONCLUSION: Separate OMERACT CPPD Core Domain Sets will be developed for "short term" studies for an individual flare of acute CPP crystal arthritis and for "long term" studies that may include participants with any clinical presentation of CPPD (acute CPP crystal arthritis, chronic CPP crystal inflammatory arthritis, and/or CPPD + OA).

Gout management and outcomes during the COVID-19 pandemic: a cross-sectional internet survey.

AIM: We aimed to assess the gout management during the COVID-19 pandemic. METHODS: We assessed medication use, healthcare utilization, gout-specific health-related quality of life (HRQoL) on the Gout Impact Scale (GIS), psychological distress using the patient health questionnaire-4 (PHQ-4), and resilience in people with self-reported physician-diagnosed gout during the COVID-19 pandemic in a cross-sectional Internet survey. RESULTS: Among the 122 survey respondents with physician-diagnosed gout, 82% were prescribed urate-lowering therapy (ULT) and 66% were taking ULT daily; mean age was 54.2 years [standard deviation (SD), 13.8], 65% were male, and 79% were White. More regular use of gout medication was reported during the COVID-19 pandemic: allopurinol, 44%; colchicine, 37%; non-steroidal anti-inflammatory drugs, 36%. Gout flares were common: 63% had ⩾1 gout flare monthly; 11% went to emergency room/urgent care; and 2% were hospitalized with gout flares. Between 41% and 56% of respondents reported more difficulty with gout management and related functional status related to COVID-19; 17-37% had difficulty with healthcare access for gout. HRQOL deficits were evident for gout concern overall, 79.4 (SD, 25); unmet gout treatment need, 64.5 (SD, 27.1); and gout concern during flare, 67.3 (SD, 27.1); but less so for gout medication side effects, 48.9 (SD, 27.4). Psychological distress was moderate in 19% and severe in 15% (mild, 22%; normal, 45%). Resilience score on Connor-Davidson Resilience Scale (CD-RISC2) was 5.6 (SD, 1.8; range 0-8). Compared with no/mild psychological distress, moderate-severe psychological distress during the COVID-19 pandemic was significantly associated with more difficulty getting gout medication filled (p = 0.02), flares treated (p = 0.005), and receiving gout education (p = 0.001). CONCLUSION: Healthcare gaps, psychological distress, and HRQoL deficits were commonly reported by people with gout during the COVID-19 pandemic. Interventions to address these challenges for people with gout during the COVID-19 pandemic are needed.

Management of Gout in the United States: A Claims-based Analysis.

OBJECTIVE: Gout is the most common inflammatory arthritis in the United States. Although numerous guidelines exist for the management of gout, they are not routinely implemented. This study evaluated the real-world practice patterns in gout patients using large administrative claims databases. METHODS: An analysis of patients diagnosed with gout from October 2015 to November 2018 was carried out using the Symphony Integrated Dataverse and Truven Marketscan administrative claims databases. Patients were identified as having gout if they were more than18 years of age and had 2 or more primary gout diagnoses on different days, separated by 3 or more months. Patients were further identified as having either acute gout or advanced forms of gout including chronic nontophaceous, tophaceous, and uncontrolled gout. Percent and frequency of serum urate testing, rheumatology specialist visits, prescriptions for urate lowering therapies (ULTs), and emergency room (ER) visits for gout flares were evaluated. RESULTS: We identified 1 162 747 gout patients. Gout patients were seen most frequently by internists and family medicine practitioners. Neither urate testing nor prescriptions for ULTs were uniform. Patients with acute gout were infrequently seen by rheumatologists, whereas rheumatologist care progressively increased in patients with advanced gout. The frequency of serum urate testing and prescriptions for ULTs significantly increased, whereas the frequency of ER visits decreased in gout patients seen by a rheumatologist. CONCLUSION: Measurement of serum urate and prescriptions for ULTs are not consistent in gout patients. Rheumatologist care increases the frequency of urate measurement and ULT prescriptions and may also improve outcomes for gout patients.

Development of a multivariable improvement measure for gout.

BACKGROUND: Gout is a heterogeneous inflammatory disease with numerous clinical manifestations. A composite means to assess the impact of therapy on numerous aspects of gout could be useful. METHODS: Results from patients treated with pegloticase or placebo in two randomized clinical trials and their open-label extension were assessed using a novel evidence-based Gout Multivariable Improvement Measure (GMIM) derived from previously reported criteria for remission and complete response. Improvement was defined as serum urate (sU) < 6 mg/dL and absence of flares during the preceding 3 months plus 20, 50, and 70% improvement in tophus size, patient global assessment, pain, and swollen and tender joints. RESULTS: Patients treated with pegloticase manifested a significantly greater GMIM20, 50, and 70 response vs those treated with placebo (GMIM20 at 6 months 37.1% vs 0%, respectively). Higher response rates were significantly more frequent in subjects with persistent urate lowering (GMIM 58.1% at 6 months) in response to pegloticase versus those with only transient urate lowering (GMIM 7.1% at 6 months). However, when the requirement for a decrease in sU to < 6 mg/dL was omitted, a substantial percentage of subjects with transient urate lowering met the GMIM clinical criteria. A sensitivity analysis indicated that gout flares contributed minimally to the model. The response measured by GMIM persisted into the open-level extension for as long as 2 years. Finally, subjects who received placebo in the randomized control trials, but pegloticase in the open-label extension, manifested GMIM responses comparable to that noted with pegloticase-treated subjects in the randomized controlled trials. CONCLUSIONS: GMIM captures changes in disease activity in response to treatment with pegloticase and may serve as an evidence-based tool for assessment of responses to other urate-lowering therapies in gout patients.

The role of hyperuricemia in vascular disorders.

PURPOSE OF REVIEW: The role of uric acid as a mediator of vascular damage is not a new idea but has only recently gained widespread acceptance. Uric acid has previously been viewed as a benign solute in serum until it exceeds its saturation level. Others have viewed it as an important antioxidant. These opinions have given way to strong epidemiologic evidence that uric acid elevation may damage endothelial cells and cause significant medical problems. RECENT FINDINGS: The comorbidities associated with gout include hypertension, renal failure, obesity and diabetes. Multiple large epidemiologic studies cited in this review show that uric acid itself may play an important role in initiating the vascular endothelial dysfunction associated with this cluster of medical problems and ultimately lead to stroke, coronary artery disease and chronic kidney disease. These studies are supported by experiments in animals demonstrating how uric acid can gain entrance into cells and function as a 'pro-oxidant'. SUMMARY: Uric acid has been long recognized as the cause of gouty arthritis and kidney stones. There is mounting evidence that it may also have an important role in the development of vascular conditions such as coronary heart disease, stroke and kidney disease. These findings have important implications for the way we view asymptomatic hyperuricemia and for future therapeutic interventions.

Febuxostat: a new treatment for hyperuricaemia in gout.

Febuxostat is a new non-purine xanthine oxidase inhibitor that is more potent than allopurinol 300 mg daily. In two Phase III trials, significantly more febuxostat-treated gout patients met the primary endpoint [serum urate (sUA) <6 mg/dl (<360 mumol/l) at the last three visits] (48 and 53% with 80 mg; 65 and 62% with 120 mg), compared with those receiving allopurinol 300 mg (22 and 21%; P < 0.001 in both studies). Febuxostat was more effective than allopurinol in the subset with impaired renal function; no dose adjustment is required in mild-to-moderate renal impairment. Long-term extension studies confirmed the efficacy and tolerability of febuxostat. In patients who achieved the sUA target of 6 mg/dl (360 mumol/l), the incidence of gout flares fell steadily and tophi resolved in many patients. The incidence of adverse events such as dizziness, diarrhoea, headache and nausea with febuxostat was similar to allopurinol. The incidence of cardiovascular side-effects (Antiplatelet Trialists Collaboration events) was numerically higher with febuxostat than with allopurinol, but this was not statistically significant. Co-administration of febuxostat with AZA or 6-mercaptopurine is not recommended. Prophylaxis (colchicine and/or NSAIDs) against acute attacks should be used for at least the first 6 months, since early mobilization flares were observed in the clinical trials. In conclusion, febuxostat is more effective than allopurinol 300 mg daily in reducing sUA levels <6 mg/dl (360 mumol/l), the target recommended by EULAR, and offers a new option for the long-term treatment of gout.