OA07 The therapeutic dead-end in gout: a case of failed conventional and uricosuric therapies

Objective To evaluate monosodium urate (MSU) crystal deposition and related lesions in the joints of patients with gout and hyperuricemia (HUA) using ultrasound. To explore the association between ultrasound findings and clinical features in gout and HUA. Methods A total of 202 patients with gout and 43 asymptomatic patients with HUA were included. The clinical data and ultrasonic assessment results were collected and statistically analyzed. Results Deposition of MSU crystals was found in 25.58% (11/43) of patients with asymptomatic HUA and 76.24% (154/202) of patients with gout. Of the 1,082 joints from patients with gout examined, 33.09% (358/1082) displayed MSU crystal deposition. In the joints with MSU crystal deposition, 77.37% (277/358) had a history of attacks. Among the joints of gouty arthritis, double contour sign (DCS), hyperechoic aggregate (HAG), and tophi were found in 32.65% (159/487), 7.80% (38/487), and 24.64% (120/487) of the joints, respectively. DCS and tophi, but not HAG, increasingly appeared with the extension of gout duration. In patients with more than 15 years of gout history, DCS, Tophi, and HAG were found in 48.18%, 40.00%, and 6.36% of US assessed joints, respectively. In patients with gout, synovial lesion and bone erosion were found in 17.74% (192/1082) and 7.58% (82/1082) of joints, respectively. The synovial lesion was related to HAG, while bone erosion was related to tophi and DCS. Nephrolithiasis was detected in 20.30% (41/202) of patients with gout and 4.65% (2/43) of HUA patients, indicating that nephrolithiasis occurred in more patients with gout than in patients with HUA. Conclusion HAG is an early performance of MSU crystal deposition in joints of gout and HUA. Both DCS and tophi are risk factors for bone erosion. Early urate-lowering therapy (ULT) should be considered in patients with gout, DCS, or tophi.

ABSTRACTIntroduction: Gout is a rheumatologic condition associated with elevated serum uric acid levels and deposition of monosodium urate crystals in joints and soft tissues.Areas covered: In this article, we describe the role of currently available drug therapies for managing acute gout flares and used in reducing serum urate levels. Further, we explore the role of novel small molecular therapies and biologic agents in the treatment of refractory or severe gout symptoms. A literature search of MEDLINE and MEDLINE In-Process & Other Non-Indexed Citations Databases (1996-June 2017) was conducted utilizing the key words ‘gout’, ‘interleukin-1 inhibitors’, ‘acute gout’, ‘gout treatment’, ‘urate lowering therapies’, ‘hyperuricemia’, ‘colchicine’, ‘pegloticase’, ‘lesinurad’, ‘xanthine oxidase’, ‘xanthine oxidase inhibitors’, ‘allopurinol’, ‘febuxostat’, ‘uricosurics’, ‘probenecid’, and ‘benzbromarone’. All published articles regarding therapeutic management of gout and hyperuricemia were evaluated. References of selected articles, data from poster presentations, and abstract publications were additionally reviewed.Expert opinion: Numerous therapies are currently available to managing acute gout flares and for lowering serum urate levels; advances in the understanding of the pathophysiology of this disorder has led to the emergence of targeted therapies and novel biologic preparations currently in development which may improve the clinical management of severe or refractory cases of disease that fail to respond to traditional therapies.

In response to a request for proposal from the American College of Rheumatology (ACR), our group was charged with developing non-pharmacologic and pharmacologic guidelines for treatments in gout that are safe and effective, i.e., with acceptable risk-benefit ratio. These guidelines for the management and anti-inflammatory prophylaxis of acute attacks of gouty arthritis complements our manuscript on guidelines to treat hyperuricemia in patients with evidence of gout (or gouty arthritis) (1). Gout is the most common cause of inflammatory arthritis in adults in the USA. Clinical manifestations in joints and bursa are superimposed on top of local deposition of monosodium urate crystals. Acute gout characteristically presents as self-limited, attack of synovitis (also called “gout flares”). Acute gout attacks account for a major component of the reported decreased health-related quality of life in patients with gout (2, 3). Acute gout attacks can be debilitating and are associated with decreased work productivity (4, 5). Urate lowering therapy (ULT) is a cornerstone in the management of gout, and, when effective in lowering serum urate (SUA), is associated with decreased risk of acute gouty attacks (6). However, during the initial phase of ULT, there is an early increase in acute gout attacks, which has been hypothesized due to remodeling of articular urate crystal deposits as a result of rapid and substantial lowering of ambient urate concentrations (7). Acute gout attacks attributable to the initiation of ULT may contribute to non-adherence in long-term gout treatment, as reported in recent studies (8). In order to systematically evaluate a broad spectrum of acute gouty arthritis, we generated multifaceted case scenarios to elucidate decision making based primarily on clinical and laboratory test-based data that can be obtained in a gout patient by both non-specialist and specialist health care providers in an office practice setting. This effort was not intended to create a novel classification system of gout, or new gout diagnostic criteria, as such endeavors are beyond the scope of this work. Prior gout recommendations and guidelines, at the independent (i.e, non pharmaceutical industry-sponsored) national or multinational rheumatology society level, have been published by EULAR (9, 10), the Dutch College of General Practitioners (11), and the British Society for Rheumatology (BSR)(12). The ACR requested new guidelines, in view of the increasing prevalence of gout (13), the clinical complexity of management of gouty arthritis imposed by co-morbidities common in gout patients (14), and increasing numbers of treatment options via clinical development of agents(15–17). The ACR charged us to develop these guidelines to be useful for both rheumatologists and other health care providers on an international level. As such, this process and resultant recommendations, involved a diverse and international panel of experts. In this manuscript, we concentrate on 2 of the 4 gout domains that the ACR requested for evaluation of pharmacologic and non-pharmacologic management approaches: (i) analgesic and anti-inflammatory management of acute attacks of gouty arthritis, and (ii) pharmacologic anti-inflammatory prophylaxis of acute attacks of gouty arthritis. Part I of the guidelines focused on systematic non-pharmacologic measures (patient education, diet and lifestyle choices, identification and management of co-morbidities) that impact on hyperuricemia, and made recommendations on pharmacologic ULT in a broad range of case scenarios of patients with disease activity manifested by acute and chronic forms of gouty arthritis, including chronic tophaceous gouty arthropathy(1). Each individual and specific statement is designated as a “recommendation”, in order to reflect the non-prescriptive nature of decision making for the hypothetical clinical scenarios. So that the voting panel could focus on gout treatment decisions, a number of key assumptions were made, as described in Part I of the guidelines (1). Importantly, each proposed recommendation assumed that correct diagnoses of gout and acute gouty arthritis attacks had been made for the voting scenario in question. For treatment purposes, it was also assumed that treating clinicians were competent, and considered underlying medical comorbidities (including diabetes, gastrointestinal disease, hypertension, and hepatic, cardiac, and renal disease), and potential drug toxicities and drug-drug interactions, when making both treatment choicesand dosing decisions on chosen pharmacologic interventions. The RAND/UCLA methodology used here emphasizes level of evidence, safety, and quality of therapy, and excludes analyses of societal cost of health care. As such, the ACR gout guidelines are designed to reflect best practice, supported either by level of evidence or consensus-based decision-making. These guidelines cannot substitute for individualized, direct assessment of the patient, coupled with clinical decision making by a competent health care practitioner. The motivation, financial circumstances, and preferences of the gout patient also need to be considered in clinical practice, and it is incumbent on the treating clinician to weigh the issues not addressed by this methodology, such as treatment costs, when making management decisions. Last, the guidelines for gout management presented herein were not designed to determine eligibility for health care cost coverage by third party payers.

To determine if there is a difference in early relapse rates and adrenal suppression between patients receiving an 8-day course of 40 mg/day prednisolone and those receiving an 8-day tapering course of prednisolone. This was a prospective, randomized, open clinical trial conducted in a tertiary care center. All asthmatic patients with exacerbation who were judged well enough for discharge home from the emergency department were eligible for participation. Patients with a history of chronic obstructive pulmonary disease, congestive heart failure, pneumonia, pneumothorax, or other pulmonary process and asthmatics already using inhaled or oral steroids within 2 weeks of admission to the emergency department were excluded. Patients on discharge were administered either on 8-day course of 40 mg/day prednisolone or an 8-day tapering course of prednisolone (tapering from 40 mg to 0 mg). Patients were asked to return on Day 12 for cosyntropin stimulated test and pulmonary function testing and on Day 21 for pulmonary function testing only. A group of 13 patients treated with non-tapering course (40 mg/day) of prednisolone for 8 days were compared to a group of 13 patients treated with a tapering course (40 mg taper by 5 mg/day) for 8 days. There were no differences in the FEV1 percent predicted (Days 12 and 21), the incidence of relapse, or the incidence of adrenal suppression between the 2 groups. In this small study, we found no significant difference in relapse rate or adrenal suppression between asthmatics receiving an 8-day tapering dose of prednisolone and those receiving 40 mg/day prednisolone upon discharge from the emergency department.

(1) Background: To determine which factors are associated with the volume of monosodium urate (MSU) crystal deposition quantified by dual-energy computed tomography (DECT) in urate-lowering therapy (ULT)-naive gout patients. (2) Methods: In this multicenter cross-sectional study, DECT scans of knees and feet/ankles were prospectively obtained from ULT-naive gout patients. Demographic, clinical (including gout history and comorbidities), and biological data were collected, and their association with DECT MSU crystal volume was analyzed using bivariate and multivariate analyses. A second bivariate analysis was performed by splitting the dataset depending on an arbitrary threshold of DECT MSU volume (1 cm3). (3) Results: A total of 91 patients were included. In the bivariate analysis, age (p = 0.03), gout duration (p = 0.003), subcutaneous tophi (p = 0.004), hypertension (p = 0.02), diabetes mellitus (p = 0.05), and chronic heart failure (p = 0.03) were associated with the total DECT volume of MSU crystal deposition. In the multivariate analysis, factors associated with DECT MSU volumes ≥1 cm3 were gout duration (odds ratio (OR) for each 10-year increase 3.15 (1.60; 7.63)), diabetes mellitus (OR 4.75 (1.58; 15.63)), and chronic heart failure (OR 7.82 (2.29; 31.38)). (4) Conclusion: Specific comorbidities, particularly chronic heart failure and diabetes mellitus, are more strongly associated with increased MSU crystal deposition in knees and feet/ankles than gout duration, regardless of serum urate level.

AB0893 Disease related knowledge in gout patients and the relationship with adherence to urate-lowering therapy in east china

Radiologic evidence of symmetric and polyarticular monosodium urate crystal deposition in gout – A cluster pattern analysis of dual-energy CT

AB0934 DUAL-ENERGY COMPUTED TOMOGRAPHY IN GOUT PATIENTS: IS IT USEFUL IN GENERAL PRACTICE?

POS1477-HPR GOUT PATIENTS IN REMISSION, AND THEIR PERSPECTIVES ON URATE LOWERING THERAPY TREATMENT STOP OR CONTINUATION STRATEGIES

Hyperuricemia and chronic deposition of monosodium urate crystals are the main cause of the gout. Urate lowering therapy (ULT) is the mainstay of chronic gout treatment. In this study, we evaluated demographic features and disease properties of the patients that would relate with the success of ULT. Sixty-six gout patients on pharmacologic ULT were enrolled in the study. Non-adherence to pharmacologic ULT was an exclusion criterium. Demographic and therapeutic features and co-illnesses and disease features of the patients were obtained during the study. Then, we compared these parameters between the patients with successful ULT and inadequate ULT. Adherence to diet was found different between the groups (OR, 7.00; CL%95 2.27 - 21.56). All other features including maximum allopurinol dosage were similar. We found that diet was the only factor that relate with success of ULT, while patients were on pharmacologic ULT. Non-adherence to both pharmacologic and non-pharmacologic measures is the main problem during ULT. Therefore, clinicians should emphasize the importance of all segments of ULT, including diet with informing patients during visits about the nature of disease and benefits of ULT.

Editorial: Do Not Let Gout Apathy Lead to Gouty Arthropathy.

Prior imaging studies have suggested that monosodium urate (MSU) crystal deposits in joints dissolve more rapidly than those in tendons during urate-lowering therapy (ULT) for gout. This study aimed to examine whether urate deposits visible on dual-energy computed tomography (DECT) reduce at different rates in joints and tendons during ULT. Participants with gout from 2 clinical trials of oral ULT with the following criteria were included: paired DECT scans of the feet and ankles over 1-year of ULT, first DECT scan showing total urate volume ≥ 0.5 cm3, second DECT scan showing reduced total urate volume, and DECT deposition visible in at least 1 joint and 1 tendon on the first scan. DECT urate volumes in up to 3 index joints and up to 3 index tendons at baseline and year 1 were measured in known order. Data were analyzed using a general linear mixed analysis of covariance. In total, 125 joint deposits and 95 tendon deposits were analyzed from 50 participants. The least means change (95% CI) in DECT urate volumes of the joint deposits was -0.37 (-0.47 to -0.26) cm3 and of the tendon deposits was -0.39 (-0.50 to -0.27) cm3 (both P < 0.001). There was no difference in the change in DECT urate volumes between the joint and tendon deposits; least means difference was 0.02 (95% CI -0.09 to 0.13) cm3 (P = 0.73). This DECT study indicates that similar rates of MSU crystal dissolution occur at both joints and tendons during oral ULT.

AB0901 Clinical significance of urate deposition in tendon: a dual-energy ct study

BackgroundIt is currently unknown whether bone erosion in gout occurs through an ‘inside-out’ mechanism due to direct intra-osseous crystal deposition or through an ‘outside-in’ mechanism from the surface of bone. The aim of this study was to examine the mechanism (‘outside-in’ vs. ‘inside-out’) of monosodium urate (MSU) crystal deposition in bone erosion in gout. Specifically, we used three-dimensional dual-energy computed tomography (DECT) to analyse the positional relationship between bone and MSU crystal deposition in tophaceous gout, and to determine whether intra-osseous crystal deposition occurs in the absence of erosion.MethodsOne hundred forty-four participants with gout and at least one palpable tophus had a DECT scan of both feet. Two readers independently scored all metatarsal heads (1433 bones available for scoring). For bones in contact with urate, the bone was scored for whether urate was present within an erosion, on the surface of bone or within bone only (true intra-osseous deposit). Data were analysed using generalised estimating equations.ResultsUrate in contact with bone was present in 370 (54.3 %) of 681 joints with urate deposition. For those bones in contact with urate, deposition was present on the surface of bone in 143 (38.6 %) of 370 joints and within erosion in 227 (61.4 %) of 370. True intra-osseous urate deposition was not observed at any site (p < 0.0001). For all bones with apparent intra-osseous deposition in one plane, examination in other planes revealed urate deposition within an en face erosion.ConclusionsIn tophaceous gout, MSU crystal deposition is present within the joint, on the bone surface and within bone erosion, but it is not observed within bone in the absence of a cortical break. These data support the concept that MSU crystals deposit outside bone and contribute to bone erosion through an ‘outside-in’ mechanism.

Background:Gout is a painful and disabling inflammatory arthritis of increasing prevalence associated with hyperuricemia and the deposition of monosodium urate crystals in soft tissues and joints. Diagnosed gout cases have been estimated at 2.13% of the 2009 US population. The highest incidence occurs in the 65+ year age group, with males more than twice as likely to be afflicted as females.Objective:To present the epidemiology of chronic gout and to discuss its disease burden.Methods:This commentary is based on expert opinion and supplemented with published/presented information identified through PubMed and rheumatology associations.Results:The steady rise of diagnosed gout cases can generally be linked to an aging population with multiple comorbidities, the use of certain prescription medications, and changes in diet and lifestyle. Progression to chronic gout has numerous causes such as poor compliance with, ineffectiveness of, or inability to tolerate prescribed regimens. Despite the availability of urate-lowering therapies (ULT), patients may either have contraindications to them or may not adequately respond. Patients with high flare frequency, tophi, and the inability to maintain serum urate levels below 6 mg/dL with ULT can be categorized as having chronic gout that is refractory, with a substantial disease burden. Based on lack of therapeutic options for urate-lowering for patients with chronic gout refractory to conventional therapy, the economic burden of this small but substantial population contributes disproportionately to the overall economic burden of chronic gout. Recent availability of gout-specific ICD-9-CM codes capturing the cost intense and impactful aspects of the disease – flares and tophi – is likely contribute to understanding the full health economic burden in gout.Conclusion:The impact of chronic gout, especially if refractory to treatment, on functionality, productivity, quality of life and health care costs can be substantial and is deserving of future research.