Susan J. Lee

2012 American College of Rheumatology Guidelines for Management of Gout. Part 1: Systematic Nonpharmacologic and Pharmacologic Therapeutic Approaches to Hyperuricemia

DINESH KHANNA, JOHN D. FITZGERALD, PUJA P. KHANNA, SANGMEE BAE, MANJIT K. SINGH, TUHINA NEOGI, MICHAEL H. PILLINGER, JOAN MERILL, SUSAN LEE, SHRADDHA PRAKASH, MARIAN KALDAS, MANEESH GOGIA, FERNANDO PEREZ-RUIZ, WILL TAYLOR, FREDERIC LIOTE, HYON CHOI, JASVINDER A. SINGH, NICOLA DALBETH, SANFORD KAPLAN, VANDANA NIYYAR, DANIELLE JONES, STEVEN A. YAROWS, BLAKE ROESSLER, GAIL KERR, CHARLES KING, GERALD LEVY, DANIEL E. FURST, N. LAWRENCE EDWARDS, BRIAN MANDELL, H. RALPH SCHUMACHER, MARK ROBBINS, NEIL WENGER, AND ROBERT TERKELTAUB

2012 American College of Rheumatology guidelines for management of gout. Part 2: Therapy and antiinflammatory prophylaxis of acute gouty arthritis

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.

Utilization Trends of Tumor Necrosis Factor Inhibitors Among Patients with Rheumatoid Arthritis in a United States Observational Cohort Study

Objective. Studies have suggested that early institution of tumor necrosis factor (TNF) inhibitors improves functional status and slows radiographic progression among patients with rheumatoid arthritis (RA). To determine whether these findings have altered practice patterns, we used the Consortium of Rheumatology Researchers of North America (CORRONA) registry to assess the pattern of TNF inhibitor utilization in the US over time. Methods. Demographics and disease activity data were collected for patients with RA. The trend of TNF inhibitor use during 2002–06 was evaluated prospectively using linear and logistic regression models. Results. Of the 11,397 patients with RA, 66% and 34% had established RA and early RA (disease duration < 3 yrs), respectively. The majority of patients were female and Caucasian. Despite comparable levels of disease activity, more of the patients with established RA were taking TNF inhibitors than those with early RA (40% vs 25%; p < 0.0001). The majority of patients (70%) taking TNF inhibitors were also receiving disease modifying antirheumatic drugs. The use of TNF inhibitors increased at a rate of 2.8% per year in established RA and 1.2% per year in early RA. The mean Clinical Disease Activity Index at the start of TNF inhibitors decreased at a rate of −0.233 per quarter (p = 0.006), while the mean Disease Activity Score decreased at a rate of −0.04 per quarter (p = 0.022). Conclusion. Utilization of TNF inhibitors in this multicenter, observational US cohort is increasing in both early and established RA, although it is more prominent among patients with established RA. The level of disease activity at which TNF inhibitors were initiated decreased over time in patients with both established and early RA.

Recent developments in diet and gout.

Purpose of reviewGout is the most common inflammatory arthritis in men, affecting approximately 1–2% of adult men in Western countries. United States gout prevalence has approximately doubled over the past two decades. In recent years, key prospective epidemiological and open-labeled dietary studies, coupled with recent advances in molecular biology elucidating proximal tubular urate transport, have provided novel insights into roles of diet and alcohol in hyperuricemia and gout. This review focuses on recent developments and their implications for clinical practice, including how we advise patients on appropriate diets and alcoholic beverage consumption. Recent findingsStudies have observed an increased risk of gout among those who consumed the highest quintile of meat, seafood and alcohol. Although limited by confounding variables, low-fat dairy products, ascorbic acid and wine consumption appeared to be protective for the development of gout. SummaryThe most effective forms of dietary regimen for both hyperuricemia and gout flares remains to be unidentified. Until confirmed by a large, controlled study, it is prudent to advise patients to consume meat, seafood and alcoholic beverages in moderation, with special attention to food portion size and content of non-complex carbohydrates which are essential for weight loss and improved insulin sensitivity.

Health Care Utilization in Patients with Gout

OBJECTIVE To study health care utilization patterns in patients with gout. METHODS In a gout population from primary care and rheumatology clinics in 3 U.S. metropolitan cities, we collected data on gout-related utilization (primary care, rheumatology, urgent care, emergency room, and other) in the past year. We evaluated the association of comorbidities, age, gender, gout characteristics (time since last gout attack and tophi), and gout severity ratings (mean of serum uric acid, patient-rated, and physician-rated gout severity) and with emergency/urgent care and primary care utilization using regression and correlation analyses. RESULTS Of the 296 patients who reported visiting at least 1 type of health practitioner for gout in the past year, the percentage of patients utilizing the service at least once and annual utilization rates among utilizers were as follows: primary care physician, 60%, 3.0 ± 3.4; nurse practitioner/physician assistant, 26%, 2.7 ± 2.5; rheumatologist, 51%, 3.7 ± 5.7; urgent care, 23%, 2.1 ± 2.2; emergency room, 20%, 2.0 ± 1.7; and hospitalization, 7%, 2.1 ± 1.4. Higher overall gout severity was associated with greater use of each resource type and with overall gout-related utilization. Nonemergency/nonurgent care utilization (primary care physician, nurse practitioner, physicians assistant, and rheumatologist for gout) was the strongest predictor of gout-related emergency/urgent care utilization. Patients with more comorbidities had greater gout-related primary care utilization. CONCLUSIONS Overall gout severity was associated with all types of gout-related utilization. This may help to screen high utilizers for targeted behavioral and therapeutic interventions. Having a higher number of comorbid conditions was a risk factor for higher gout-related primary care utilization.

Monoclonal antibodies and fusion proteins and their complications: Targeting B cells in autoimmune diseases

The immune system consists of a complex array of immunocompetent cells and inflammatory mediators that exist in complex networks. These components interact through cascades and feedback circuits, maintaining physiologic inflammation and immunosurveillance. In various autoimmune conditions, a foreign or auto-antigen may upset this fine balance, leading to dysregulated immunity, persistent inflammation, and ultimately pathologic sequelae. In recent years, there has been tremendous progress delineating the specific components of the immune system that contribute to normal immunity and specific disease states. With this greater understanding of pathogenesis coupled with advances in biotechnology, many immunomodulatory agents, commonly called biologic agents, have been introduced. The 2 most common classes of biologic agents are monoclonal antibodies and fusion proteins. These agents can inhibit targets with exquisite specificity to optimize outcomes and minimize toxicity. B cells contribute significantly to the initiation and perpetuation of the immune responses. B cells not only can produce potentially pathologic autoantibodies and proinflammatory cytokines but also can present antigens to T cells and provide costimulatory signals essential for T-cell activation, clonal expansion, and effector function. This review focuses on biologic agents targeting B cells in the treatment of rheumatoid arthritis and systemic lupus erythematosus.

Discontinuation of tumour necrosis factor inhibitors in patients with rheumatoid arthritis in low-disease activity: persistent benefits. Data from the Corrona registry

BACKGROUND There is increasing interest in discontinuing biological therapies for patients with rheumatoid arthritis (RA) achieving good clinical responses, provided patients maintain clinical benefit. METHODS We assessed patients with RA from the Corrona registry who discontinued treatment with their first tumour necrosis factor inhibitor (TNFi) while in low-disease activity (LDA) or lower levels of disease activity. Patients were followed until they lost clinical benefit, defined as increased disease activity or change in RA medications. Duration of maintenance of clinical benefit was estimated using the Kaplan-Meier method. Cox proportional hazard models were assessed to identify factors related to maintenance of benefit. RESULTS We identified 717 eligible patients with RA from 35,656 in the Corrona registry. At discontinuation, patients had a median RA duration of 8 years, mean clinical disease activity score of 4.3±0.11; 41.8% were using TNFi as monotherapy. 73.4% of patients maintained benefit for >12 months after discontinuing therapy and 42.2% did so through 24 months. Factors predictive of maintaining clinical benefit in multivariate analysis included lower disease activity, less pain and better functional status at the time of TNFi discontinuation. Among 301 patients initiating their first TNFi within the registry, faster responders (ie, those who achieved LDA in 4 months or less) did better than slower responders (HR 1.54 (95% CI 1.17 to 2.04)). RA disease duration did not affect maintenance of clinical benefit. CONCLUSIONS Discontinuation of a first course of TNFi may be associated with persistent clinical benefit. Half of patients maintained response through 20 months. Several patient characteristics may help predict persistent benefit.

Gout disease-specific quality of life and the association with gout characteristics.

Purpose: Assess the association of gout characteristics with health-related quality of life (HRQoL) using a new gout-specific HRQoL instrument, the Gout Impact Scale (GIS). Patients and methods: Gout patients completed the GIS (five scales [0–100 score each] representing impact of gout overall [three scales] and during an attack [two scales]) and other questions describing recent gout attacks, treatment, gout history, comorbidities, and demographics. Physicians confirmed gout diagnosis, presence of tophi, and most recent serum uric acid (sUA) level. Relationships between gout characteristics and GIS scores were examined using analysis of variance and correlation analyses. Results: The majority of patients were male (90.2%) with a mean age of 62.2 (±11.8) years. Approximately one-half (49.7%) reported ≥3 gout attacks in the past year and the majority (57.9%) reported experiencing gout-related pain between attacks. Patients had appreciable concern about their gout (“gout concern overall” scale, 63.1 ± 28.0) but believed their treatment was adequate (“unmet gout treatment need” scale (38.2 ± 21.4) below scale mid-point). Significantly worse GIS scores were associated with increasing attack frequency and greater amount of time with pain between attacks (most scales, P < 0.001). Common objective measures such as sUA level, presence of tophi and the number of joints involved in a typical attack did not appear to be good indicators of the impact of gout on the patients’ HRQoL. Conclusion: Attack frequency and gout pain between attacks were important correlates of patients’ ratings of gout impact on their HRQoL. Further studies are needed to determine the minimal important difference for each GIS scale and interpret our results relative to other patient populations with gout.

Disease Severity and Pregnancy Outcomes in Women with Rheumatoid Arthritis: Results from the Organization of Teratology Information Specialists Autoimmune Diseases in Pregnancy Project

Objective. To determine the effect of rheumatoid arthritis (RA) disease severity on pregnancy outcomes in pregnant women with and without autoimmune diseases. Methods. A prospective cohort study was conducted using the Organization of Teratology Information Specialists Autoimmune Diseases in Pregnancy Project. Pregnant women with RA enrolled between 2005 and 2013 were selected if they (1) delivered a live-born singleton infant; and (2) completed 3 telephone-based measures of RA disease severity prior to 20 weeks’ gestation, including the Health Assessment Questionnaire Disability Index (HAQ-DI), pain score, and patient’s global scale. Associations between RA disease severity and preterm delivery, small for gestational age (SGA), or cesarean delivery were tested in unadjusted and multivariate analyses using modified Poisson regression models. Results. The sample consisted of 440 women with RA. Several unadjusted comparisons yielded significant associations. After adjustment for covariates, increasing disease severity was associated with risk for preterm delivery and SGA. For each unit increase in HAQ-DI (0–1), the adjusted relative risk (aRR) for preterm delivery increased by 58% (aRR 1.58, 95% CI 1.17–2.15). Among those with HAQ-DI > 0.5, the aRR for SGA was 1.81 (95% CI 1.01–3.33). Conclusion. RA disease severity in early pregnancy, as measured in this study, was predictive of preterm delivery and SGA. These findings suggest that the risk of preterm delivery and SGA in women with RA might be lowered if RA is well controlled early in pregnancy.

Minimally important differences of the gout impact scale in a randomized controlled trial

OBJECTIVE The Gout Impact Scale (GIS) is a gout-specific quality of life instrument that assesses impact of gout during an attack and impact of overall gout. The GIS has five scales and each is scored from 0 to 100 (worse health). Our objective was to assess minimally important differences (MIDs) for the GIS administered in a randomized controlled trial (RCT) assessing rilonacept vs placebo for prevention of gout flares during initiation of allopurinol therapy. METHODS Trial subjects (n = 83) included those with two or more gout flares (self-reported) in the past year. Of these, 73 had data for Weeks 8 vs 4 and formed the MID analysis group and were analysed irrespective of the treatment assignment. Subjects completed the GIS and seven patient-reported anchors. Subjects with a one-step change (e.g. from very poor to poor) were considered as the MID group for each anchor. The mean change in GIS scores and effect size (ES) was calculated for each anchors MID group. The average of these created the overall summary MID statistics for each GIS. An ES of 0.2-0.5 was considered to represent MID estimates. Results. Trial subjects (n = 73) were males (96.0%), White (90.4%), with mean age of 50.5 years and serum uric acid of 9.0 mg/dl. The mean change score for the MID improvement group for scales ranged from -5.24 to -7.61 (0-100 scale). The ES for the MID improvement group for the four scales ranged from 0.22 to 0.38. CONCLUSION The MID estimates for GIS scales are between 5 and 8 points (0-100 scale). This information can aid in interpreting the GIS results in future gout RCTs. Trial Registration. Clinicaltrials.gov, www.clinicaltrials.gov, NCT00610363.