Initiation Of Urate-lowering Therapy Research Articles

Effect of Urate Lowering Therapy on Renal Disease Progression in Hyperuricemic Patients with Chronic Kidney Disease.

To determine whether urate lowering therapy (ULT) could delay renal disease progression in hyperuricemic patients with chronic kidney disease (CKD). We performed a retrospective review of hyperuricemic patients with stage 3 CKD followed from September 2005 to July 2014 in Dongguk University Ilsan Hospital, Goyang, Korea. A total of 158 eligible patients were identified and 65 of them were treated with ULT in addition to the usual CKD management. We divided the patients according to the use of ULT and compared the estimated glomerular filtration rate (eGFR) change from baseline value and the proportion of renal disease progression (decline of eGFR > 30% of the baseline value, initiation of dialysis or eGFR < 15 ml/min/1.73m(2)) at the time of last followup. Risk factors for renal disease progression were identified by logistic regression analysis. After a median followup of 118.5 weeks (minimum 25, maximum 465), the ULT group showed better outcomes compared to the non-ULT group in terms of eGFR change from baseline (-1.19 ± 12.07 vs -7.37 ± 11.17 ml/min/1.73 m(2), p = 0.001) and the proportion of renal disease progression (12.3% vs 27.9%, p = 0.01). Goal-directed ULT showed better clinical outcomes compared to maintaining the initial ULT dose. Actual (area under the SUA-time curve adjusted by total observation time period) serum uric acid was significantly associated with the risk of renal disease progression (p for trend = 0.04) and actual serum uric acid level < 7 mg/dl reduced the risk of renal disease progression by 69.4%. ULT significantly delayed renal disease progression in hyperuricemic patients with CKD. Goal-directed ULT seems to be better than continuing the initial ULT prescription.

Patient and clinical characteristics associated with gout flares in an integrated healthcare system.

Gout flares have been challenging to identify in retrospective databases due to gout flares not being well documented by diagnosis codes, making it difficult to conduct accurate database studies. Previous studies have used different algorithms, and in this study, we used a computer-based method to identify gout flares. The objectives of this study were to identify gout flares in gout patients newly initiated on urate-lowering therapy and evaluate factors associated with a patient experiencing gout flares after starting drug treatment. This was a retrospective cohort study identifying gout patients newly initiated on a urate-lowering therapy (ULT) during the study time period of January 1, 2007–December 31, 2010. The index date was the first dispensed ULT prescription during the study time period. Patients had to be ≥18 years of age on index date, have no history of prior ULT prescription during 12 months before index date, and were required to have 12 months of continuous membership with drug benefit during pre-/post-index. Electronic chart notes were reviewed to identify gout flares; these reviews helped create a validated computer-based method to further identify patients with gout flares and were categorized into 0 gout flares, 1–2 gout flares, and ≥3 gout flares during the 12 months post-index period. Multivariable logistic regression was used to examine patient and clinical factors associated with gout flares during the 12-month follow-up period. There were 8905 patients identified as the final cohort and 68 % of these patients had one or more gout flares during the 12-month follow-up: 2797 patients (31 %) had 0 gout flares, 4836 (54 %) had 1–2 gout flares, and 1272 patients (14 %) had ≥3 gout flares. Using a multivariate regression analyses, factors independently associated with 1–2 gout flares and ≥3 gout flares versus no gout flares were similar, however, with slight differences, such as younger patients were more likely to have 1–2 gout flares and patients ≥65 years of age had ≥3 gout flares. Factors such as male gender, not attaining sUA goal, having ≥3 comorbidities, diuretics use, no changes in initial ULT dose, and not adhering to ULT all were associated with gout flares versus no gout flares. Using a new method to identify gout flares, we had the opportunity to compare our findings with the previous studies. Our study findings echo other previous studies where older patients, male, diuretics, having a greater number of comorbidities, and non-adherence are more likely to have more gout flares during the first year of newly initiating ULT. There is an unmet need for patients with gout to be educated and managed more closely, especially during the first year.

The impact of gout guidelines.

This review discusses the impact of recent treatment guidelines for the management of gout and the barriers to treating gout patients. Multiple guidelines for both the treatment and prevention of gout have been put forth in the last decade including those from the British Rheumatism Society; the European League Against Rheumatism; the Multinational Evidence, Expertise, Exchange Initiative; the Japanese Society of Gout and Nucleic Acid Metabolism; the American College of Rheumatology. These guidelines are designed to facilitate the management of gout by providers with key recommendations for the management of hyperuricemia, which is the greatest risk factor for developing gout. However, despite the extant guidelines, overall adherence to recommendations and uptake have been slow and initiation of urate-lowering therapy, titration of dosing, and monitoring of serum urate is infrequent. Greater education in proper management as well as increased awareness of new treatment strategies appear to be the primary reasons for this gap and offer avenues for improvement in management as well as areas for further research. Gout remains a treatment challenge for both acute and chronic disease. Despite the availability of management guidelines, primary care providers are struggling with appropriate management of the disease. More research tools and strategies are needed to improve overall outcomes and quality of care.

Ultrasound in gout: A useful tool for following urate-lowering therapy

ObjectiveWe aimed to determine the ability of ultrasonography (US) to show decrease or disappearance of urate deposits in gouty patients requiring urate-lowering therapy (ULT). MethodsTo be included in this prospective single-centre study, patients needed toexhibit (1) proven gout by monosodic urate (MSU) crystals in synovial fluid and (2) US-evidenced urate deposits (double contour [DC] sign and/or tophi) before starting ULT (allopurinol [n=4], febuxostat [n=12]). At baseline and after six months of ULT, one trained ultrasonographer assessed the knee and first metatarsophalangeal (MTP1s) joints. Serum uric-acid (SUA) level was assessed at baseline and at three and six months after ULT initiation. Correlation between US findings and achievement of SUA level objective (< 360μmol/L) was estimated by the kappa coefficient (κ). ResultsWe studied 16 patients (all males, mean age 61.0±18.3 years). The mean disease duration was 7.1±6.2 years. Tophi were found at clinical examination in 56% of patients. Baseline SUA levels were 688±153μmol/L. At baseline, US revealed tophi or a DC sign among 62.5 to 75% of patients in knees and 87.5% in MTP1s. After six months of ULT, none of the four patients, not achieving the SUA level objective, had disappearance of US features. Among the remaining 12 patients, US features (tophi or DC sign) disappeared or decreased in all but one with a stable DC sign in one MTP1. The correlation between the whole US examination and SUA level was excellent (κ=0.875). ConclusionsUS could show disappearance of urate deposits after ULT and appears to be well correlated with efficacy of ULT.

OP0008 Ultrasound in Gout: A Useful Tool for Follow-Up with Urate-Lowering Therapy

BackgroundRecently, ultrasonography (US) demonstratted its ability to detect urate deposition in gouty patients. Some US features have been suggested to be specific such as tophus and the double contour sign....

Prophylaxis for acute gout flares after initiation of urate-lowering therapy.

This review summarizes evidence relating to prophylaxis for gout flares after the initiation of urate-lowering therapy (ULT). We searched MEDLINE via PubMed for articles published in English from 1963 to 2013 using MEsH terms covering all aspects of prophylaxis for flares. Dispersion of monosodium urate crystals during the initial phase of deposit dissolution with ULT exposes the patient to an increased rate of acute flares that could contribute to poor treatment adherence. Slow titration of ULT might decrease the risk of flares. According to the most recent international recommendation, the two first-line options for prophylaxis are low-dose colchicine (0.5 mg once or twice a day) or low-dose NSAIDs such as naproxen 250 mg orally twice a day. They can be given for up to 6 months. If these drugs are contraindicated, not tolerated or ineffective, low-dose corticosteroids (prednisone or prednisolone) might be used. Recently, reports for four trials described the efficacy of canakinumab and rilonacept, two IL-1 inhibitors, for preventing flares during the initiation of allopurinol therapy. Prophylaxis for flares induced by ULT is an important consideration in gout management. Low-dose colchicine and low-dose NSAIDs are the recommended first-line therapies. Although no IL-1 blockers are approved as prophylactic treatment, this class of drug could become an interesting option for patients with gout with intolerance or contraindication to colchicine, NSAIDs or corticosteroids.

Gouty arthritis: an approach for general practice

Gout is a common crystal-induced inflammatory arthritis, the prevalence and clinical complexity of which is increasing in the face of a growing aged population with multiple co-morbidities. Recent epidemiological studies emphasise that lifestyle factors strongly influence the development of hyperuricaemia and gout. Moreover, there is growing evidence that gout is an independent risk factor for cardiovascular disease. Acute attacks of gout are extremely painful and disabling, and if repeated attacks go untreated, chronic deforming arthritis ensues. Early diagnosis and appropriate therapy is essential to reduce long-term disability. Identification of monosodium urate crystals on synovial fluid analysis is the gold standard in gout diagnosis. Nonsteroidal anti-inflammatory drugs and oral or intra-articular corticosteroids remain central to the treatment of acute attacks. Prophylactic colchicine use, during the intercritical period, reduces gout flares, a common complication on initiation of urate-lowering therapy (ULT). Allopurinol is the treatment of choice when ULT is indicated. Gout management is suboptimal in many patients because of non-adherence to treatment and underutilisation of available treatments. Treating to target: a serum uric acid level < 0.35mmol/l, prevents crystal deposition in joints and soft tissues, thereby preventing acute attacks and ongoing inflammation, as well as decreasing the size and number of tophi. Treatment strategies should include attention to cardiovascular risk. The family practitioner is paramount to gout management which should be individualised. Emphasis should be placed on ongoing education and prevention.

AB0639 Usefulness of musculoskeletal high resolution ultrasonography (hru) in routine clinical evaluation of “real world” patients with gout

BackgroundThe identification of urate monosodium crystals in aspirated joint fluid or tophi is the “gold standard” for its diagnosis, however clinical features helps in the assessment of typical cases. Ultrasound...

FRI0397 Adherence to EULAR recommendations for the treatment of GOUT

BackgroundGout is a relatively common condition with low adherence to urate-lowering therapy (ULT) which leads to frequent flares and disability. To improve patient care the European League Against Rheumatism (EULAR)...

Primary care providers' knowledge, beliefs and treatment practices for gout: results of a physician questionnaire

We sought to examine primary care providers' gout knowledge and reported treatment patterns in comparison with current treatment recommendations. We conducted a national survey of a random sample of US primary care physicians to assess their treatment of acute, intercritical and tophaceous gout using published European and American gout treatment recommendations and guidelines as a gold standard. There were 838 respondents (response rate of 41%), most of whom worked in private practice (63%) with >16 years experience (52%). Inappropriate dosing of medications in the setting of renal disease and lack of prophylaxis when initiating urate-lowering therapy (ULT) accounted for much of the lack of compliance with treatment recommendations. Specifically for acute podagra, 53% reported avoidance of anti-inflammatory drugs in the setting of renal insufficiency, use of colchicine at a dose of ≤2.4 mg/day and no initiation of a ULT during an acute attack. For intercritical gout in the setting of renal disease, 3% would provide care consistent with the recommendations, including initiating a ULT at the appropriate dose with dosing titration to a serum urate level of ≤6 mg/dl and providing prophylaxis. For tophaceous gout, 17% reported care consistent with the recommendations, including ULT use with dosing titration to a serum urate level of ≤6 mg/dl and prophylaxis. Only half of primary care providers reported optimal treatment practices for the management of acute gout and <20% for intercritical or tophaceous gout, suggesting that care deficiencies are common.

A qualitative and quantitative analysis of the characteristics of gout patient education resources

Patient education is an important aspect of gout management, but there is evidence that many patients lack adequate knowledge of their condition. Our aim was to examine the characteristics of gout patient education resources. Ten gout patient information resources were examined for readability (Flesch-Kincaid reading level, the Simple Measure of Gobbledygook measure and the Flesch Reading Ease Score), qualitative characteristics such as figure and jargon use and whether they included information on the major points of gout. The median readability grade level of the examined resources was 8.5. The difference in readability grade level between the highest and the lowest education resource was 6.3 grade levels. The information content of the resources was high with an average of only 3.9 proposed criteria of 19 (19 %) absent from the resources. Jargon use was low and concepts were usually explained. However, important information regarding acute flare prophylaxis during urate-lowering therapy initiation and titration and treating serum uric acid to target was absent from 60 % of the patient education resources. There was poor use of key messages at the start. Gout patient resources have a wide range of readability. Thirty percent of resources were above the average reading level of rheumatology outpatients reported in previous studies. Sixty percent of gout patient resources omit education items that could impact on patient adherence and in turn patient outcomes. Further research is needed into the literacy levels and education requirements of patients with gout.

Rilonacept in the treatment of acute gouty arthritis: a randomized, controlled clinical trial using indomethacin as the active comparator

IntroductionIn phase-3 clinical trials, the interleukin (IL-1) blocker, rilonacept (IL-1 Trap), demonstrated efficacy for gout flare prevention during initiation of urate-lowering therapy. This trial evaluated rilonacept added to a standard-of-care, indomethacin, for treatment of acute gout flares.MethodsAdults, aged 18-70 years, with gout presenting within 48 hours of flare onset and having at least moderate pain as well as swelling and tenderness in the index joint were randomized to subcutaneous (SC) rilonacept 320 mg at baseline plus oral indomethacin 50 mg TID for 3 days followed by 25 mg TID for up to 9 days (n = 74); SC placebo at baseline plus oral indomethacin as above (n = 76); or SC rilonacept 320 mg at baseline plus oral placebo (n = 75). The primary efficacy endpoint was change in pain in the index joint (patient-reported using a Likert scale (0 = none; 4 = extreme)) from baseline to the average of values at 24, 48 and 72 hours (composite time point) for rilonacept plus indomethacin versus indomethacin alone. Comparison of rilonacept monotherapy with indomethacin monotherapy was dependent on demonstration of significance for the primary endpoint. Safety evaluation included clinical laboratory and adverse event (AE) assessments.ResultsPatient characteristics were comparable among the groups; the population was predominantly male (94.1%), white (75.7%), with mean ± SD age of 50.3 ± 10.6 years. All treatment groups reported within-group pain reductions from baseline (P < 0.0001). Although primary endpoint pain reduction was greater with rilonacept plus indomethacin (-1.55 ± 0.92) relative to indomethacin alone (-1.40 ± 0.96), the difference was not statistically significant (P = 0.33), so formal comparison between monotherapy groups was not performed. Pain reduction over the 72-hour period with rilonacept alone (-0.69 ± 0.97) was less than that in the other groups, but pain reduction was similar among groups at 72 hours. Treatment with rilonacept was well-tolerated with no reported serious AEs related to rilonacept. Across all groups, the most frequent AEs were headache and dizziness.ConclusionsAlthough generally well-tolerated, rilonacept in combination with indomethacin and rilonacept alone did not provide additional pain relief over 72 hours relative to indomethacin alone in patients with acute gout flare.Trial registrationClinicalTrials.gov registration number NCT00855920.

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.

Treatment of Chronic Gouty Arthritis: It Is Not Just About Urate-Lowering Therapy

The management of gouty arthritis is focused on treating pain and inflammation associated with acute flares and preventing further acute flares and urate crystal deposition. A challenge associated with the successful management of gouty arthritis is an increased risk of acute flares during the first months after initiation of urate-lowering therapy (ULT). This increase in flare frequency can occur regardless of the choice of ULT and is linked to suboptimal patient adherence to ULT. Current treatment recommendations for the use of prophylaxis are limited. There are no definitive recommendations as to which agents should be used or for how long therapy is beneficial after starting ULT. This article aims to improve awareness of the importance of gouty arthritis flare prophylaxis when initiating ULT and to summarize current recommendations and clinical findings related to the efficacy and safety of currently available and investigational new therapies. This review discusses the pathophysiology of acute gouty arthritis flares during initiation of ULT and examines the literature on the use of anti-inflammatory prophylaxis for reduction of these flares. It has recently become clear that, even when the patient is asymptomatic, chronic inflammation is often present in patients with chronic gouty arthritis. Chronic anti-inflammatory therapy should therefore be added to chronic ULT. Prophylaxis with colchicine as well as with nonsteroidal anti-inflammatory drugs (NSAIDs) during ULT initiation can reduce the incidence and severity of gouty arthritis flares substantially; however, safety concerns associated with colchicine and NSAIDs may limit their use. When colchicine and NSAIDs are contraindicated or poorly tolerated, rilonacept and canakinumab, interleukin-1 inhibitors in trials, may prove to be useful alternatives for flare prevention. (Of note, although both inhibit the IL-1β pathway, rilonacept also binds to IL-1α and IL-1RA, in contrast to canakinumab, which binds selectively to IL-1β.).

Rilonacept (Interleukin‐1 Trap) in the prevention of acute gout flares during initiation of urate‐lowering therapy: Results of a phase II randomized, double‐blind, placebo‐controlled trial

To evaluate the interleukin-1 inhibitor rilonacept (Interleukin-1 Trap) for prevention of gout flares occurring in the first few months following initiation of urate-lowering therapy. In this double-blind study, adult patients with hyperuricemia and gout were randomized to receive rilonacept administered subcutaneously once per week (loading dose 320 mg followed by 160 mg weekly) or placebo, and started on allopurinol (300 mg/day, titrated to serum urate <6 mg/dl). At study visits, physical and laboratory assessments were performed and information on any adverse events was ascertained. Baseline characteristics were similar between the rilonacept and placebo groups (n = 41 and n = 42, respectively). The mean number of gout flares per patient through week 12 (primary efficacy end point) was markedly lower in the rilonacept group than in the placebo group (0.15 [6 flares] versus 0.79 [33 flares]; P = 0.0011). Fewer flares were observed with rilonacept as early as 4 weeks after initiation of treatment (P = 0.007). The proportion of patients experiencing a flare during the 12 weeks was lower in the rilonacept group than in the placebo group (14.6% versus 45.2%; P = 0.0037). No rebound in the flare rate was observed for 6 weeks after discontinuation of rilonacept or placebo at week 16. Adverse events were similar between groups, and no deaths or serious infectious adverse events were reported; the most common adverse events were infections (14.6% and 26.2% of rilonacept- and placebo-treated patients, respectively) and musculoskeletal disorders (14.6% and 21.4%, respectively). A higher percentage of rilonacept-treated patients (98%) compared with placebo-treated patients (79%) completed the primary 12-week evaluation period (P = 0.015). The current findings indicate that rilonacept significantly reduces the frequency of gout flares during the initial period of treatment with urate-lowering therapy, with a favorable safety profile.

Pilot Studies of Cherry Juice Concentrate for Gout Flare Prophylaxis

The management of gout involves treating pain and inflammation associated with acute flares and lowering the uric acid pool. A challenge associated with the successful management of gout is an increased risk of acute flares after initiation of urate-lowering therapy (ULT). Prophylactic anti-inflammatory therapy is recommended to prevent flares and foster compliance with urate lowering therapy. The aim of our studies was to assess whether use of cherry juice concentrate is useful for gout flare prophylaxis. We report the results of three studies using cherry juice concentrate for gout prophylaxis. The first is a randomized controlled study comparing the use of cherry juice concentrate versus pomegranate juice concentrate for flare prophylaxis. The second is a retrospective study evaluating flare prophylaxis when cherry juice concentrate was taken over a 4 month period or longer. Lastly, a third study evaluating the effect of cherry juice concentrate compared with pomegranate juice concentrate on secretion of interleukins by human monocytes exposed to monosodium urate (MSU) crystals in vitro. Ingesting cherry juice concentrate reduced the incidence of flares in gout patients regardless of whether or not they were treated with ULT. The number of flares was further reduced by cherry juice ingestion in patients receiving ULT than in patients not on ULT. We did not find a significant change in serum urate levels from baseline following intake of the cherry juice concentrate for 4 months or longer. Thus, cherry juice concentrate was most likely contributing to a reduction in flares via anti-inflammatory actions. We found cherry juice concentrate to inhibit in vitro secretion of IL-1β by up to 60%. In conclusion, our studies suggest that, consumption of cherry juice concentrate for a period of 4 months or longer, reduces acute gout flares, via anti-inflammatory actions such as inhibition of IL-1β secretion. Large long-term randomized controlled trials are needed to further evaluate the usefulness of cherries and cherry juice concentrate for gout flare prophylaxis.

Managing Your Patient with Gout: A Review of Treatment Options

Gout is an inflammatory arthritis that typically presents as acute onset, recurrent, monoarticular pain. In most patients, management of pain, risk assessment for future flares, and disability is not optimal and diagnostic and management approaches are applied inconsistently. Obtaining an accurate patient history, including comorbidities, concomitant medications, and familial history, is important for optimal results. Recognizing the acute flare in the patient at risk and establishing a definitive diagnosis of gout should be conducted promptly. Therapeutic options appropriate for treating the acute flare include colchicine, nonsteroidal anti-inflammatory drugs, and corticosteroids. After flare remission, prophylaxis with a flare prevention medication, such as colchicine, should be administered followed by initiation of urate-lowering therapy with allopurinol or febuxostat. Patient education, especially counseling on risk factors and contributors to hyperuricemia and gout, can improve the likelihood of successful therapy for this often suboptimally managed disease.

Canakinumab Reduces The Risk Of Acute Gouty Arthritis Flares During Initiation Of Allopurinol Therapy: Results Of A Double-blind, Randomised Study

RATIONALE: This study assessed the efficacy and safety of canakinumab, a fully human anti-interleukin-1beta monoclonal antibody, for prophylaxis against acute gouty arthritis flares in patients initiating urate-lowering therapy.

Effect of Prophylaxis on Gout Flares After the Initiation of Urate-Lowering Therapy: Analysis of Data From Three Phase III Trials

Background Use of urate-lowering therapy (ULT), such as febuxostat or allopurinol, is recommended for the long-term management of hyperuricemia in patients with gout to reduce the incidence of acute flares. Because of the paradoxical relationship between early use of ULT and the increased incidence of gout flares, prophylaxis with either low-dose colchicine or NSAIDs has been recommended, although there have been concerns about the long-term prophylactic use of these agents. Objectives The present analysis examined flare rates during the 3 Phase III trials of febuxostat based on mean postbaseline serum urate (sUA) concentrations and duration of prophylaxis. Adverse events (AEs) were assessed by prophylaxis with colchicine or naproxen. Methods This investigator-initiated, post hoc reanalysis of data on gout flares from the 3 randomized, placebo-controlled, Phase III trials evaluated the proportion of patients requiring treatment for gout flares at 4-week intervals based on mean postbaseline sUA concentrations <6.0 and ≥6.0 mg/dL. The 3 trials enrolled males or females aged 18–85 years who had a diagnosis of gout and a baseline sUA concentration ≥8.0 mg/dL. Patients received ULT (febuxostat or allopurinol) or placebo for 6 months or 1 year and flare prophylaxis with colchicine 0.6 mg/d or naproxen 250 mg BID for 8 weeks or 6 months. The prophylactic regimen was chosen at the discretion of the investigator, based on renal function and known intolerance to either drug. Patients with an estimated creatinine clearance <50 mL/min were not to receive naproxen. AEs were summarized based on prophylaxis with colchicine or naproxen. Results The 3 trials enrolled a total of 4101 patients with gout. The majority were white (80.1%), male (94.5%), and obese (body mass index ≥30 kg/m 2) (62.8%). The mean duration of gout ranged from 10.9–11.9 years, and the mean baseline sUA concentration ranged from 9.6–9.9 mg/dL. Flare rates increased sharply (up to 40%) at the end of 8 weeks of prophylaxis and then declined gradually, whereas flare rates were consistently low (range, 3%–5%) at the end of 6 months of prophylaxis. Mean postbaseline sUA concentrations were correlated with flare rates; by the end of each study, patients with a mean postbaseline sUA concentration <6.0 mg/dL had fewer flares than did those with a mean postbaseline sUA concentration ≥6.0 mg/dL. There were differences in rates of AEs between prophylaxis groups, but the rates did not increase with increased duration of prophylaxis. Conclusion This analysis of gout flare data from the 3 Phase III trials of febuxostat found that flare prophylaxis for up to 6 months during the initiation of ULT appeared to provide greater benefit than flare prophylaxis for 8 weeks, with no increase in AEs.

Interleukin‐1 antagonism in acute gout: Is targeting a single cytokine the answer?

Despite the existence of effective treatments, persons with gout continue to experience acute attacks. Among those who had an attack during the previous year, the risk of having at least 1 recurrent attack in the following year is 69% (1). Not surprisingly, persons with gout experience diminished quality of life and work disability (2), related not only to these recurrent flares, but also to the presence of painful and at times disfiguring tophi. Given that gout is a common crystalinduced inflammatory arthritis, with up to 6.1 million US adults having gout at some point in their lifetime (3), this disease presents a substantial public health burden. Management of gout consists of the following 3 strategies: treatment of acute attacks; lowering of serum uric acid levels in order to prevent acute flares and tissue deposition of uric acid crystals (tophi); and prophylaxis against flares, particularly during the initiation of uratelowering therapy, and other strategies to prevent flares. Unfortunately, management of hyperuricemia in gout is suboptimal (4), and inappropriate treatment of acute attacks occurs frequently (1). The recommended options for management of acute attacks include agents that nonspecifically target inflammation, such as nonsteroidal antiinflammatory drugs (NSAIDs), colchicine, corticosteroids, and possibly adrenocorticotropic hormone (ACTH) (5). Although NSAIDs and colchicine are accepted as effective treatments for gout attacks and are typically used as first-line agents for acute attacks (5), there are few placebo-controlled trials of these agents (6,7). In fact, despite its widespread use, oral colchicine was only recently (in 2009) approved by the Food and Drug Administration (FDA) for use in acute gout, an action supported by the results of a recent trial (7). While the relative efficacy of colchicine compared with NSAIDs is not known, the various NSAIDs appear to have similar benefits in acute gout. Unfortunately, NSAIDs and/or colchicine may be poorly tolerated or contraindicated in the presence of certain comorbidities. In such instances, intraarticular corticosteroids may be given for monarticular attacks, while systemic corticosteroids or ACTH may be used for polyarticular attacks or when sites not easily amenable to intraarticular injection are involved. However, the body of evidence for intraarticular corticosteroids and ACTH is poor (8). Systemic oral corticosteroids have recently been evaluated for the treatment of gout in 2 randomized placebo-controlled trials, with 1 trial evaluating prednisolone 30 mg daily and the other prednisolone 35 mg daily, both for 5 days. Both trials demonstrated equivalence to relatively standard regimens of NSAIDs (indomethacin and naproxen, respectively) (9,10). An alternate route for systemic administration of corticosteroids, intramuscular injection, was evaluated for acute gout in 2 studies (11,12). A 60 mg intramuscular triamcinolone dose with optional repeat administration demonstrated equivalent efficacy with its comparators, indomethacin and ACTH, respectively. However, both studies were small and of low quality (13). Most studies in acute gout have evaluated single drug regimens despite the regular use of combination therapies in clinical practice (8), suggesting that such practices merit further examination. While there are several effective management options for acute gout, refractory flares are a problem, particularly for persons with polyarticular and tophaceous gout. As such, multiple courses of corticosteroids are not infrequent among persons with chronic gout. Dr. Neogi’s work was supported by the NIH (National Institute of Arthritis and Musculoskeletal and Skin Diseases grant K23-AR-055127), an Arthritis Foundation Arthritis Investigator Award, an American College of Rheumatology Research and Education Foundation Junior Career Development Award in Geriatrics (T. Franklin Williams Scholar Award), and the Boston Claude D. Pepper Older Americans Independence Center (NIH grant P30-AG-031679). Tuhina Neogi, MD, PhD, FRCPC: Boston University School of Medicine and Boston University School of Public Health, Boston, Massachusetts. Address correspondence and reprint requests to Tuhina Neogi, MD, PhD, FRCPC, Boston University School of Medicine, Clinical Epidemiology Unit, 650 Albany Street, Suite X-200, Boston, MA 02118. E-mail: tneogi@bu.edu. Submitted for publication June 22, 2010; accepted in revised form June 24, 2010.