Herbert S. B. Baraf

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.

Abstract 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 physician practices. Primary care physicians have a significant opportunity to diagnose and manage patients with gout and improve patient outcomes. Following publication of the 2006 European League Against Rheumatism (EULAR) gout guidelines, significant evidence on gout has accumulated and new treatments for patients with gout have become available. It is the objective of these 2011 recommendations for the diagnosis and management of gout and hyperuricemia to update the 2006 EULAR guidelines, paying special attention to the needs of primary care physicians, who manage most patients with gout. 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 strength of recommendation in clinical practice. A total of 26 key recommendations for diagnosis (n = 10) and management (n = 16) were evaluated. Presence of tophus (proven or suspected) and response to colchicine had the highest clinical diagnostic value (likelihood ratio [LR], 15.56 [95% CI, 2.11–114.71] and LR, 4.33 [95% CI, 1.16–16.16], respectively). The key aspect of effective management of an acute gout attack is initiation of treatment within hours of onset of first symptoms. Low–dose colchicine is better tolerated than and is as effective as high–dose colchicine (number needed to treat [NNT], 5 [95% CI, 3–13] and NNT, 6 [95% CI, 3–72], respectively). For urate–lowering therapy, allopurinol in combination with probenecid was shown to be more effective than either agent alone (effect size [ES], 5.51 for combination; ES, 4.46 for probenecid; and ES, 2.80 for allopurinol). Febuxostat, also a xanthine oxidase inhibitor, has a slightly different mechanism of action and can be prescribed at unchanged doses for patients with mild–to–moderate renal or hepatic impairment. Febuxostat 40 mg versus 80 mg (NNT, 6 [95% CI, 4–11]) and 120 mg (NNT, 6 [95% CI, 3–26]) both demonstrated long–term efficacy. The target of urate–lowering therapy should be a serum uric acid level of # 6 mg∕dL. For patients with refractory and tophaceous gout, intravenous pegloticase is a new treatment option.

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.

Tophus burden reduction with pegloticase: results from phase 3 randomized trials and open-label extension in patients with chronic gout refractory to conventional therapy

IntroductionTwo replicate randomized, placebo-controlled six-month trials (RCTs) and an open-label treatment extension (OLE) comprised the pegloticase development program in patients with gout refractory to conventional therapy. In the RCTs, approximately 40% of patients treated with the approved dose saw complete response (CR) of at least one tophus. Here we describe the temporal course of tophus resolution, total tophus burden in patients with multiple tophi, tophus size at baseline, and the relationship between tophus response and urate-lowering efficacy.MethodsBaseline subcutaneous tophi were analyzed quantitatively using computer-assisted digital images in patients receiving pegloticase (8 mg biweekly or monthly) or placebo in the RCTs, and pegloticase in the OLE. Tophus response, a secondary endpoint in the trials, was evaluated two ways. Overall tophus CR was the proportion of patients achieving a best response of CR (without any new/enlarging tophi) and target tophus complete response (TT-CR) was the proportion of all tophi with CR.ResultsAmong 212 patients randomized in the RCTs, 155 (73%) had ≥1 tophus and 547 visible tophi were recorded at baseline. Overall tophus CR was recorded in 45% of patients in the biweekly group (P = 0.002 versus placebo), 26% in the monthly group, and 8% in the placebo group after six months of RCT therapy. TT-CR rates at six months were 28%, 19%, and 2% of tophi, respectively. Patients meeting the primary endpoint of sustained urate-lowering response to therapy (responders) were more likely than nonresponders to have an overall tophus CR at six months (54% vs 20%, respectively and 8% with placebo).Both overall tophus CR and TT-CRs increased with treatment duration in the OLE, reaching 70% (39/56) of patients and 55% (132/238) of target tophi after one year of treatment in patients receiving pegloticase during both the RCTs and OLE. At that time point, more tophi had resolved in responders (102/145 or 70% of tophi) than nonresponders (30/93; 32%).ConclusionsPegloticase reduced tophus burden in patients with refractory tophaceous gout, especially those achieving sustained urate-lowering. Complete resolution of tophi occurred in some patients by 13 weeks and in others with longer-term therapy.Trial registrationsNCT00325195, NCT01356498

A modified Delphi exercise to determine the extent of consensus with OMERACT outcome domains for studies of acute and chronic Gout

Objectives: To reach consensus with recommendations made by an OMERACT Special Interest Group (SIG). Methods: Rheumatologists and industry representatives interested in gout rated and clarified, in three iterations, the importance of domains proposed by the OMERACT SIG for use in acute and chronic gout intervention studies. Consensus was defined as a value of less than 1 of the UCLA/RAND disagreement index. Results: There were 33 respondents (61% response rate); all agreed the initial items were necessary, except “total body urate pool”. Additional domains were suggested and clarification sought for defining “joint inflammation” and “musculoskeletal function”. Items that demonstrated no clear decision were re-rated in the final iteration. There were six highly rated items (rating 1–2) with four slightly lower rating items (rating 3) for acute gout; and 11 highly rated items with eight slightly lower ratings for chronic gout. Conclusions: Consensus is that the following domains be considered mandatory for acute gout studies: pain, joint swelling, joint tenderness, patient global, physician global, functional disability; and for chronic gout studies: serum urate, gout flares, tophus regression, health-related quality of life, functional disability, pain, patient global, physician global, work disability and joint inflammation. Several additional domains were considered discretionary.

2011 Recommendations for the Diagnosis and Management of Gout and Hyperuricemia

Abstract 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.

Long-term safety of pegloticase in chronic gout refractory to conventional treatment

Objective To evaluate the long-term safety (up to 3 years) of treatment with pegloticase in patients with refractory chronic gout. Methods This open-label extension (OLE) study was conducted at 46 sites in the USA, Canada and Mexico. Patients completing either of two replicate randomised placebo-controlled 6-month trials received pegloticase 8 mg every 2 weeks (biweekly) or every 4 weeks (monthly). Safety was evaluated as the primary outcome, with special interest in gout flares and infusion-related reactions (IRs). Secondary outcomes included urate-lowering and clinical efficacy. Results Patients (n=149) received a mean±SD of 28±18 pegloticase infusions and were followed for a mean of 25±11 months. Gout flares and IRs were the most frequently reported adverse events; these were least common in patients with a sustained urate-lowering response to treatment and those receiving biweekly treatment. In 10 of the 11 patients with a serious IR, the event occurred when uric acid exceeded 6 mg/dl. Plasma and serum uric acid levels remained <6 mg/dl in most randomised controlled trial (RCT)-defined pegloticase responders throughout the OLE study and were accompanied by sustained and progressive improvements in tophus resolution and flare incidence. Conclusions The safety profile of long-term pegloticase treatment was consistent with that observed during 6 months of RCT treatment; no new safety signals were identified. Improvements in clinical status, in the form of flare and tophus reduction initiated during RCT pegloticase treatment in patients maintaining goal range urate-lowering responses were sustained or advanced during up to 2.5 years of additional treatment.

Safety and efficacy of topical diclofenac sodium gel for knee osteoarthritis in elderly and younger patients: Pooled data from three randomized, double-blind, parallel-group, placebo-controlled, multicentre trials

AbstractBackground: NSAIDs used for the treatment of osteoarthritis (OA) have dose-related risks for gastrointestinal, cardiovascular and renal adverse events (AEs), particularly in elderly patients. Topical NSAIDs reduce systemic NSAID exposure and may mitigate these risks. Objective: To evaluate the safety and efficacy of topical diclofenac sodium 1% gel (DSG) versus vehicle in patients aged 25–64 or ≥65 years who have been diagnosed with knee OA. Study Design: Pooled data from three 12-week, randomized, double-blind, parallel-group, multicentre trials. Setting: US primary care, internal medicine, orthopaedic and rheumatology practices. Patients: Aged ≥25 years with mild to moderate (Kellgren-Lawrence grade 1–3) knee OA. Intervention: After a 1-week analgesic washout, patients applied 4 g of DSG or vehicle four times daily to one knee. Rescue paracetamol (acetaminophen) up to 4 g/day was allowed. Main Outcome Measure: Key efficacy outcomes common to the three trials were Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain (0–20) and physical function (0–68) subscales, global rating of disease (GRD; 100-mm visual analogue scale [VAS]) and pain on movement (POM; 100-mm VAS). ANOVA was used to compare efficacy outcome differences (DSG vs vehicle) by age (25–64 or ≥65 years). A flare design was used that defined a subset of patients who experienced increased pain during the washout period (modified efficacy subpopulation [MES]). Results: The MES included both patients aged 25–64 (n=602) and ≥65 (n = 374) years. Patients in each age group applied >90% of scheduled doses. Among patients aged 25–64 years, the improvement from baseline to week 12 (least squares mean [standard error]) was greater for DSG versus vehicle for WOMAC pain (−5.8 [0.3] vs −4.7 [0.3], p = 0.007), WOMAC physical function (−17.9 [0.9] vs −14.2 [0.9], p = 0.002), GRD (−29.5 [1.6] vs −23.8 [1.6], p = 0.01) and POM (−37.3 [1.8] vs −29.0 [1.8], p <0.001). Among patients aged ≥65 years, the improvements from baseline for most efficacy outcome scores were significantly greater with DSG versus vehicle: WOMAC pain (−5.3 [0.3] vs −4.1 [0.4], p = 0.02), WOMAC physical function (−15.5 [1.1] vs −11.0 [1.1], p = 0.004) and POM (−33.7 [2.2] vs −26.4 [2.2], p = 0.02). The efficacy of DSG did not differ significantly between patients aged 25–64 years and ≥65 years: WOMAC pain (p = 0.85), WOMAC physical function (p = 0.70), GRD (p = 0.86) and POM (p = 0.81). The incidence of any AE was greater with DSG than with vehicle among patients aged 25–64 years (56.6% vs 50.8%) and ≥65 years (55.8% vs 43.9%). Treatment-related application site dermatitis was more common with DSG compared with vehicle in both younger (4.0% vs 0.7%, respectively) and older (5.8% vs 0.4%, respectively) patients and was the main reason for the difference in treatment-related AEs between the DSG and vehicle groups. Gastrointestinal AEs were infrequent among patients treated with DSG and similar to incidence rates with vehicle in both age groups. Conclusions: DSG was effective and generally well tolerated in adults regardless of age. These data support the topical application of DSG for relief of OA knee pain in elderly and younger patients.Clinicaltrials.gov registration numbers NCT00171626, NCT00171678, NCT00426621.

Safety and efficacy of topical diclofenac sodium 1% gel in knee osteoarthritis: A randomized controlled trial

Abstract Background: Topical nonsteroidal anti-inflammatory drugs (NSAIDs) may provide an alternative to oral NSAIDs to relieve pain from osteoarthritis (OA), reducing systemic exposure. This 12-week, randomized, double-blind, parallel-group, multicenter trial examined the efficacy and safety of topical diclofenac sodium 1% gel (DSG) for symptomatic knee OA. Methods: Eligible patients were aged ≥ 35 years with symptomatic Kellgren-Lawrence grade (KLG) 1 to 3 OA in 1 or both knees for ≥ 6 months. Patients meeting entry criteria applied DSG 4 g or vehicle 4 times daily to the symptomatic knee(s). Primary endpoints were Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain and physical function subscales and global rating of benefit at week 12. Pain on movement at week 4 was an additional primary endpoint for European regulatory purposes. Secondary endpoints included primary outcomes at weeks 1, 4, and 8; WOMAC stiffness subscale; spontaneous pain; global rating of disease; and global evaluation of treatment. Subanalyses were performed according to KLG, the number of knees treated, and age. Results: Four hundred twenty patients were randomly assigned to DSG (n = 208) or vehicle (n = 212). At week 12, DSG provided significantly greater reductions in WOMAC pain (52.6% vs 43.1%; P = 0.008) and physical function (49.7% vs 39.4%; P = 0.004) versus vehicle and provided significant improvements in most secondary endpoints. Treatment-related adverse events (AEs) were infrequent (DSG, 7.7%; vehicle, 4.2%), with application site dermatitis being the most common AE (DSG, 4.8%; vehicle, 0%). No treatment-related gastrointestinal or serious AEs occurred with DSG. Conclusion: Topical DSG treatment provided effective pain relief and functional improvement of OA in 1 or both knees and was well tolerated, irrespective of disease severity or patient age.

Exploratory Study of Radiographic Change in Patients With Tophaceous Gout Treated With Intensive Urate‐Lowering Therapy

Tophi are strongly associated with structural damage in gout, and urate‐lowering therapy reduces tophus size. Pegloticase leads to dramatic reductions in serum urate and subcutaneous tophi in treatment responders. The aim of this analysis was to examine whether profound urate lowering can alter radiographic findings in gout.