Integrated safety studies of the urate reabsorption inhibitor lesinurad in treatment of gout.

Objective: Lesinurad (LESU) is a selective urate reabsorption inhibitor approved at 200 mg daily for use with a xanthine oxidase inhibitor (XOI) to treat hyperuricaemia in gout patients failing to achieve target serum urate on XOI. The aim of the study was to investigate the long-term safety of LESU + XOI therapy. Methods: Safety data were pooled from three 12-month phase III (core) trials evaluating LESU 200 and 400 mg/day combined with an XOI (LESU200+XOI and LESU400+XOI), and two 12-month extension studies using descriptive statistics. To adjust for treatment duration, treatment-emergent adverse events (TEAEs) were expressed as exposure-adjusted incidence rates (patients with events per 100 person-years). Results: In the core studies, exposure-adjusted incidence rates for total and total renal-related TEAEs were comparable for XOI alone and LESU200+XOI but higher with LESU400+XOI. Exposure-adjusted incidence rates for serum creatinine (sCr) elevations ⩾1.5×baseline were 2.9, 7.3 and 18.7, respectively. Resolution (sCr ⩽1.2×baseline) occurred in 75-90% of all events, with 66-75% occurring without any study medication interruption. Major adverse cardiovascular events were 3, 4 and 9 with XOI, LESU200+XOI and LESU400+XOI, respectively. Longer exposure in core+extension studies did not increase rates for any safety signals. Conclusion: At the approved dose of 200 mg once-daily combined with an XOI, LESU did not increase renal, cardiovascular or other adverse events compared with XOI alone, except for sCr elevations. With extended exposure in the core+extension studies, the safety profile was consistent with that observed in the core studies, and no new safety concerns were identified.

Vitamin D treatment for the prevention of falls in older adults: systematic review and meta-analysis.

OBJECTIVES: To systematically review and quantitatively synthesize the effect of vitamin D therapy on fall prevention in older adults. DESIGN: Systematic review and meta-analysis. SETTING: MEDLINE, CINAHL, Web of Science, EMBASE, Cochrane Library, LILACS, bibliographies of selected articles, and previous systematic reviews through February 2009 were searched for eligible studies. PARTICIPANTS: Older adults (aged > or = 60) who participated in randomized controlled trials that both investigated the effectiveness of vitamin D therapy in the prevention of falls and used an explicit fall definition. MEASUREMENTS: Two authors independently extracted data, including study characteristics, quality assessment, and outcomes. The I(2) statistic was used to assess heterogeneity in a random-effects model. RESULTS: Of 1,679 potentially relevant articles, 10 met inclusion criteria. In pooled analysis, vitamin D therapy (200-1,000 IU) resulted in 14% (relative risk (RR)=0.86, 95% confidence interval (CI)=0.79-0.93; I(2)=7%) fewer falls than calcium or placebo (number needed to treat =15). The following subgroups had significantly fewer falls: community-dwelling (aged <80), adjunctive calcium supplementation, no history of fractures or falls, duration longer than 6 months, cholecalciferol, and dose of 800 IU or greater. Meta-regression demonstrated no linear association between vitamin D dose or duration and treatment effect. Post hoc analysis including seven additional studies (17 total) without explicit fall definitions yielded smaller benefit (RR=0.92, 95% CI=0.87-0.98) and more heterogeneity (I(2)=36%) but found significant intergroup differences favoring adjunctive calcium over none (P=.001). CONCLUSION: Vitamin D treatment effectively reduces the risk of falls in older adults. Future studies should investigate whether particular populations or treatment regimens may have greater benefit.

Rituximab therapy for myopathy associated with anti-signal recognition particle antibodies: a case series.

OBJECTIVE: The myopathy associated with anti-signal recognition particle (anti-SRP) is a severe necrotizing immune-mediated disease characterized by rapidly progressive proximal muscle weakness, markedly elevated serum creatine kinase (CK) levels, and poor responsiveness to traditional immunosuppressive therapies. Reports on the efficacy of B cell depletion therapy for anti-SRP-associated myopathy are mixed. We describe 8 patients with anti-SRP-associated myopathy and their response to treatment with the anti-CD20 monoclonal antibody rituximab. METHODS: We identified 8 patients with myopathy who tested positive for anti-SRP antibodies by immunoprecipitation and were treated with rituximab as part of clinical care. We reviewed their medical records to assess clinical, serologic, and histologic characteristics and response to therapy. In 5 patients, serum was collected before and after rituximab therapy. Autoantibodies were detected by immunoprecipitation and quantitated by densitometry, and the percent decreases in anti-SRP autoantibody levels were calculated. RESULTS: Six of 8 patients who had been refractory to standard immunosuppressive therapy demonstrated improved manual muscle strength and/or decline in CK levels as early as 2 months after rituximab treatment. Three patients sustained the response for 12-18 months after initial dosing. All of the patients were continued on adjunctive corticosteroids, but doses were substantially reduced after rituximab. Quantitative levels of serum anti-SRP antibodies also decreased after rituximab treatment. CONCLUSION: B cell depletion therapy with rituximab is effective for patients with myopathy associated with anti-SRP. The substantial decrease in anti-SRP antibody levels after rituximab treatment also suggests that B cells and anti-SRP antibodies may play a role in the pathogenesis of this myopathy.

Drug-related myopathies of which the clinician should be aware.

Many drugs used for therapeutic interventions can cause unanticipated toxicity in muscle tissue, often leading to considerable morbidity. A drug-induced, or toxic, myopathy is defined as the acute or subacute manifestation of myopathic symptoms such as muscle weakness, myalgia, creatine kinase elevation, or myoglobinuria that can occur in patients without muscle disease when they are exposed to certain drugs. A brief review of agents with a known association with myotoxicity and the proposed mechanisms linked to that toxicity is outlined; however, the purpose of this review is to highlight recent discoveries and advances in the field of toxic myopathies that have practical implications for practicing physicians. Because many drug-related myopathies are potentially reversible at early stages, it is important for clinicians to recognize toxic myopathies early in their course to determine when to discontinue therapy and potentially prevent irreversible muscle damage.