Efficacy and safety of tildrakizumab in patients with active psoriatic arthritis: results of a randomised, double-blind, placebo-controlled, multiple-dose, 52-week phase IIb study.

OBJECTIVES: To evaluate efficacy and safety of the anti-interleukin-23p19 monoclonal antibody tildrakizumab in patients with psoriatic arthritis (PsA). METHODS: In this randomised, double-blind, placebo-controlled, phase IIb study, patients with active PsA were randomised 1:1:1:1:1 to tildrakizumab 200 mg every 4 weeks (Q4W); tildrakizumab 200, 100 or 20 mg Q12W; or placebo Q4W. Patients receiving tildrakizumab 20 mg or placebo switched to tildrakizumab 200 mg Q12W at W24; treatment continued to W52. The primary efficacy endpoint was proportion of patients with ACR20 response (≥20% improvement by American College of Rheumatology criteria) at W24. Secondary efficacy endpoints were assessed without adjustment for multiplicity. Safety was evaluated from treatment-emergent adverse events (TEAEs). RESULTS: 391/500 patients screened were randomised and treated. At W24, 71.4%-79.5% of tildrakizumab-treated versus 50.6% of placebo-treated patients achieved ACR20 (all p<0.01). Patients receiving tildrakizumab versus placebo generally achieved higher rates of ACR50, Disease Activity Score in 28 joints with C reactive protein <3.2, minimal disease activity and 75%/90%/100% improvement from baseline Psoriasis Area and Severity Index responses at W24 and through W52. Improvement in dactylitis and enthesitis was not observed; results were mixed for other outcomes. Responses in patients switched to tildrakizumab 200 mg at W24 were consistent with treatment from baseline. TEAEs and serious TEAEs occurred in 64.5% and 3.3%, respectively, of all patients through W52 and were comparable among treatment arms. CONCLUSIONS: Tildrakizumab treatment significantly improved joint and skin manifestations of PsA other than dactylitis and enthesitis. Treatment was generally well tolerated through W52. Clinicaltrials.gov NCT02980692.

Cardiovascular safety of febuxostat and allopurinol in patients with gout and cardiovascular comorbidities.

Comprehensive safety evaluation of new drugs for noncardiac indications is needed in the area of cardiovascular (CV) outcomes, particularly in populations with high CV risk such as gout. Febuxostat is a potent nonpurine selective inhibitor of xanthine oxidase approved for the treatment of gout. Long-term CV safety of febuxostat is being established in a randomized, allopurinol-controlled clinical study in patients with gout who have increased CV risk using an analytical approach that provides 90% power to meet a noninferiority margin of 1.3 for the hazard ratio (HR) (febuxostat relative to allopurinol). The primary CV end point for this trial is a composite of CV death, nonfatal myocardial infarction, nonfatal stroke, and unstable angina requiring urgent coronary revascularization. Approximately 7,500 men and women with gout and CV disease are being recruited and will be followed up for up to 5 years postrandomization. The statistical plan for the trial uses a design that evaluates the HR of febuxostat to allopurinol based on the primary CV composite end point when there are a maximum of 624 CV events. Interim analyses will be conducted when approximately 25%, 50%, and 75% of events have occurred. At each analysis, if the upper 1-sided confidence limit of the HR is <1.3, the study will be stopped, and the noninferiority of febuxostat relative to allopurinol with regard to CV risk will be declared. The CARES trial will define the CV safety profile of febuxostat and allopurinol in gout patients at high risk for CV events.

Update on emerging urate-lowering therapies.

PURPOSE OF REVIEW: To discuss currently available urate-lowering therapeutic options for gout in the United States and newer therapeutic initiatives in development. RECENT FINDINGS: Currently available urate-lowering drugs include allopurinol and probenecid. These drugs are effective but are often underdosed or underutilized, and caution must be taken in patients with multiple comorbidities. Newer therapeutic agents in development include febuxostat, a nonpurine analogue xanthine oxidase inhibitor, and pegloticase, a pegylated recombinant uricase. SUMMARY: There have been no new US Food and Drug Administration-approved urate-lowering drugs for gout in the past 40 years. Recent advances in therapeutics promise to provide the opportunity for much needed improvement in patient outcomes in this disorder.

Acute myocardial infarction after treatment of thrombocytopenia in a young woman with systemic lupus erythematosus.

We describe a case of an acute myocardial infarction (MI) coincident with correction of severe thrombocytopenia in a 23-year old African American woman with systemic lupus erythematosus (SLE) in the absence of coronary artery disease on angiography. Despite a history of anticardiolipin and beta(2)-glycoprotein I antibodies, she had no prior thromboembolic events. The occurrence of an acute MI after rapid normalization in the platelet count suggests the need for close monitoring of possible cardiovascular events during and after treatment of severe thrombocytopenia in the presence of antiphospholipid antibodies.

Long-term management of gout: nonpharmacologic and pharmacologic therapies.

Gout is a common disorder with clinical signs and symptoms resulting from inflammatory responses to monosodium urate crystals deposited in tissues from extracellular fluids saturated for urate. Long-term management of gout focuses on nonpharmacologic and pharmacologic means to achieve and maintain serum urate levels in a subsaturating range. Despite a firm understanding of gout pathophysiology, means to achieve certain diagnosis, and a variety of effective therapies, treatment outcomes remain suboptimal. In this review, available nonpharmacologic and pharmacologic therapies for chronic gout are discussed and a framework is provided for successful achievement and maintenance of goal-range serum urate levels.

Women with gout: efficacy and safety of urate-lowering with febuxostat and allopurinol.

OBJECTIVE: To compare the characteristics of female versus male gout patients and assess urate-lowering efficacy and safety of febuxostat or allopurinol treatment in women with gout. METHODS: This was a retrospective analysis of 4,101 hyperuricemic (serum urate [sUA] level ≥8.0 mg/dl) gout subjects enrolled in 3 phase III comparative trials and randomized to receive placebo, febuxostat (40 mg, 80 mg, 120 mg, or 240 mg daily), or allopurinol (100 mg, 200 mg, or 300 mg daily, based on renal function). Baseline demographics and characteristics were summarized and compared between female and male subjects. Urate-lowering efficacy, which was defined as the proportion of subjects with sUA levels <6.0 mg/dl at final visit, was assessed for all subjects and, among women, according to baseline renal function. RESULTS: Female gout subjects (n = 226) were older with significantly higher rates of obesity and metabolic and cardiovascular comorbidities than their male counterparts. The percentage of female subjects with sUA levels <6.0 mg/dl at final visit was 0% in the placebo group, 54.3%, 85.1%, 81.0%, and 100.0% in the febuxostat 40 mg, 80 mg, 120 mg, and 240 mg groups, respectively, and 45.9% in the allopurinol group. Similar patterns of urate-lowering efficacy rates were observed when stratified by renal function. Among all the female subjects, febuxostat 80 mg was significantly more efficacious than allopurinol (P < 0.001). Rates of adverse events (AEs) were low. The most frequently reported AEs were upper respiratory tract infections, musculoskeletal/connective tissue disorders, and diarrhea. CONCLUSION: These data suggest that febuxostat 80 mg may be more efficacious than commonly prescribed doses of allopurinol in female gout subjects with high rates of comorbidities.

Safety and efficacy of febuxostat treatment in subjects with gout and severe allopurinol adverse reactions.

OBJECTIVE: Allopurinol, a purine base analog inhibitor of xanthine oxidase (XO) activity, remains the standard for pharmacologic urate-lowering management of gout. Allopurinol is efficacious and safe in most patients, but intolerance is estimated to occur in up to 10% of treated patients. Severe or life-threatening allopurinol adverse reactions (AE) occur much less frequently, and include severe cutaneous allopurinol reactions, vasculitis, and/or a multisystem allopurinol hypersensitivity syndrome. During clinical development of febuxostat (FEB), a recently approved non-purine analog inhibitor of XO, subjects with severe allopurinol intolerance were excluded from randomized double-blind FEB/allopurinol comparative trials. METHODS: In this retrospective study, safety and urate-lowering efficacy of FEB was assessed in 13 successively encountered gout patients with prior documented severe allopurinol reactions. RESULTS: FEB was well tolerated in 12 of 13 patients, each of whom remains on treatment. One patient previously hospitalized with documented exfoliative erythroderma during allopurinol treatment, developed biopsy-confirmed cutaneous leukocytoclastic vasculitis. None of the other 12 patients treated with FEB showed rash, worsening hepatic function, blood cytopenia or eosinophilia. CONCLUSION: In 12 of our 13 gout patients with previously documented severe allopurinol AE, FEB treatment was safe. However, the development of a hypersensitivity type cutaneous vasculitis (likely but not definitively FEB-related) early in treatment mandates caution, careful dose escalation, and close monitoring when FEB urate-lowering therapy of allopurinol-intolerant patients is considered.

We can make gout management more successful now.

PURPOSE OF REVIEW: The purpose of this editorial review is to identify and comment on factors contributing to the current less-than-optimal state of gout management and to emphasize immediate opportunities to improve management practices affecting many patients with gout. RECENT FINDINGS: Numerous publications document deficits in the current management and clinical outcomes of gout despite detailed understanding of the pathogenesis and pathophysiology of the disorder, the ability to establish the diagnosis with certainty, and the likely effectiveness, for most patients, of available lifestyle and pharmacological interventions. Among impediments to successful gout management are diagnostic inaccuracy; a paucity of validated management recommendations to guide care providers; incomplete patient education about gout and the aims and modalities of management; suboptimal patient adherence, even to demonstrably effective therapeutic recommendations; comorbidities and drug interferences that complicate treatment of gout; patient groups at special risk for progression to chronic tophaceous gout; and limited urate-lowering alternatives. SUMMARY: Recent publication of evidence-based recommendations for the diagnosis and management of gout and the impending availability of new urate-lowering agents suggest that this is an opportune time to initiate professional and patient education efforts toward improved management of this increasingly common disorder.

Correlates of formal work disability in an urban university systemic lupus erythematosus practice.

OBJECTIVE: Work disability in systemic lupus erythematosus (SLE) has been sparsely studied. We sought to determine the demographic, disease-specific, and psychological features associated with work disability in patients with SLE at our medical center. METHODS: Ambulatory patients with SLE were enrolled in a cross-sectional study. Data collected by standardized interview, examination, questionnaire, and chart review were compared between formally work-disabled and never-disabled subjects. Multivariate logistic regression with outcome of formal work disability was then performed, using significant variables on univariate analysis. RESULTS: One hundred thirty-two of 143 subjects were working or students at time of SLE diagnosis. After a mean of 9.2 years' disease duration, 42.7% reported formal work disability due to SLE. On univariate analysis, lower education, African American ethnicity, marital status, and high disease activity and damage scores were associated with increased prevalence of work disability. Work type did not affect risk of work disability. Work-disabled subjects had more severe pain, fatigue, depression, and anxiety. On multivariate logistic regression, damage, African American ethnicity, and fatigue were associated with formal work disability, while global pain had a marginal association. CONCLUSION: Formal work disability was highly prevalent in SLE, occurring in 42.7% of subjects. Disease damage, global pain, and fatigue were independently associated with formal work disability status on multivariate logistic regression. Premorbid work types did not strikingly influence rates of work disability.

Whole blood viscosity and arterial thrombotic events in patients with systemic lupus erythematosus.

OBJECTIVE: To determine if whole blood viscosity (WBV), a rheologic variable contributing to risk of myocardial infarction and stroke in the general population, is elevated in patients with systemic lupus erythematosus (SLE), particularly SLE patients with a history of thrombotic or atherothrombotic events. Because the high rates of arterial and venous thrombosis in lupus cannot be explained by traditional risk factors, elevated WBV may be an easily measurable nontraditional risk factor to identify SLE patients at high risk for thrombotic events. METHODS: Sixty SLE patients (30 with a history of a thrombotic event) and 20 matched controls were recruited into the study. The thrombosis group was further subdivided into an arterial thrombosis group (n = 17). WBV values were determined at 9 different shear rates (1, 2, 5, 10, 50, 100, 150, 300, and 1,000 seconds(-1)). WBV was then compared between groups by repeated-measures analysis of variance. RESULTS: SLE patients with a history of arterial events had significantly elevated WBV relative to either controls (P = 0.022) or SLE patients without arterial events (P = 0.014). WBV in the total SLE group did not differ from controls. Differences in WBV were most prominent at lower shear rates (1, 2, 5, 10, 50, and 100 seconds(-1)). Anticoagulation, prednisone dose, and antiphospholipid antibodies did not significantly impact WBV. CONCLUSION: Our study demonstrated that WBV is selectively elevated in patients with SLE with a history of arterial events. Although this association is striking, longitudinal studies are needed to assess the positive predictive value of WBV for atherothrombotic events in SLE.