April W. Armstrong

Phase 3 Studies Comparing Brodalumab with Ustekinumab in Psoriasis

BACKGROUND Early clinical studies suggested that the anti-interleukin-17 receptor A monoclonal antibody brodalumab has efficacy in the treatment of psoriasis. METHODS In two phase 3 studies (AMAGINE-2 and AMAGINE-3), patients with moderate-to-severe psoriasis were randomly assigned to receive brodalumab (210 mg or 140 mg every 2 weeks), ustekinumab (45 mg for patients with a body weight ≤100 kg and 90 mg for patients >100 kg), or placebo. At week 12, patients receiving brodalumab were randomly assigned again to receive a brodalumab maintenance dose of 210 mg every 2 weeks or 140 mg every 2 weeks, every 4 weeks, or every 8 weeks; patients receiving ustekinumab continued to receive ustekinumab every 12 weeks, and patients receiving placebo received 210 mg of brodalumab every 2 weeks. The primary aims were to evaluate the superiority of brodalumab over placebo at week 12 with respect to at least a 75% reduction in the psoriasis area-and-severity index score (PASI 75) and a static physicians global assessment (sPGA) score of 0 or 1 (clear or almost clear skin), as well as the superiority of brodalumab over ustekinumab at week 12 with respect to a 100% reduction in PASI score (PASI 100). RESULTS At week 12, the PASI 75 response rates were higher with brodalumab at the 210-mg and 140-mg doses than with placebo (86% and 67%, respectively, vs. 8% [AMAGINE-2] and 85% and 69%, respectively, vs. 6% [AMAGINE-3]; P<0.001); the rates of sPGA scores of 0 or 1 were also higher with brodalumab (P<0.001). The week 12 PASI 100 response rates were significantly higher with 210 mg of brodalumab than with ustekinumab (44% vs. 22% [AMAGINE-2] and 37% vs. 19% [AMAGINE-3], P<0.001). The PASI 100 response rates with 140 mg of brodalumab were 26% in AMAGINE-2 (P=0.08 for the comparison with ustekinumab) and 27% in AMAGINE-3 (P=0.007). Rates of neutropenia were higher with brodalumab and with ustekinumab than with placebo. Mild or moderate candida infections were more frequent with brodalumab than with ustekinumab or placebo. Through week 52, the rates of serious infectious episodes were 1.0 (AMAGINE-2) and 1.3 (AMAGINE-3) per 100 patient-years of exposure to brodalumab. CONCLUSIONS Brodalumab treatment resulted in significant clinical improvements in patients with moderate-to-severe psoriasis. (Funded by Amgen; AMAGINE-2 and AMAGINE-3 ClinicalTrials.gov numbers, NCT01708603 and NCT01708629.).

The association between psoriasis and obesity: a systematic review and meta-analysis of observational studies.

Objective:Psoriasis is an inflammatory skin disease affecting 2–4% of the world population. The objective of this study was to perform a systematic review and meta-analysis synthesizing the epidemiological associations between psoriasis and obesity.Data sources:We searched for observational studies from MEDLINE, EMBASE and Cochrane Central Register from 1 January 1980 to 1 January 2012. We applied the Meta-Analysis of Observational Studies in Epidemiology guidelines in the conduct of this study.Study selection:We identified 16 observational studies with a total of 2.1 million study participants (201 831 psoriasis patients) fulfilling the inclusion criteria.Results:Using random-effects meta-analysis, the pooled odds ratio (OR) for obesity among patients with psoriasis was 1.66 (95% confidence interval (CI) 1.46–1.89) compared with those without psoriasis. From the studies that reported psoriasis severity, the pooled OR for obesity among patients with mild psoriasis was 1.46 (95% CI 1.17–1.82) and the pooled OR for patients with severe psoriasis was 2.23 (95% CI 1.63–3.05). One incidence study found that psoriasis patients have a hazard ratio of 1.18 (95% CI 1.14–1.23) for new-onset obesity.Conclusions:Overall, compared with the general population, psoriasis patients have higher prevalence and incidence of obesity. Patients with severe psoriasis have greater odds of obesity than those with mild psoriasis.

Group for Research and Assessment of Psoriasis and Psoriatic Arthritis 2015 Treatment Recommendations for Psoriatic Arthritis.

To update the 2009 Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) treatment recommendations for the spectrum of manifestations affecting patients with psoriatic arthritis (PsA).

Psoriasis and metabolic syndrome: A systematic review and meta-analysis of observational studies

BACKGROUND Increasing population-based studies have suggested a relationship between psoriasis and metabolic syndrome. OBJECTIVE The objective of this study was to perform a systematic review and meta-analysis that synthesizes the epidemiologic associations between psoriasis and metabolic syndrome. METHODS We searched for observational studies from MEDLINE, EMBASE, and Cochrane Central Register from Jan 1, 1980 to Jan 1, 2012. We applied the Meta-Analysis of Observational Studies in Epidemiology (MOOSE) guidelines in the conduct of this study. RESULTS We identified 12 observational studies with a total of 1.4 million study participants fulfilling the inclusion criteria, among whom 41,853 were patients with psoriasis. Based on random-effects modeling of cross-sectional and case-controlled studies, the pooled odds ratio (OR) for metabolic syndrome among patients with psoriasis was 2.26 (95% confidence interval [CI] 1.70-3.01) compared with the general population. Visual inspection of a funnel plot and formal analysis with the Egger test suggested publication bias and absence of small studies in the published literature (P = .03). A dose-response relationship was also observed between psoriasis severity and prevalence of metabolic syndrome. LIMITATIONS No studies to date have assessed incidence of metabolic syndrome among patients with psoriasis. CONCLUSIONS Compared with the general population, psoriasis patients have higher prevalence of metabolic syndrome, and patients with more severe psoriasis have greater odds of metabolic syndrome than those with milder psoriasis.

Undertreatment, treatment trends, and treatment dissatisfaction among patients with psoriasis and psoriatic arthritis in the United States: findings from the National Psoriasis Foundation surveys, 2003-2011.

IMPORTANCE Psoriasis and psoriatic arthritis inflict significant morbidity. Data on undertreatment, treatment use, and treatment satisfaction are paramount to identify priority areas for advocacy, education, and research to improve patient outcomes. OBJECTIVES To determine the extent of nontreatment and undertreatment of psoriatic diseases, trends in treatment use, treatment satisfaction, and reasons for medication discontinuation among patients with psoriasis and psoriatic arthritis. DESIGN, SETTING, AND PARTICIPANTS We used the national survey data collected by the National Psoriasis Foundation via biannual surveys conducted from January 1, 2003, through December 31, 2011, in the United States. Survey data were collected from randomly sampled patients with psoriasis and psoriatic arthritis in the US population from a database of more than 76,000 patients with psoriatic diseases. MAIN OUTCOMES AND MEASURES Nontreatment, undertreatment, and treatment trends determined by the use of prescription medication (topical, phototherapeutic, oral systemic, and biologic), as well as treatment satisfaction and reasons for medication discontinuation. RESULTS A total of 5604 patients with psoriasis or psoriatic arthritis completed the survey. From 2003 through 2011, patients who were untreated ranged from 36.6% to 49.2% of patients with mild psoriasis, 23.6% to 35.5% of patients with moderate psoriasis, and 9.4% to 29.7% of patients with severe psoriasis. Among those receiving treatment, 29.5% of patients with moderate psoriasis and 21.5% of patients with severe psoriasis were treated with topical agents alone. The most frequently used phototherapy modality is UV-B, whereas methotrexate is the most commonly used oral agent. Although adverse effects and a lack of effectiveness were primary reasons for discontinuing biological agents, the inability to obtain adequate insurance coverage was among the top reasons for discontinuation. Overall, 52.3% of patients with psoriasis and 45.5% of patients with psoriatic arthritis were dissatisfied with their treatment. CONCLUSIONS AND RELEVANCE Nontreatment and undertreatment of patients with psoriasis and psoriatic arthritis remain a significant problem in the United States. While various treatment modalities are available for psoriasis and psoriatic arthritis, widespread treatment dissatisfaction exists. Efforts in advocacy and education are necessary to ensure that effective treatments are accessible to this patient population.

Psoriasis and Major Adverse Cardiovascular Events: A Systematic Review and Meta-Analysis of Observational Studies

Background Psoriasis is a chronic inflammatory disease that may be associated with increased risk of cardiovascular events, including cardiovascular mortality, myocardial infarction, and stroke. Methods and Results We searched the MEDLINE, EMBASE, and Cochrane Central Register databases for relevant studies in English between January 1, 1980, and January 1, 2012. Extraction was by 3 independent reviewers. Summary incidence, risk ratios (RRs), and confidence intervals (CIs) were calculated using fixed‐effects and random‐effects modeling. Meta‐regression was also performed to identify sources of between‐study variation. Nine studies were included, representing a total of 201 239 patients with mild and 17 415 patients with severe psoriasis. The level of covariate adjustment varied among studies, leading to the possibility of residual confounding. Using the available adjusted effect sizes, mild psoriasis remained associated with a significantly increased risk of myocardial infarction (RR, 1.29; 95% CI, 1.02 to 1.63) and stroke (RR, 1.12; 95% CI, 1.08 to 1.16). Severe psoriasis was associated with a significantly increased risk of cardiovascular mortality (RR, 1.39; 95% CI, 1.11 to 1.74), myocardial infarction (RR, 1.70; 95% CI, 1.32 to 2.18), and stroke (RR, 1.56 95% CI, 1.32 to 1.84). Based on these risk ratios and the background population event rates, psoriasis is associated with an estimated excess of 11 500 (95% CI, 1169 to 24 407) major adverse cardiovascular events each year. Conclusions Mild and severe psoriasis are associated with an increased risk of myocardial infarction and stroke. Severe psoriasis is also associated with an increased risk of cardiovascular mortality. Future studies should include more complete covariate adjustment and characterization of psoriasis severity.

Angiogenesis and oxidative stress: Common mechanisms linking psoriasis with atherosclerosis

Shared angiogenic and oxidative mechanisms underlie the pathophysiology of psoriasis and atherosclerosis. During the pathogenesis of both diseases, stimuli such as injury or local hypoxia trigger the release of pro-angiogenic factors including IL-8, HIF-1α, ETS-1, and VEGF. These factors stimulate increased permeability and encourage leukocyte transmigration into areas of inflammation by enhanced expression of cell adhesion molecules. Psoriasis and atherosclerosis also share common enzymatic sources of reactive oxygen species (ROS), and these ROS influence several cellular signaling pathways implicated in the pathogenesis of both diseases. Pharmacologic and genetic therapies that target key factors in these pathways could provide innovative approaches to the management of psoriasis and potentially mitigate the cardiovascular complications suffered by psoriasis patients.

The association between psoriasis and hypertension: A systematic review and meta-analysis of observational studies

Population-based observational studies have suggested a relationship between psoriasis and hypertension. We performed a systematic review and meta-analysis to better understand the association between psoriasis and hypertension. We systematically searched MEDLINE, EMBASE, and the Cochrane Central Register from 1 January 1980 to 1 January 2012. Two authors independently assessed trial eligibility and quality. We applied the Meta-Analysis of Observational Studies in Epidemiology guidelines in the conduct of this study. We identified 24 observational studies with a total of approximately 2.7 million study participants fulfilling our inclusion criteria. Among them, 309 469 were patients with psoriasis. On the basis of random effects modeling of case–control and cross–sectional studies, the odds ratio (OR) for hypertension among patients with psoriasis was 1.58 [95% confidence interval (CI) 1.42–1.76] compared with the controls. The OR for hypertension among patients with mild psoriasis was 1.30 (95% CI 1.15–1.47) and the OR for hypertension among patients with severe psoriasis was 1.49 (95% CI 1.20–1.86) compared with the controls. Two cohort studies examining incidence of hypertension found that psoriasis was associated with a hazard ratio of 1.09 (95% CI 1.05–1.14) and 1.17 (95% CI 1.06–1.30) for development of hypertension. In a subgroup analysis, patients with psoriatic arthritis also had an increased prevalence of hypertension (OR 2.07, 95% CI 1.41–3.04). Psoriasis and psoriatic arthritis are associated with greater prevalence of hypertension. Patients with severe psoriasis have greater odds of hypertension than those with mild psoriasis.

Quality of Life and Work Productivity Impairment among Psoriasis Patients: Findings from the National Psoriasis Foundation Survey Data 2003–2011

Objective To ascertain impairment in quality of life and work productivity among patients with psoriasis and psoriatic arthritis. Design From 2003 through 2011, the National Psoriasis Foundation collected survey data from patients with psoriasis and psoriatic arthritis via email and telephone correspondences. Setting Survey data were collected from psoriasis and psoriatic arthritis patients in the general community in the U.S. Main Outcome Measures Quality of life focusing on emotional impact (anger, frustration, helplessness, etc.) and physical impact (pain, pruritus, physical irritation, etc.); employment status. Patients The surveys were performed through random sampling of participants from a database of over 75,000 patients. Results From 2003 to 2011, 5,604 patients completed the surveys. Psoriasis and psoriatic arthritis affected overall emotional wellbeing in 88% of patients, and they interfered with enjoyment of life in 82%. Most patients reported experiencing anger (89%), frustration (89%), helplessness (87%), embarrassment (87%), and self-consciousness (89%). Many patients also actively concealed physical manifestations of their diseases (83%), and experienced pain (83%) and pruritus (93%) regularly. Of note, 12% of patients were unemployed, and 11% worked part-time. Among unemployed patients, 92% cited psoriasis and/or psoriatic arthritis as the sole reasons for not working. Among working patients, 49% missed work days regularly due to psoriasis. Compared to patients with mild psoriasis, patients with severe psoriasis have 1.8 times greater odds to be unemployed after adjusting for age and gender (Adjusted OR = 1.7, 95% CI 1.4–2.3). Conclusion Patients with psoriasis and psoriatic arthritis continue to experience significant impairment of quality of life and work productivity.

Efficacy and safety of guselkumab, an anti-interleukin-23 monoclonal antibody, compared with adalimumab for the treatment of patients with moderate to severe psoriasis with randomized withdrawal and retreatment: Results from the phase III, double-blind, placebo- and active comparator–controlled VOYAGE 2 trial

Background: Phase II data suggested that guselkumab, an anti‐interleukin‐23 monoclonal antibody, was efficacious in psoriasis. Objective: We sought to assess efficacy and safety of guselkumab in moderate to severe psoriasis versus placebo and adalimumab, including interrupted treatment and switching adalimumab nonresponders to guselkumab. Methods: Patients were randomized to guselkumab 100 mg (weeks 0 and 4, then every 8 weeks; n = 496); placebo→guselkumab (weeks 0, 4, and 12 then guselkumab at weeks 16 and 20; n = 248); or adalimumab (80 mg week 0, then 40 mg week 1, and every 2 weeks through week 23; n = 248). At week 28, guselkumab 90% or greater improvement in Psoriasis Area and Severity Index (PASI) score from baseline (PASI 90) responders were rerandomized to guselkumab or placebo with guselkumab after loss of response. Placebo→guselkumab responders and adalimumab responders received placebo, then guselkumab after loss of response. Nonresponders received guselkumab. Results: At week 16, more patients receiving guselkumab achieved an Investigator Global Assessment (IGA) score 0/1 (cleared/minimal) (84.1% vs 8.5%) and PASI 90 (70.0% vs 2.4%) versus placebo (coprimary end points). Guselkumab was superior to adalimumab at week 16 (IGA score 0/1, 75% or greater improvement in PASI score from baseline, and PASI 90) and week 24 (IGA score 0/1 and 0, PASI 90, 100% improvement in PASI score from baseline) (P < .001). From weeks 28 to 48, better persistence of response was observed in guselkumab maintenance versus withdrawal groups (P < .001). Of adalimumab nonresponders who switched to guselkumab, 66.1% achieved PASI 90 at week 48. Guselkumab improved patient‐reported outcomes. Adverse events were comparable among groups. Limitations: One‐year follow‐up limits retreatment data. Conclusions: Guselkumab is a highly effective, well‐tolerated, maintenance therapy, including in adalimumab nonresponders.