Alexa B. Kimball

Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 76-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 1)

BACKGROUND Interleukins 12 and 23 have important roles in the pathophysiology of psoriasis. We assessed ustekinumab, a human monoclonal antibody directed against these cytokines, for the treatment of psoriasis. METHODS In this phase III, parallel, double-blind, placebo-controlled study, 766 patients with moderate-to-severe psoriasis were randomly assigned to receive ustekinumab 45 mg (n=255) or 90 mg (n=256) at weeks 0 and 4 and then every 12 weeks; or placebo (n=255) at weeks 0 and 4, with subsequent crossover to ustekinumab at week 12. Patients who were initially randomised to receive ustekinumab at week 0 who achieved long-term response (at least 75% improvement in psoriasis area and severity index [PASI 75] at weeks 28 and 40) were re-randomised at week 40 to maintenance ustekinumab or withdrawal from treatment until loss of response. Both randomisations were done with a minimisation method via a centralised interactive voice response system. The primary endpoint was the proportion of patients achieving PASI 75 at week 12. Analyses were by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00267969. FINDINGS All randomised patients were included in the efficacy analysis. 171 (67.1%) patients receiving ustekinumab 45 mg, 170 (66.4%) receiving ustekinumab 90 mg, and eight (3.1%) receiving placebo achieved PASI 75 at week 12 (difference in response rate vs placebo 63.9%, 95% CI 57.8-70.1, p<0.0001 for 45 mg and 63.3%, 57.1-69.4, p<0.0001 for 90 mg). At week 40, long-term response had been achieved by 150 patients in the 45 mg group and 172 patients in the 90 mg group. Of these, 162 patients were randomly assigned to maintenance ustekinumab and 160 to withdrawal. PASI 75 response was better maintained to at least 1 year in those receiving maintenance ustekinumab than in those withdrawn from treatment at week 40 (p<0.0001 by log-rank test). During the placebo-controlled phase, adverse events occurred in 278 (54.5%) of the 510 patients receiving ustekinumab and 123 (48.2%) of the 255 receiving placebo. Serious adverse events occurred in six (1.2%) of 510 patients receiving ustekinumab and in two (0.8%) of 255 receiving placebo in this phase. The pattern of adverse events was much the same in the placebo crossover and randomised withdrawal phases as it was in the placebo-controlled phase. INTERPRETATION Ustekinumab seems to be efficacious for the treatment of moderate-to-severe psoriasis; dosing every 12 weeks maintains efficacy for at least a year in most patients.

National Psoriasis Foundation clinical consensus on psoriasis comorbidities and recommendations for screening

There have been several articles and reports in recent months about comorbidities and risks that affect psoriasis patients in addition to their underlying disease. This piece reviews the current literature and begins to address what should be done with this new information by updating the clinician about what health screening tests, preventative exams, and referrals should be considered in this population.

The Psychosocial Burden of Psoriasis

AbstractBackground: Skin diseases such as psoriasis can profoundly influence a patient’s self-image, self-esteem, and sense of well-being. Psoriasis is a multifactorial inflammatory condition with a disease burden that extends beyond the physical symptoms experienced by patients. Psoriasis affects all aspects of quality of life, including physical, psychologic, social, sexual, and occupational elements. Objective: The goal of this article was to review the published literature on the impact of psoriasis on quality of life. Methods: Relevant studies were identified through a comprehensive search of MEDLINE, EMBASE, and the Derwent Drug File databases of English-language articles published between 1993 and 2005 using the terms psoriasis in combination with quality of life, cost, cost-benefit analysis, economic, employment, days lost, healthcare, hospitalization, managed care, outcomes research, occupation, payers, and psychosocial. The reference lists of identified articles were checked for additional studies that might have been missed in the original searches. Results: Data suggest that social stigmatization, high stress levels, physical limitations, depression, employment problems and other psychosocial co-morbidities experienced by patients with psoriasis are not always proportional to, or predicted by, other measurements of disease severity such as body surface area involvement or plaque severity. Conclusion: It is essential to include measures of psychosocial morbidity when assessing psoriasis severity and treatment efficacy because of the substantial role that psychosocial burden plays in patient perception of disease severity, quality of life, and disease course.

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.).

Association between biologic therapies for chronic plaque psoriasis and cardiovascular events: A meta-analysis of randomized controlled trials

CONTEXT Ustekinumab and briakinumab, monoclonal antibodies to the shared p40 subunit of interleukin (IL)-12 and IL-23, have shown efficacy in treating chronic plaque psoriasis (CPP). Preliminary reports of major adverse cardiovascular events (MACEs) in psoriasis patients receiving anti-IL-12/23 agents have prompted concern. OBJECTIVE To evaluate a possible association between biologic therapies for CPP and MACEs via meta-analysis. DATA SOURCES Randomized controlled trials (RCTs) of anti-IL-12/23 (ustekinumab and briakinumab) agents and anti-tumor necrosis factor α (TNF-α) agents (adalimumab, etanercept, and infliximab) used in treating CPP were reviewed using the Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, and Ovid MEDLINE from database inception to May 2011. The results of registered nonpublished completed studies were procured through abstract publications or poster presentations. STUDY SELECTION Randomized, placebo-controlled, double-blind, monotherapy studies (with safety outcome data for MACE) of IL-12/23 antibodies and anti-TNF-α agents in adults. Studies of psoriatic arthritis were excluded. DATA EXTRACTION Two investigators independently searched data while 6 investigators reviewed the abstracted data. RESULTS A total of 22 RCTs comprising 10 183 patients met the predefined inclusion criteria. The primary outcome measure was MACE, a composite end point of myocardial infarction, cerebrovascular accident, or cardiovascular death during the placebo-controlled phase of treatment in patients receiving at least 1 dose of study agent or placebo. Absolute risk differences were used as an effect measure. There was no evidence of statistical heterogeneity across the studies using the I(2) statistic (I(2) = 0), allowing for combination of trial results using the Mantel-Haenszel fixed-effects method. During the placebo-controlled phases of the anti-IL-12/23 studies, 10 of 3179 patients receiving anti-IL-12/23 therapies experienced MACEs compared with zero events in 1474 patients receiving placebo (Mantel-Haenszel risk difference, 0.012 events/person-year; 95% confidence interval [CI], -0.001 to 0.026; P =.12). In the anti-TNF-α trials, only 1 of 3858 patients receiving anti-TNF-α agents experienced a MACE compared with 1 of 1812 patients receiving placebo (Mantel-Haenszel risk difference, -0.0005 events/person-year; 95% CI, -0.010 to 0.009; P = .94). CONCLUSIONS Compared with placebo, there was no significant difference in the rate of MACEs observed in patients receiving anti-IL-12/IL-23 antibodies or anti-TNF-α treatments. This study may have been underpowered to identify a significant difference.

Safety and Efficacy of ABT-874, a Fully Human Interleukin 12/23 Monoclonal Antibody, in the Treatment of Moderate to Severe Chronic Plaque Psoriasis : Results of a Randomized, Placebo-Controlled, Phase 2 Trial

OBJECTIVE To investigate the efficacy and safety of ABT-874, an interleukin 12/23 monoclonal antibody, in psoriasis. DESIGN Phase 2, 12-week, multicenter, randomized, double-blind, placebo-controlled trial. SETTING Outpatient dermatology clinics. Patients One hundred eighty patients with clinically stable moderate to severe chronic plaque psoriasis. Interventions Patients were randomized in groups of 30 to receive 1 of 6 treatments with ABT-874 provided as a subcutaneous injection: one 200-mg dose at week 0; 100 mg every other week for 12 weeks; 200 mg weekly for 4 weeks; 200 mg every other week for 12 weeks; 200 mg weekly for 12 weeks; or placebo. Main Outcome Measure At least a 75% reduction in the Psoriasis Area and Severity Index. RESULTS The percentage of patients achieving a 75% reduction in the Psoriasis Area and Severity Index at week 12 was statistically significantly greater in all of the ABT-874 treatment groups than in the placebo group (200 mg once, 63% [19 of 30]; 100 mg every other week for 12 weeks, 93% [28 of 30]; 200 mg weekly for 4 weeks, 90% [27 of 30]; 200 mg every other week for 12 weeks, 93% [28 of 30]; 200 mg weekly for 12 weeks, 90% [27 of 30]; placebo, 3% [1 of 30]; P < .001). Treatment with ABT-874 was well tolerated. The most common adverse event was injection-site reaction, and the most common infectious adverse events were nasopharyngitis and upper respiratory tract infection. There were no serious infectious adverse events. CONCLUSIONS ABT-874, an interleukin 12/23 monoclonal antibody, was highly effective and well tolerated in the treatment of psoriasis. Longer-term studies are required to confirm these findings.

Adalimumab for the Treatment of Moderate to Severe Hidradenitis Suppurativa: A Parallel Randomized Trial

BACKGROUND Hidradenitis suppurativa (HS) is a chronic, painful skin disease characterized by abscesses, nodules, and draining fistulas in the axilla and groin of young adults. OBJECTIVE To evaluate the efficacy and safety of adalimumab, an anti-tumor necrosis factor-α antibody, in patients with moderate to severe HS. DESIGN Phase 2, parallel, randomized, placebo-controlled trial consisting of a blinded 16-week period (period 1) and an open-label 36-week period (period 2). All study personnel, investigators, and patients remained blinded to treatment group throughout the study. (ClinicalTrials.gov: NCT00918255) SETTING 26 academic and private practice medical centers in the United States and Europe. PATIENTS 154 adult patients with moderate to severe HS who were unresponsive or intolerant to oral antibiotics. INTERVENTION Patients were assigned in a 1:1:1 ratio to adalimumab, 40 mg/wk; adalimumab, 40 mg every other week (EOW); or placebo. All patients received adalimumab, 40 mg EOW, at the beginning of period 2 but switched to weekly dosing if the response was suboptimal (HS Physicians Global Assessment [PGA] score of moderate or worse) at weeks 28 or 31. MEASUREMENTS The primary outcome measure (clinical response) was the proportion of patients achieving an HS-PGA score of clear, minimal, or mild with at least a 2-grade improvement relative to baseline at week 16. RESULTS At week 16, 3.9% of placebo patients (2 of 51), 9.6% of EOW patients (5 of 52), and 17.6% of weekly patients (9 of 51) achieved clinical response (EOW vs. placebo strata-adjusted difference, 5.6% [95% CI, -4.0% to 15.3%]; P = 0.25; weekly vs. placebo strata-adjusted difference, 13.7% [CI, 1.7% to 25.7%]; P = 0.025). Serious adverse event rates were 3.9%, 5.8%, and 7.8% for placebo, EOW, and weekly patients, respectively (EOW vs. placebo difference, 1.8% [CI, -6.4% to 10.1%]; weekly vs. placebo difference, 3.9% [CI, -5.2% to 13.0%]). Significantly greater improvements in patient-reported outcomes and pain were seen in the weekly dosing group than in the placebo group. A decrease in response was seen after the switch from weekly to EOW dosing in period 2. LIMITATIONS Weeks 16 to 52 of the study were open-label. The study was not powered to assess the risk for known serious adverse effects of adalimumab, such as tuberculosis, other serious infections, and demyelinating disorders. CONCLUSION Adalimumab dosed once per week alleviates moderate to severe HS. PRIMARY FUNDING SOURCE Abbott Laboratories.

Cardiovascular Disease and Risk Factors among Psoriasis Patients in Two US Healthcare Databases, 2001–2002

Background: Cardiovascular diseases or risk factors (CVDR) seem to be more common in psoriasis patients than in the general population. Objective: We assessed the relationship of psoriasis with CVDR by analysis of healthcare claims data using a cross-sectional, prevalence-based study design. Patients and Methods: The IMS Health and MarketScan® claims databases were used to identify adults with psoriasis diagnostic codes. Non-psoriasis controls were matched 3:1 based on age, gender, census region and previous medical insurance coverage. Odds ratios evaluated the relative prevalence of CVDR, and Mantel-Haenszel confidence intervals were estimated. Results: CVDR prevalence was generally higher in psoriasis patients than controls in both datasets. Odds ratios for atherosclerosis, congestive heart failure, type 2 diabetes, and peripheral vascular disease were ≧1.20 for psoriasis patients. Elevated disease severity was associated with a higher rate of CVDR, but varied somewhat by dataset and condition. Conclusions: Elevated CVDR rates were found in psoriasis patients compared with controls. This pattern merits further examination.

Psoriasis: is the impairment to a patient’s life cumulative?

Psoriasis is associated with significant physical and psychological burden affecting all facets of a patient’s life – relationships, social activities, work and emotional wellbeing. The cumulative effect of this disability may be self‐perpetuating social disconnection and failure to achieve a ‘full life potential’ in some patients. Health‐related quality of life studies have quantified the burden of psoriasis providing predominantly cross‐sectional data and point‐in‐time images of patients’ lives rather than assessing the possible cumulative disability over a patient’s lifetime. However, social and economic outcomes indicate there are likely negative impacts that accumulate over time. To capture the cumulative effect of psoriasis and its associated co‐morbidities and stigma over a patient’s life course, we propose the concept of ‘Cumulative Life Course Impairment’ (CLCI). CLCI results from an interaction between (A) the burden of stigmatization, and physical and psychological co‐morbidities and (B) coping strategies and external factors. Several key aspects of the CLCI concept are supported by data similar to that used in health‐related quality of life assessments. Future research should focus on (i) establishing key components of CLCI and determining the mechanisms of impairment through longitudinal or retrospective case–control studies, and (ii) assessing factors that put patients at increased risk of developing CLCI. In the future, this concept may lead to a better understanding of the overall impact of psoriasis, help identify more vulnerable patients, and facilitate more appropriate treatment decisions or earlier referrals. To our knowledge, this is a first attempt to apply and develop concepts from ‘Life Course Epidemiology’ to psoriasis research.

Efficacy and safety of guselkumab, an anti-interleukin-23 monoclonal antibody, compared with adalimumab for the continuous treatment of patients with moderate to severe psoriasis: Results from the phase III, double-blinded, placebo- and active comparator–controlled VOYAGE 1 trial

Background: Guselkumab, an interleukin‐23 blocker, was superior to adalimumab in treating moderate to severe psoriasis in a phase II trial. Objectives: We sought to compare efficacy and safety of guselkumab with adalimumab and placebo in patients with psoriasis treated for 1 year. Methods: Patients were randomized to guselkumab 100 mg (weeks 0 and 4, then every 8 weeks; n = 329); placebo→guselkumab (weeks 0, 4, and 12 then guselkumab at weeks 16 and 20, then every 8 weeks; n = 174); or adalimumab (80 mg week 0, 40 mg week 1, then 40 mg every 2 weeks through week 47; n = 334). Physician‐reported outcomes (Investigator Global Assessment, Psoriasis Area and Severity Index [PASI]), patient‐reported outcomes (Dermatology Life Quality Index, Psoriasis Symptoms and Signs Diary), and safety were evaluated through week 48. Results: Guselkumab was superior (P < .001) to placebo at week 16 (85.1% vs 6.9% [Investigator Global Assessment score of 0/1 (cleared/minimal)] and 73.3% vs 2.9% [90% or greater improvement in PASI score from baseline (PASI 90)]). Guselkumab was also superior (P < .001) to adalimumab for Investigator Global Assessment 0/1 and PASI 90 at week 16 (85.1% vs 65.9% and 73.3% vs 49.7%), week 24 (84.2% vs 61.7% and 80.2% vs 53.0%), and week 48 (80.5% vs 55.4% and 76.3% vs 47.9%). Furthermore, guselkumab significantly improved patient‐reported outcomes through week 48. Adverse event rates were comparable between treatments. Limitations: Analyses were limited to 48 weeks. Conclusions: Guselkumab demonstrated superior efficacy compared with adalimumab and was well tolerated in patients with psoriasis through 1 year.