Craig L. Leonardi

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 PASI 75 response was better maintained to at least 1 year in those receiving maintenance ustekinumab than in those withdrawn from treatment at week 40 (p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.

Guidelines of care for the management of psoriasis and psoriatic arthritis Section 1. Overview of psoriasis and guidelines of care for the treatment of psoriasis with biologics

Psoriasis is a common, chronic, inflammatory, multisystem disease with predominantly skin and joint manifestations affecting approximately 2% of the population. In this first of 5 sections of the guidelines of care for psoriasis, we discuss the classification of psoriasis; associated comorbidities including autoimmune diseases, cardiovascular risk, psychiatric/psychologic issues, and cancer risk; along with assessment tools for skin disease and quality-of-life issues. Finally, we will discuss the safety and efficacy of the biologic treatments used to treat patients with psoriasis.

Etanercept and clinical outcomes, fatigue, and depression in psoriasis: double-blind placebo-controlled randomised phase III trial

BACKGROUND Psoriasis has substantial psychological and emotional effects. We assessed the effect of etanercept, an effective treatment for the clinical symptoms of psoriasis, on fatigue and symptoms of depression associated with the condition. METHODS 618 patients with moderate to severe psoriasis received double-blind treatment with placebo or 50 mg twice-weekly etanercept. The primary efficacy endpoint was a 75% or greater improvement from baseline in psoriasis area and severity index score (PASI 75) at week 12. Secondary and other endpoints included the functional assessment of chronic illness therapy fatigue (FACIT-F) scale, the Hamilton rating scale for depression (Ham-D), the Beck depression inventory (BDI), and adverse events. Efficacy analyses were based on the allocated treatment. Analyses and summaries of safety data were based on the actual treatment received. This study is registered with with the identifier NCT00111449. FINDINGS 47% (147 of 311) of patients achieved PASI 75 at week 12, compared with 5% (15 of 306) of those receiving placebo (p<0.0001; difference 42%, 95% CI 36-48). Greater proportions of patients receiving etanercept had at least a 50% improvement in Ham-D or BDI at week 12 compared with the placebo group; patients treated with etanercept also had significant and clinically meaningful improvements in fatigue (mean FACIT-F improvement 5.0 vs 1.9; p<0.0001, difference 3.0, 95% CI 1.6-4.5). Improvements in fatigue were correlated with decreasing joint pain, whereas improvements in symptoms of depression were less correlated with objective measures of skin clearance or joint pain. INTERPRETATION Etanercept treatment might relieve fatigue and symptoms of depression associated with this chronic disease.

Brodalumab, an Anti–Interleukin-17–Receptor Antibody for Psoriasis

BACKGROUND In this phase 2, randomized, double-blind, placebo-controlled, dose-ranging study, we assessed the efficacy and safety of brodalumab (AMG 827), a human anti-interleukin-17-receptor monoclonal antibody, for the treatment of moderate-to-severe plaque psoriasis. METHODS We randomly assigned patients with a score of 12 or higher on the psoriasis area-and-severity index (PASI, on which scores range from 0 to 72, with higher scores indicating more severe disease) and with 10% or more of their body-surface area affected by psoriasis to receive brodalumab (70 mg, 140 mg, or 210 mg at day 1 and weeks 1, 2, 4, 6, 8, and 10 or 280 mg monthly) or placebo. The primary end point was the percentage improvement from baseline in the PASI score at week 12. Secondary end points included improvement of at least 75% and at least 90% in the PASI score and the score on the static physicians global assessment at week 12. RESULTS A total of 198 patients underwent randomization. At week 12, the mean percentage improvements in the PASI score were 45.0% among patients receiving 70 mg of brodalumab, 85.9% among those receiving 140 mg, 86.3% among those receiving 210 mg, 76.0% among those receiving 280 mg, and 16.0% among those receiving placebo (P<0.001 for all comparisons with placebo). An improvement of at least 75% and at least 90% in the PASI score at week 12 was seen in 77% and 72%, respectively, of the patients in the 140-mg brodalumab group and in 82% and 75%, respectively, of the patients in the 210-mg group, as compared with 0% in the placebo group (P<0.001 for all comparisons). The percentage of patients with a static physicians global assessment of clear or minimal disease was 26%, 85%, 80%, and 69% with the 70-mg, 140-mg, 210-mg, and 280-mg doses, respectively, of brodalumab, as compared with 3% with placebo (P<0.01 for all comparisons with placebo). Two cases of grade 3 neutropenia were reported in the 210-mg brodalumab group. The most commonly reported adverse events in the combined brodalumab groups were nasopharyngitis (8%), upper respiratory tract infection (8%), and injection-site erythema (6%). CONCLUSIONS Brodalumab significantly improved plaque psoriasis in this 12-week, phase 2 study. (Funded by Amgen; ClinicalTrials.gov number, NCT00975637.).

Anti–Interleukin-17 Monoclonal Antibody Ixekizumab in Chronic Plaque Psoriasis

BACKGROUND Type 17 helper T cells have been suggested to play a pathological role in psoriasis. They secrete several proinflammatory cytokines, including interleukin-17A (also known as interleukin-17). We evaluated the safety and efficacy of ixekizumab (LY2439821), a humanized anti-interleukin-17 monoclonal antibody, for psoriasis treatment. METHODS In our phase 2, double-blind, placebo-controlled trial, we randomly assigned 142 patients with chronic moderate-to-severe plaque psoriasis to receive subcutaneous injections of 10, 25, 75, or 150 mg of ixekizumab or placebo at 0, 2, 4, 8, 12, and 16 weeks. The primary end point was the proportion of patients with reduction in the psoriasis area-and-severity index (PASI) score by at least 75% at 12 weeks. Secondary end points included the proportion of patients with reduction in the PASI score by at least 90% or by 100%. RESULTS At 12 weeks, the percentage of patients with a reduction in the PASI score by at least 75% was significantly greater with ixekizumab (except with the lowest, 10-mg dose)--150 mg (82.1%), 75 mg (82.8%), and 25 mg (76.7%)--than with placebo (7.7%, P<0.001 for each comparison), as was the percentage of patients with a reduction in the PASI score by at least 90%: 150 mg (71.4%), 75 mg (58.6%), and 25 mg (50.0%) versus placebo (0%, P<0.001 for each comparison). Similarly, a 100% reduction in the PASI score was achieved in significantly more patients in the 150-mg group (39.3%) and the 75-mg group (37.9%) than in the placebo group (0%) (P<0.001 for both comparisons). Significant differences occurred at as early as 1 week and were sustained through 20 weeks. Adverse events occurred in 63% of patients in both the combined ixekizumab groups and in the placebo group. No serious adverse events or major cardiovascular events were observed. CONCLUSIONS Use of a humanized anti-interleukin-17 monoclonal antibody, ixekizumab, improved the clinical symptoms of psoriasis. Further studies are needed to establish its long-term safety and efficacy in patients with psoriasis. (Funded by Eli Lilly; ClinicalTrials.gov number, NCT01107457.).

Guidelines of care for the management of psoriasis and psoriatic arthritis: Section 2. Psoriatic arthritis: Overview and guidelines of care for treatment with an emphasis on the biologics

Psoriasis is a common, chronic, inflammatory, multisystem disease with predominantly skin and joint manifestations affecting approximately 2% of the population. In this second of 5 sections of the guidelines of care for psoriasis, we give an overview of psoriatic arthritis including its cardinal clinical features, pathogenesis, prognosis, classification, assessment tools used to evaluate psoriatic arthritis, and the approach to treatment. Although patients with mild to moderate psoriatic arthritis may be treated with nonsteroidal anti-inflammatory drugs and/or intra-articular steroid injections, the use of disease-modifying antirheumatic drugs, particularly methotrexate, along with the biologic agents, are considered the standard of care in patients with more significant psoriatic arthritis. We will discuss the use of disease-modifying antirheumatic drugs and the biologic therapies in the treatment of patients with moderate to severe psoriatic arthritis.

European S3‐Guidelines on the systemic treatment of psoriasis vulgaris

Of the 131 studies on monotherapy or combination therapy assessed, 56 studies on the different forms of phototherapy fulfilled the criteria for inclusion in the guidelines. Approximately three-quarters of all patients treated with phototherapy attained at least a PASI 75 response after 4 to 6 weeks, and clearance was frequently achieved (levels of evidence 2 and 3). Phototherapy represents a safe and very effective treatment option for moderate to severe forms of psoriasis vulgaris. The onset of clinical effects occurs within 2 weeks. Of the unwanted side effects, UV erythema from overexposure is by far the most common and is observed frequently. With repeated or long-term use, the consequences of high, cumulative UV doses (such as premature aging of the skin) must be taken into consideration. In addition, carcinogenic risk is associated with oral PUVA and is probable for local PUVA and UVB. The practicability of the therapy is limited by spatial, financial, human, and time constraints on the part of the physician, as well as by the amount of time required by the patient. From the perspective of the cost-bearing institution, phototherapy has a good cost-benefit ratio. However, the potentially significant costs for, and time required of, the patient must be considered.

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.

Phase 3 Trials of Ixekizumab in Moderate-to-Severe Plaque Psoriasis

BACKGROUND Two phase 3 trials (UNCOVER-2 and UNCOVER-3) showed that at 12 weeks of treatment, ixekizumab, a monoclonal antibody against interleukin-17A, was superior to placebo and etanercept in the treatment of moderate-to-severe psoriasis. We report the 60-week data from the UNCOVER-2 and UNCOVER-3 trials, as well as 12-week and 60-week data from a third phase 3 trial, UNCOVER-1. METHODS We randomly assigned 1296 patients in the UNCOVER-1 trial, 1224 patients in the UNCOVER-2 trial, and 1346 patients in the UNCOVER-3 trial to receive subcutaneous injections of placebo (placebo group), 80 mg of ixekizumab every 2 weeks after a starting dose of 160 mg (2-wk dosing group), or 80 mg of ixekizumab every 4 weeks after a starting dose of 160 mg (4-wk dosing group). Additional cohorts in the UNCOVER-2 and UNCOVER-3 trials were randomly assigned to receive 50 mg of etanercept twice weekly. At week 12 in the UNCOVER-3 trial, the patients entered a long-term extension period during which they received 80 mg of ixekizumab every 4 weeks through week 60; at week 12 in the UNCOVER-1 and UNCOVER-2 trials, the patients who had a response to ixekizumab (defined as a static Physicians Global Assessment [sPGA] score of 0 [clear] or 1 [minimal psoriasis]) were randomly reassigned to receive placebo, 80 mg of ixekizumab every 4 weeks, or 80 mg of ixekizumab every 12 weeks through week 60. Coprimary end points were the percentage of patients who had a score on the sPGA of 0 or 1 and a 75% or greater reduction from baseline in Psoriasis Area and Severity Index (PASI 75) at week 12. RESULTS In the UNCOVER-1 trial, at week 12, the patients had better responses to ixekizumab than to placebo; in the 2-wk dosing group, 81.8% had an sPGA score of 0 or 1 and 89.1% had a PASI 75 response; in the 4-wk dosing group, the respective rates were 76.4% and 82.6%; and in the placebo group, the rates were 3.2% and 3.9% (P<0.001 for all comparisons of ixekizumab with placebo). In the UNCOVER-1 and UNCOVER-2 trials, among the patients who were randomly reassigned at week 12 to receive 80 mg of ixekizumab every 4 weeks, 80 mg of ixekizumab every 12 weeks, or placebo, an sPGA score of 0 or 1 was maintained by 73.8%, 39.0%, and 7.0% of the patients, respectively. Patients in the UNCOVER-3 trial received continuous treatment of ixekizumab from weeks 0 through 60, and at week 60, at least 73% had an sPGA score of 0 or 1 and at least 80% had a PASI 75 response. Adverse events reported during ixekizumab use included neutropenia, candidal infections, and inflammatory bowel disease. CONCLUSIONS In three phase 3 trials involving patients with psoriasis, ixekizumab was effective through 60 weeks of treatment. As with any treatment, the benefits need to be weighed against the risks of adverse events. The efficacy and safety of ixekizumab beyond 60 weeks of treatment are not yet known. (Funded by Eli Lilly; UNCOVER-1, UNCOVER-2, and UNCOVER-3 ClinicalTrials.gov numbers NCT01474512, NCT01597245, and NCT01646177, respectively.).

A classification of psoriasis vulgaris according to phenotype

For nearly 200 years it has been appreciated that plaque psoriasis consists of a number of distinct clinical phenotypes. However, a reliable and simple stratification of clinical presentation of psoriasis is lacking. In the era of immunogenetic association studies and an advanced understanding of the pathomechanisms of psoriasis it is important that a classification of the disease according to phenotype is readily available. Such a classification would facilitate clinically relevant interpretation of investigational data. A meeting of the International Psoriasis Council produced a consensus on clinical phenotypes of psoriasis equally relevant to clinical practitioners and psoriasis researchers.