IGAxBSA composite for assessing disease severity and response in patients with atopic dermatitis.

BACKGROUND: Accurate assessment of atopic dermatitis (AD) severity is critical when initiating and monitoring therapy. Use of existing research tools such as the Eczema Area and Severity Index (EASI) and Scoring Atopic Dermatitis (SCORAD) is complex and time-consuming in clinical practice. A previous analysis found the product of validated Investigator's Global Assessment (vIGA) and affected body surface area (BSA) to be an accurate and practical tool for routine assessment of paediatric AD. OBJECTIVE: To evaluate the IGAxBSA composite as an alternative to EASI or SCORAD for assessment of AD disease severity and disease responsiveness. METHODS: The relationship between IGAxBSA, EASI and SCORAD was assessed in a post hoc analysis of pooled data from the dupilumab clinical trial programme in adult and paediatric patients with moderate-to-severe AD who had received dupilumab or placebo, with or without topical corticosteroids (TCS). The trials are registered at ClinicalTrials.gov and EudraCT: LIBERTY AD SOLO 1 (NCT02277743, 2014-001198-15), LIBERTY AD SOLO 2 (NCT02277769, 2014-002619-40), LIBERTY AD SOLO-CONTINUE (NCT02395133, 2014-003384-38), LIBERTY AD CHRONOS (NCT02260986, 2013-003254-24), LIBERTY AD CAFÉ (NCT02755649, 2015-002653-35), LIBERTY AD ADOL (NCT03054428, 2015-004458-16), LIBERTY AD PEDS (NCT03345914, 2016-004997-16), LIBERTY AD OLE (NCT01949311, 2013-001449-15) and LIBERTY AD PEDS OLE (NCT02612454, 2015-001396-40). RESULTS: Using datapoints from pooled dupilumab randomized controlled trials (n = 3473) and open-label extension trials (n = 3045), we found that IGAxBSA correlated well with EASI and SCORAD, irrespective of treatment group and race (white, Asian, black). IGAxBSA correlated better with objective measures (EASI, SCORAD) than with patient- or caregiver-reported subjective measures. IGAxBSA correlated strongly with EASI and SCORAD in assessing disease change over time (r = 0·90, r = 0·76, respectively; P < 0·0001), and concordance between IGAxBSA-50/75/90 and EASI-50/75/90 was excellent (88-94%). CONCLUSIONS: IGAxBSA is a valid alternative for assessment of AD disease severity and response over time, compared with EASI or SCORAD in patients with AD, irrespective of race.

Effect of baseline disease severity on achievement of treatment target with apremilast: results from a pooled analysis.

BACKGROUND: Treating to absolute treatment targets rather than relative measures such as Psoriasis Area and Severity Index (PASI)-75 is emerging as an important clinical concept included in psoriasis guidelines and clinical practice. Achieving treatment targets is associated with achievement of long-term outcomes. OBJECTIVE: To evaluate the relationship between psoriasis severity, disease characteristics and achievement of PASI ≤2 with apremilast in a pooled analysis of the phase 3 ESTEEM 1 and 2 (NCT01194219 and NCT01232283), phase 3b LIBERATE (NCT01690299) and phase 4 UNVEIL (NCT02425826) clinical trials. METHODS: Pooled data from patients with moderate-to-severe plaque psoriasis randomized to apremilast 30 mg BID were analysed by baseline PASI quartiles (Q1: 2.4-13.1; Q2: 13.2-15.9; Q3: 16.0-20.0; Q4: 20.1-57.8). Assessments included PASI, Dermatology Life Quality Index (DLQI), Scalp Physician's Global Assessment (ScPGA; ScPGA ≥1) and target (worst) Nail Psoriasis Severity Index (NAPSI; NAPSI ≥1). RESULTS: Of 1062 patients, 963 had ScPGA ≥1 and 643 had NAPSI ≥1; 771 patients with baseline and Week 32 PASI assessments were included in analyses of Week 32 PASI target achievement. Rates of PASI ≤2 at Week 32 were greater in lower PASI quartiles (Q1: 43.5%; Q2: 31.2%; Q3: 26.8%; Q4: 18.4%). Most patients achieving PASI ≤2 target (83.6%) achieved DLQI ≤5 at Week 32; 59.3% of patients who did not achieve PASI ≤2 target achieved DLQI ≤5. At Week 32, mean improvements in ScPGA and NAPSI were similar with more moderate vs. more severe disease (ScPGA, range: 1.1-1.4; NAPSI, range: 1.6-2.5). In a subgroup analysis, achievement of PASI ≤2 target was higher in the lowest PASI quartile and with disease duration <5 years. CONCLUSIONS: Greater achievement of PASI ≤2 was observed in patients with more moderate vs. more severe skin disease. Apremilast may be particularly beneficial in more moderate disease early in the treatment paradigm.

Secukinumab maintains superiority over ustekinumab in clearing skin and improving quality of life in patients with moderate to severe plaque psoriasis: 52-week results from a double-blind phase 3b trial (CLARITY).

BACKGROUND: Secukinumab demonstrated superior efficacy over ustekinumab in the treatment of moderate to severe plaque psoriasis over 16 weeks in the CLARITY study and over 52 weeks in the CLEAR study. OBJECTIVE: To compare the efficacy and safety of secukinumab vs. ustekinumab over 52 weeks in CLARITY. METHODS: Analysis of 52-week data from CLARITY (NCT02826603), a phase 3b study in which patients were randomized to receive secukinumab 300 mg (n = 550) or ustekinumab 45/90 mg (n = 552) per label. RESULTS: At week 52, secukinumab was superior to ustekinumab in the proportion of patients who achieved ≥ 90% improvement in Psoriasis Area and Severity Index (73.2% vs. 59.8%; odds ratio [OR], 1.84 [95% CI, 1.41-2.41]; P < 0.0001), Investigator's Global Assessment modified 2011 responses of clear (0) or almost clear (1) skin (76.0% vs. 60.2%; OR, 2.12 [95% CI, 1.61-2.79]; P < 0.0001) and Dermatology Life Quality Index response of no effect (0/1) (69.9% vs. 61.2%; P = 0.0028). Proportions of patients with any adverse events were comparable between treatment arms. CONCLUSIONS: This second head-to-head study confirmed the superior efficacy of secukinumab over ustekinumab in skin clearance and quality of life through 52 weeks, with safety comparable to that reported in previous trials. Clinicaltrials.gov identifier: NCT02826603.

Efficacy and safety of ixekizumab in a phase III, randomized, double-blind, placebo-controlled study in paediatric patients with moderate-to-severe plaque psoriasis (IXORA-PEDS).

BACKGROUND: Plaque psoriasis affects children and adults, but treatment options for paediatric psoriasis are limited. OBJECTIVES: To evaluate the efficacy and safety of ixekizumab (IXE), a high-affinity monoclonal antibody that selectively targets interleukin-17A, for moderate-to-severe paediatric psoriasis. METHODS: In a randomized, double-blind, placebo-controlled, phase III study (IXORA-PEDS), patients aged 6 to < 18 years with moderate-to-severe plaque psoriasis were randomized 2 : 1 to weight-based dosing of IXE every 4 weeks (IXE Q4W, n = 115) or placebo (n = 56) through week 12, followed by open-label IXE Q4W. Coprimary endpoints were the proportions of patients at week 12 achieving ≥ 75% improvement in Psoriasis Area and Severity Index (PASI 75) and those achieving a static Physician's Global Assessment score of 0 or 1 (sPGA 0,1). RESULTS: IXE was superior (P < 0·001) to placebo for both coprimary endpoints of PASI 75 (IXE Q4W, 89%; placebo, 25%) and sPGA (0,1) (IXE Q4W, 81%; placebo, 11%). IXE was also superior for all gated secondary endpoints, including PASI 75 and sPGA (0,1) at week 4, improvement in itch, and complete skin clearance. IXE Q4W provided significant (P < 0·001) improvements vs. placebo in quality of life and clearance of scalp and genital psoriasis. Responses at week 12 were sustained or further improved through week 48. Through week 12, 45% (placebo) and 56% (IXE) of patients reported treatment-emergent adverse events. One serious adverse event was reported (IXE), one patient discontinued due to an adverse event (placebo) and no deaths were reported. CONCLUSIONS: IXE was superior to placebo in the treatment of moderate-to-severe paediatric psoriasis, and the safety profile was generally consistent with that observed in adults. What is already known about this topic? Paediatric psoriasis affects approximately 1% of children and can negatively impact health-related quality of life. Treatment options for paediatric psoriasis are typically limited to off-label treatments and approved systemic biologics. Ixekizumab, a high-affinity monoclonal antibody that selectively targets interleukin-17A, is approved for moderate-to-severe plaque psoriasis in adults and was recently approved by the US Food and Drug Administration for moderate-to-severe paediatric psoriasis. What does this study add? Ixekizumab resulted in rapid and statistically significant improvements over placebo in skin involvement, itch and health-related quality of life, which persisted through 48 weeks of treatment in paediatric patients with moderate-to-severe plaque psoriasis. The safety profile of ixekizumab was generally consistent with that seen in adults. Ixekizumab may be an additional potential therapeutic option and an additional class of biologic therapy (interleukin-17A antagonist) for the treatment of moderate-to-severe paediatric psoriasis. Plain language summary available online.

A head-to-head comparison of ixekizumab vs. guselkumab in patients with moderate-to-severe plaque psoriasis: 12-week efficacy, safety and speed of response from a randomized, double-blinded trial.

BACKGROUND: Patients with psoriasis value rapid and complete skin clearance. No head-to-head studies have focused on early responses to interleukin (IL)-17 vs. IL-23 inhibitors. OBJECTIVES: To compare early and complete skin clearance by the IL-17A inhibitor ixekizumab vs. the IL-23p19 inhibitor guselkumab. METHODS: IXORA-R, a 24-week, randomized, double-blinded study, enrolled adults with moderate-to-severe plaque psoriasis [static Physician's Global Assessment of Disease (sPGA) score of ≥ 3, Psoriasis Area and Severity Index (PASI) ≥ 12, and ≥ 10% body surface area]. Patients were randomized (1 : 1) to receive the approved dose of subcutaneous ixekizumab or guselkumab. Primary end point was 100% improvement in PASI (PASI 100) at week 12. Major secondary end points included other levels of improved PASI and sPGA at different time points. Comparisons were made using the Cochran-Mantel-Haenszel test with a multiple testing strategy. Nonresponder imputation was used for missing data. After the completion of the study, the final secondary end point (PASI 100 at 24 weeks) and safety data through week 24 will be reported. RESULTS: In total, 1027 patients were randomized. The primary end point PASI 100 at week 12 was met [215/520 ixekizumab (41%); 126/507 guselkumab (25%); P < 0·001]. All major secondary end points measured up to week 12 were met, including PASI 50 at week 1 and PASI 75 at week 2. Serious adverse event frequency was 3% for each group; no new safety signals were identified. CONCLUSIONS: Ixekizumab was superior to guselkumab for rapidly improving signs and symptoms in patients with moderate-to-severe plaque psoriasis by week 12. Adverse events were similar to previous ixekizumab and guselkumab studies. Compared with the IL-23 inhibitor guselkumab, ixekizumab can offer complete skin clearance more rapidly to patients with moderate-to-severe plaque psoriasis. What's already known about this topic? Patients with plaque psoriasis desire both high levels of clearance and rapid onset of treatment effects. Ixekizumab, a high-affinity monoclonal antibody that selectively targets interleukin (IL)-17A, has demonstrated greater and faster skin clearance than etanercept and ustekinumab, with consistent long-term efficacy, safety and durability of response. Clinical trial data and systematic reviews have suggested that IL-17 inhibitors can improve a patient's psoriasis more rapidly than IL-23 inhibitors. What does this study add? The head-to-head study design directly compares the efficacy and speed of response of ixekizumab and the IL-23 inhibitor guselkumab in moderate-to-severe plaque psoriasis. The primary end point was met, showing superiority of ixekizumab over guselkumab for achieving complete skin clearance at week 12. The safety profile of ixekizumab was consistent with previous studies. Ixekizumab can deliver patients complete skin clearance and improved quality of life more rapidly than guselkumab.

The National Psoriasis Foundation psoriasis treatment targets in real-world patients: prevalence and association with patient-reported outcomes in the Corrona Psoriasis Registry.

INTRODUCTION: The National Psoriasis Foundation (NPF) published treat-to-target guidelines for psoriasis, yet their applicability in clinical practice remains unknown. OBJECTIVES: To estimate the proportion of psoriasis patients meeting the NPF's body surface area (BSA) 'target' (≤1%) and 'acceptable' (≤3%) response criteria and the cross-sectional associations of these criteria with patient-reported outcomes (PROs) in the Corrona Psoriasis Registry. METHODS: Separately for three independent cross-sectional cohorts of patients at the (i) enrolment, (ii) 6-month and (iii) 12-month visits, we calculated the proportion of patients with BSA ≤1% and ≤3%. Furthermore, we calculated odds ratios estimating the risk of PROs associated with not meeting criteria in the 6-month cohort. RESULTS: The enrolment, 6- and 12-month cohorts included 2794, 1310 and 629 patients, respectively. At enrolment, 24% of patients had a BSA ≤ 1% and 41% a BSA ≤ 3%. In the 6-month cohort, 43%/64% had a BSA ≤ 1%/BSA ≤ 3%. In the 12-month cohort, 46%/69% of patients had a BSA ≤ 1%/BSA ≤ 3%. Patients not at target/acceptable criteria had higher odds for worse quality of life compared with those who were. CONCLUSION: While most patients at 6- and 12-month visits were at the 'acceptable' response, less than half were at the 'target' response despite systemic therapy. There remain unmet needs to optimize psoriasis therapy and further validate current treat-to-target guidelines.

Dupilumab provides important clinical benefits to patients with atopic dermatitis who do not achieve clear or almost clear skin according to the Investigator's Global Assessment: a pooled analysis of data from two phase III trials.

BACKGROUND: In the U.S.A., an Investigator's Global Assessment (IGA) score of ≤ 1 (clear or almost clear skin) has been the standard measure in regulatory outcomes for registration clinical trials in atopic dermatitis (AD), including those supporting the recent approval of dupilumab. OBJECTIVES: To evaluate the treatment effect of dupilumab in patients with IGA > 1 at the end of treatment, using other validated outcome measures for AD signs, symptoms and quality of life. METHODS: LIBERTY AD SOLO 1 and 2 were two 16-week, randomized, double-blind trials enrolling adult patients with moderate-to-severe AD (IGA ≥ 3) inadequately controlled with topical treatment. We performed a post hoc analysis in patients receiving dupilumab 300 mg every 2 weeks (q2w) or placebo. Outcome measures in patients with IGA > 1 included Eczema Area and Severity Index (EASI), pruritus numerical rating scale (NRS), affected body surface area (BSA), Patient-Oriented Eczema Measure (POEM) and Dermatology Life Quality Index (DLQI). The trials were registered at ClinicalTrials.gov: NCT02277743 and NCT02277769. RESULTS: At week 16, 278 of 449 dupilumab q2w-treated patients (median age 36·0 years) and 396 of 443 placebo-treated patients had IGA > 1. Among patients with IGA > 1 at week 16, dupilumab significantly improved several outcome measures compared with placebo: EASI (-48·9% vs. -11·3%, P < 0·001), pruritus NRS (-35·2% vs. -9·1%, P < 0·001), affected BSA (-23·1% vs. -4·5%, P < 0·001), POEM score ≥ 4-point improvement (57·4% vs. 21·0%, P < 0·001) and DLQI score ≥ 4-point improvement (59·3% vs. 24·4%, P < 0·001). CONCLUSIONS: In patients with IGA > 1 at week 16, dupilumab induced statistically significant benefits in multiple validated outcome measures compared with placebo. The IGA ≤ 1 end point significantly underestimates clinically relevant dupilumab treatment effects.

Open-label study of etanercept treatment in patients with moderate-to-severe plaque psoriasis who lost a satisfactory response to adalimumab.

BACKGROUND: Some patients with plaque psoriasis experience secondary failure of tumour necrosis factor inhibitor therapy. OBJECTIVES: To evaluate efficacy, safety and patient-reported outcomes (PROs) with etanercept in patients with secondary adalimumab failure. METHODS: This phase IV open-label single-arm estimation study (NCT01543204) enrolled patients on adalimumab who had achieved static Physician's Global Assessment (sPGA) score 0/1 (clear/almost clear). Patients subsequently lost response, defined as sPGA ≥ 3 or loss of 50% improvement in Psoriasis Area and Severity Index (PASI 50). At baseline, patients had involved body surface area ≥ 10%, sPGA ≥ 3 and PASI ≥ 10. Antiadalimumab antibodies (ADAs) were measured at screening. Patients received etanercept 50 mg twice weekly for 12 weeks, followed by 50 mg weekly. The primary end point was sPGA 0/1 at week 12 (intention-to-treat analysis; no hypothesis tested). Additional outcomes included rates of sPGA 0/1, PASI responses, safety, PROs of itch, pain and flaking, Dermatology Life Quality Index, treatment satisfaction and Work Productivity and Activity Impairment questionnaire. RESULTS: Sixty-four patients enrolled; 67% had ADAs. sPGA 0/1 rates at week 12 were 39·7% [95% confidence interval (CI) 27·6-52·8; primary end point] and 45% (95% CI 29·3-61·5) for patients positive for ADAs and 35% (95% CI 15·4-59·2) for patients negative for ADAs. PASI 75 response rates at week 12 were 47·5% (95% CI 31·5-63·9) for patients who were positive for ADAs and 50% (95% CI 27·2-72·8) for patients negative for ADAs. No new safety signals were observed. PROs of itch, pain and flaking consistently improved at week 12 and were maintained through week 24. CONCLUSIONS: Patients with psoriasis who experienced secondary failure of adalimumab achieved satisfactory response to etanercept regardless of ADA status.

Phase 3, open-label, randomized study of the pharmacokinetics, efficacy and safety of ixekizumab following subcutaneous administration using a prefilled syringe or an autoinjector in patients with moderate-to-severe plaque psoriasis (UNCOVER-A).

BACKGROUND: The efficacy of ixekizumab, an anti-interleukin-17A (anti-IL-17A) monoclonal IgG4 antibody, was demonstrated in moderate-to-severe psoriasis patients when administered via prefilled syringe (PFS). OBJECTIVE: To evaluate the effect of two drug delivery devices on the pharmacokinetics (PK) of ixekizumab as well as efficacy and safety with both devices. METHODS: In the first 12 weeks of an open-label, phase 3 study, moderate-to-severe psoriasis patients were randomized to ixekizumab delivery via PFS or autoinjector device. Randomization was stratified by weight (<80 kg, 80-100 kg, >100 kg), injection assistance (yes/no) and injection site (arm, thigh or abdomen). Following a 160-mg initial dose at week 0, patients received subcutaneous 80-mg ixekizumab as a single injection every 2 weeks for 12 weeks. Blood samples were collected following the initial 160-mg dose on days 2, 4, 7, 10 and 14 for PK analysis. Primary PK parameters were maximum concentration (Cmax ) and area under the curve (AUC0-tlast ) where tlast is the time of last sample (14 days ± 24 h). Efficacy was assessed by percent improvement on the Psoriasis Area and Severity Index (PASI) at week 12. Adverse event reporting, vital signs and clinical laboratory data were used to evaluate safety. RESULTS: Of 204 randomized patients, 192 were included in the PK analysis (PFS: 94; autoinjector: 98). The PFS and autoinjector showed similar geometric mean Cmax (90% CI) [15.0 µg/mL (13.9-16.1) vs. 14.8 µg/mL (13.8-15.9)] and geometric mean AUC0-tlast (90% CI) [157 µg × day/mL (147-168) vs. 154 µg × day/mL (144-165)]. When comparing Cmax and AUC0-tlast of the autoinjector to PFS, the geometric LS mean ratios were 0.97. At week 12, mean percent PASI improvement (via modified baseline observation carried forward) was similar with the PFS (89.3%) and autoinjector (86.9%). Both devices had safety results that were consistent with the known safety profile of ixekizumab. CONCLUSION: The PK, efficacy and safety of ixekizumab administered subcutaneously by PFS and autoinjector were similar. Clinicaltrials.gov number: NCT01777191 https://clinicaltrials.gov/ct2/show/NCT01777191.

Adeno-associated virus serotypes 9 and rh10 mediate strong neuronal transduction of the dog brain.

Canine models have many advantages for evaluating therapy of human central nervous system (CNS) diseases. In contrast to nonhuman primate models, naturally occurring canine CNS diseases are common. In contrast to murine models, the dog's lifespan is long, its brain is large and the diseases affecting it commonly have the same molecular, pathological and clinical phenotype as the human diseases. We compared the ability of four intracerebrally injected adeno-associated virus vector (AAV) serotypes to transduce the dog brain with green fluorescent protein as the first step in using these vectors to evaluate both delivery and efficacy in naturally occurring canine homologs of human diseases. Quantitative measures of transduction, maximum diameter and area, identified both AAV2/9 and AAV2/rh10 as significantly more efficient than either AAV2/1 or AAV2/5 at transducing cerebral cortex, caudate nucleus, thalamus and internal capsule. Fluorescence co-labeling with cell-type-specific antibodies demonstrated that AAV2/9 and AAV2/rh10 were capable of primarily transducing neurons, although glial transduction was also identified and found to be more efficient with the AAV2/9 vector. These data are a prerequisite to evaluating the efficacy of recombinant AAV vectors carrying disease-modifying transgenes to treat naturally occurring canine models in preclinical studies of human CNS disease therapy.

Subcutaneous nodules in Pseudomonas sepsis.

Approximately 60 nontender, nonfluctuant, red, hot subcutaneous nodules developed on the trunk, extremities, and face due to Pseudomonas aeruginosa septicemia in a 56-year-old woman with stage III ovarian adenocarcinoma. Two years later, these lesions appeared atrophic with central scarring. Complete eradication with systemic antibiotics and without incision and drainage was accomplished.

Establishing a practical and effective psoriasis treatment center.

Running an effective psoriasis treatment center requires 1) capable phototherapists who have received the appropriate education and training; 2) a full range of equipment, including light boxes, hand-foot units, scalp débridement machines, and a whirlpool bath; 3) adequate space; 4) economic considerations, including reimbursements so patients can receive treatment and the center can be paid; and 5) the medical expertise necessary to care for the most severe psoriatic patients. These and other issues are discussed in this article.

Hemorrhagic bullae associated with Morganella morganii septicemia.

To our knowledge this is the first case of hemorrhagic bullae caused by Morganella morganii septicemia. The presence of organisms in the bullae, demonstrated by Gram strain and culture, and the acral location of the bullae suggest that the skin lesions were due directly to blood-borne infection. Multiple factors predisposed this patient to gram-negative bacteremia, including lymphoma, chemotherapy, neutropenia, systemic steroids, multiple hospitalizations, and treatment with broad-spectrum antibiotics.

A multicenter dose-escalation trial with denileukin diftitox (ONTAK, DAB(389)IL-2) in patients with severe psoriasis.

BACKGROUND: Denileukin diftitox, a fusion protein targeting both malignant and normal activated lymphocytes, has been shown previously to have antipsoriatic activity. However, the ideal dosing regimen for treating psoriasis was not established. OBJECTIVE: We examined the safety and efficacy of denileukin diftitox in patients with severe plaque-type psoriasis. METHODS: This was a cohort dose-escalation trial. Patients were administered denileukin diftitox on 3 consecutive days every other week. Patients were evaluated for toxicity, improvement in psoriasis, immunogenicity, and serum levels. RESULTS: Thirty-five patients were treated at 3 dose levels. Eight patients had a 50% decrease or more in Psoriasis Area and Severity Index score from baseline (0/10 at 0.5 microg/kg per day, 1/10 at 1.5 microg/kg per day, and 7/15 at 5 microg/kg per day). Adverse events primarily consisted of constitutional events and skin reactions. CONCLUSIONS: The potential antipsoriatic activity of denileukin diftitox demonstrated in this study was comparable to that observed in other psoriasis studies with this agent. However, this dosing regimen was better tolerated than the dosing regimen used in the last study with denileukin diftitox in psoriasis patients.