Metabolomic and lipidomic fingerprints in inflammatory skin diseases - Systemic illumination of atopic dermatitis, hidradenitis suppurativa and plaque psoriasis.

Auto-inflammatory skin diseases place considerable symptomatic and emotional burden on the affected and put pressure on healthcare expenditures. Although most apparent symptoms manifest on the skin, the systemic inflammation merits a deeper analysis beyond the surface. We set out to identify systemic commonalities, as well as differences in the metabolome and lipidome when comparing between diseases and healthy controls. Lipidomic and metabolomic LC-MS profiling was applied, using plasma samples collected from patients suffering from atopic dermatitis, plaque-type psoriasis or hidradenitis suppurativa or healthy controls. Plasma profiles revealed a notable shift in the non-enzymatic anti-oxidant defense in all three inflammatory disorders, placing cysteine metabolism at the center of potential dysregulation. Lipid network enrichment additionally indicated the disease-specific provision of lipid mediators associated with key roles in inflammation signaling. These findings will help to disentangle the systemic components of autoimmune dermatological diseases, paving the way to individualized therapy and improved prognosis.

Randomized Phase 3 trial demonstrating high efficacy, favourable safety and convenience of a novel calcipotriol and betamethasone dipropionate cream for the treatment of psoriasis.

BACKGROUND: The fixed dose combination of calcipotriene (CAL) and betamethasone dipropionate (BDP) is a well-established topical treatment option for psoriasis based on strong scientific rationale for the single agents having complementary efficacy and safety. CAL/BDP PAD-cream is an easily spreadable cream based on PAD Technology™, an innovative formulation and drug delivery system. OBJECTIVES AND METHODS: A Phase 3, multicentre, randomized, investigator-blind, active and vehicle-controlled trial enrolling 490 patients with mild to moderate psoriasis according to the Physician Global Assessment (PGA) scale was conducted in three European countries. Products were applied once daily for 8 weeks. The aim of the trial was to evaluate the efficacy and safety of CAL/BDP PAD-cream as well as treatment acceptability compared to CAL/BDP gel and PAD-cream vehicle. Primary endpoint was percentage change in modified Psoriasis Area and Severity Index (mPASI) from baseline to Week 8. RESULTS: The percentage mean change from baseline to Week 8 in mPASI for CAL/BDP PAD-cream (67.5%) was superior compared to PAD-cream vehicle (11.7%; p < 0.0001) and non-inferior to CAL/BDP gel (63.5%). The proportion of patients achieving PGA treatment success (at least two-step improvement to clear or almost clear) after 8 weeks was superior for CAL/BDP PAD-cream (50.7%) compared to PAD-cream vehicle (6.1%, p < 0.0001) and statistically significantly greater than CAL/BDP gel (42.7%, p = 0.0442). Patient-reported psoriasis treatment convenience score (PTCS) for CAL/BDP PAD-cream was rated superior to CAL/BDP gel at Week 8 (p < 0.0001) and the mean change in DLQI from baseline to Week 8 improved statistically significantly more in the CAL/BDP PAD-cream group compared to both PAD-cream vehicle (p < 0.0001) and CAL/BDP gel (p = 0.0110). Safety assessments during the trial demonstrated that CAL/BDP PAD-cream was well-tolerated. CONCLUSION: CAL/BDP PAD-cream is a novel topical treatment of psoriasis that has a high efficacy and a favourable safety profile combined with a superior patient-reported treatment convenience.

Speed of clinical improvement in the real-world setting from patient-reported Psoriasis Symptoms and Signs Diary: Secondary outcomes from the Psoriasis Study of Health Outcomes through 12 weeks.

BACKGROUND: Rapid skin improvement is a key treatment goal of patients with moderate-to-severe psoriasis (PsO). OBJECTIVES: To compare the speed of clinical improvement of approved biologics on the symptoms and signs of psoriasis assessed by patients using the validated Psoriasis Symptoms and Signs Diary (PSSD) through 12 weeks. METHODS: Psoriasis Study of Health Outcomes (PSoHO) is an international, prospective, non-interventional study that compares the effectiveness of anti-interleukin (IL)-17A biologics versus other biologics, together with pairwise comparisons of ixekizumab versus five individual biologics in patients with PsO. Using the PSSD 7-day recall period, patients assessed the symptoms (itch, skin tightness, burning, stinging and pain) and signs (dryness, cracking, scaling, shedding/flaking, redness and bleeding) of their psoriasis (0-10). Symptom and sign summary scores (0-100) are derived from the average of individual scores. Percentage change in summary scores and proportion of patients with clinically meaningful improvements (CMI) in PSSD summary and individual scores are evaluated weekly. Longitudinal PSSD data are reported as observed with treatment comparisons analysed using mixed model for repeated measures (MMRM) and generalized linear mixed models (GLMM). RESULTS: Across cohorts and treatments, eligible patients (n = 1654) had comparable baseline PSSD scores. From Week 1, the anti-IL-17A cohort achieved significantly larger score improvements in PSSD summary scores and a higher proportion of patients showed CMIs compared to the other biologics cohort through 12 weeks. Lower PSSD scores were associated with a greater proportion of patients reporting their psoriasis as no longer impacting their quality-of-life (DLQI 0,1) and a high level of clinical response (PASI100). Results also indicate a relationship between an early CMI in PSSD score at Week 2 and PASI100 score at Week 12. CONCLUSIONS: Treatment with anti-IL-17A biologics, particularly ixekizumab, resulted in rapid and sustained patient-reported improvements in psoriasis symptoms and signs compared with other biologics in a real-world setting.

Early disease intervention with guselkumab in psoriasis leads to a higher rate of stable complete skin clearance ('clinical super response'): Week 28 results from the ongoing phase IIIb randomized, double-blind, parallel-group, GUIDE study.

BACKGROUND: Guselkumab is an interleukin (IL)-23 inhibitor with demonstrated efficacy in patients with psoriasis. OBJECTIVES: Evaluate the impact of early disease intervention on clinical responses following 28 weeks of guselkumab treatment in patients with moderate-to-severe plaque psoriasis. Correlate clinical response and disease duration data with serum biomarker data. METHODS: GUIDE is a phase IIIb randomized, double-blind, parallel-group, multicentre study of adults with moderate-to-severe plaque psoriasis. In study part 1, patients with a short disease duration (SDD [≤2 years]) or a long disease duration (LDD [>2 years]) received guselkumab 100 mg at Week (W) 0, 4, 12, and 20. Those achieving complete skin clearance at W20 and W28 were defined as a super responder (SRe). A multivariable logistic regression analysed the association between baseline factors and the likelihood of becoming an SRe. The relationship between clinical response, disease duration and serum biomarker data was assessed at W0 and 4. RESULTS: In total, 880 patients were enrolled (SDD/LDD = 40.6%/59.4% of patients). More SDD than LDD patients achieved absolute Psoriasis Area and Severity Index (PASI) = 0 at W28 (51.8% vs. 39.4%) and were SRes (43.7% vs. 28.1% [overall 34.4%]). SDD patients also achieved PASI = 0 quicker than LDD patients (median 141 vs. 200 days). Disease duration and prior biologic use had the greatest impact on becoming an SRe, with no strong association among these independent variables. At baseline, there were no significant differences in the serum biomarker levels of IL-17A, IL-17F, IL-22 and ß-defensin 2 between SDD and LDD patients, or between SRe and non-SRe patients. Guselkumab rapidly decreased these markers of systemic inflammation across all patient groups analysed at W4. Guselkumab was well tolerated. CONCLUSIONS: Guselkumab efficacy was consistent across subpopulations, on the skin and systemically. The proportion of SRes was higher in SDD than LDD patients, indicating early treatment intervention may improve clinical outcomes.

Direct comparison of risankizumab and fumaric acid esters in systemic therapy-naïve patients with moderate-to-severe plaque psoriasis: a randomized controlled trial.

BACKGROUND: Fumaric acid esters (FAEs; Fumaderm® ) are the most frequently prescribed first-line systemic treatment for moderate-to-severe plaque psoriasis in Germany. Risankizumab (Skyrizi® ) is a humanized IgG1 monoclonal antibody that specifically binds to the p19 subunit of interleukin 23. OBJECTIVES: To compare risankizumab treatment to FAEs in patients with psoriasis. METHODS: This phase III randomized, active-controlled, open-label study with blinded assessment of efficacy was conducted in Germany. Patients were randomized (1 : 1) to subcutaneous risankizumab 150 mg (weeks 0, 4 and 16) or oral FAEs at increasing doses from 30 mg daily (week 0) up to 720 mg daily (weeks 8-24). Enrolled patients were adults naïve to and candidates for systemic therapy, with chronic moderate-to-severe plaque psoriasis. Phototherapy was not allowed within 14 days before or during the study. RESULTS: Key efficacy endpoints were met at week 24 for risankizumab (n = 60) vs. FAEs (n = 60) (P < 0·001): achievement of a ≥ 90% improvement in Psoriasis Area and Severity Index (PASI; primary endpoint 83·3% vs. 10·0%), ≥ 100% improvement in PASI (50·0% vs. 5·0%), ≥ 75% improvement in PASI (98·3% vs. 33·3%), ≥ 50% improvement in PASI (100% vs. 53·3%) and a Static Physician's Global Assessment of clear/almost clear (93·3% vs. 38·3%). The rates of gastrointestinal disorders, flushing, lymphopenia and headache were higher in the FAE group. One patient receiving risankizumab reported a serious infection (influenza, which required hospitalization). There were no malignancies, tuberculosis or opportunistic infections in either treatment arm. CONCLUSIONS: Risankizumab was found to be superior to FAEs, providing earlier and greater improvement in psoriasis outcomes that persisted with continued treatment, and more favourable safety results, which is consistent with the known safety profile. No new safety signals for risankizumab or FAEs were observed.

A pooled analysis of randomized, controlled, phase 3 trials investigating the efficacy and safety of a novel, fixed dose calcipotriene and betamethasone dipropionate cream for the topical treatment of plaque psoriasis.

BACKGROUND: Plaque psoriasis is a common, chronic and relapsing inflammatory skin disease clinically characterized by erythema and scaling desquamation. As over 90% of psoriasis patients benefit from topical therapies, local treatments continue to play an eminent role in management strategies. One such topical treatment is the fixed dose combination of calcipotriol (CAL) and betamethasone dipropionate (BDP). OBJECTIVES: Pooled analysis of two different phase 3 clinical trails to compare superiority regarding efficacy, safety and quality of life (QoL) between CAL/BDP PAD-cream and CAL/BDP TS. METHODS: The data from two phase 3, multicentre, randomized, investigator-blind, active and vehicle-controlled trials enrolling patients with psoriasis were pooled and analysed. Investigational products included a CAL/BDP cream based on PAD™ Technology (PAD-cream) designed for high skin penetration and increased patient preference, an active control (marketed CAL/BDP topical suspension/gel, in the following abbreviated as CAL/BDP TS) and cream vehicle, which were applied once daily for 8 weeks. RESULTS: Efficacy and safety of the novel CAL/BDP PAD-cream formulation for the topical treatment of psoriasis demonstrated superiority for all efficacy end points after 8 weeks of treatment. PGA treatment success for CAL/BDP PAD-cream (43.2%) was greater than CAL/BDP TS (31.9%; P < 0.0001), the mean per cent reduction in mPASI for CAL/BDP PAD-cream was 64.6% compared to 56.4% for CAL/BDP TS (P < 0.0001) and DLQI 0/1 was obtained by 43.8% in the CAL/BDP PAD-cream group versus 34.2% in the CAL/BDP TS group (P = 0.0005). There was no adverse drug reaction reported with a frequency of >1%, associated with the CAL/BDP PAD-cream. CONCLUSIONS: The novel fixed dose combination CAL/BDP PAD-cream offers greater efficacy, superior patient QoL and equivalent favourable safety for the topical treatment of psoriasis, in comparison to the currently available topical suspension/gel.

Long-term, durable, absolute Psoriasis Area and Severity Index and health-related quality of life improvements with risankizumab treatment: a post hoc integrated analysis of patients with moderate-to-severe plaque psoriasis.

BACKGROUND: Risankizumab has demonstrated durable, high rates of efficacy in patients with moderate-to-severe plaque psoriasis as assessed by the achievement of relative Psoriasis Area and Severity Index (PASI) improvement and Dermatology Life Quality Index (DLQI) 0/1. OBJECTIVES: The aim of this post hoc analysis is to assess the achievement of absolute PASI thresholds and related improvements in health-related quality of life (HRQoL) in patients with moderate-to-severe plaque psoriasis treated with (i) risankizumab compared with ustekinumab, and (ii) long-term (>52 weeks to 172 weeks) risankizumab. METHODS: Data from patients randomised to 150 mg risankizumab or 45 or 90 mg ustekinumab in replicate randomised controlled trials UltIMMa-1 and UltIMMa-2 were analysed for the achievement of absolute PASI thresholds PASI ≤ 3, PASI ≤ 1, and PASI = 0, time to achieve these thresholds, and combined PASI and DLQI endpoints. Data from pat ients initially randomised to risankizumab who continued on risankizumab in the open-label extension study LIMMitless were analysed for the achievement of absolute PASI levels, mean DLQI scores, and DLQI 0/1. RESULTS: Significantly greater proportions of patients treated with risankizumab compared with ustekinumab achieved PASI ≤ 3, PASI ≤ 1, and PASI = 0, as well as combined endpoints for absolute PASI and DLQI [(PASI ≤ 3 and DLQI ≤ 5) or (PASI ≤ 1 and DLQI 0/1)]. The median time to first achieve PASI ≤ 3, PASI ≤ 1, and PASI = 0 was significantly lower for risankizumab-treated patients compared with ustekinumab-treated patients. Among patients treated with long-term risankizumab, more than 90% achieved PASI ≤ 3 though week 172 and more than 80% achieved DLQI 0/1. Low absolute PASI scores corresponded with low mean absolute DLQI scores through week 172 of continuous risankizumab treatment. CONCLUSIONS: Risankizumab treatment demonstrated high rates of rapid and durable efficacy as measured by absolute PASI thresholds and improvements in patient HRQoL.

A head-to-head comparison of ixekizumab vs. guselkumab in patients with moderate-to-severe plaque psoriasis: 24-week efficacy and safety results from a randomized, double-blinded trial.

BACKGROUND: Significantly more patients with moderate-to-severe plaque psoriasis treated with the interleukin (IL)-17A inhibitor ixekizumab vs. the IL-23p19 inhibitor guselkumab in the IXORA-R head-to-head trial achieved 100% improvement in Psoriasis Area and Severity Index (PASI 100) at week 12. OBJECTIVES: To compare skin and nail clearance and patient-reported outcomes for ixekizumab vs. guselkumab, up to week 24. METHODS: IXORA-R enrolled adults with moderate-to-severe plaque psoriasis, defined as static Physician's Global Assessment ≥ 3, PASI ≥ 12 and involved body surface area ≥ 10%. Statistical comparisons were performed using the Cochran-Mantel-Haenszel test stratified by pooled site. Time-to-first-event comparisons were performed using Kaplan-Meier analysis, and P-values were generated using adjusted log-rank tests stratified by treatment group. Cumulative days at clinical and patient-reported responses were compared by ancova. The trial was registered with ClinicalTrials.gov (NCT03573323). RESULTS: Of the 1027 patients randomly assigned, 90% completed the trial (465 of 520 ixekizumab and 459 of 507 guselkumab). As early as week 2 and through week 16, more patients on ixekizumab achieved PASI 100 (P < 0·01). At week 24, ixekizumab was noninferior to guselkumab (50% vs. 52%, difference -2·3%), with no statistically significant difference in PASI 100 (P = 0·41). More patients receiving ixekizumab showed completely clear nails at week 24 (52% vs. 31%, P = 0·007). The median time to first PASI 50/75/90 and PASI 100 were 2 and 7·5 weeks shorter, respectively, for patients on ixekizumab vs. guselkumab (P < 0·001). Patients on ixekizumab also had a greater cumulative benefit, with more days at PASI 90 and 100, with Dermatology Life Quality Index of 0 or 1, and itch free (P < 0·05). The frequency of serious adverse events was 3% for each group, with no new safety signals. CONCLUSIONS: Ixekizumab was noninferior to guselkumab in complete skin clearance and superior in clearing nails at week 24. Ixekizumab cleared skin more rapidly in patients with moderate-to-severe plaque psoriasis, with a greater cumulative benefit, than guselkumab. Overall, the safety findings were consistent with the known safety profile for ixekizumab.

Patient-reported outcomes with risankizumab versus fumaric acid esters in systemic therapy-naïve patients with moderate to severe plaque psoriasis: a phase 3 clinical trial.

BACKGROUND: In a phase 3 clinical study, patients from Germany with moderate to severe psoriasis who were naïve to systemic treatment and received risankizumab had greater and more rapid disease improvements compared with those who received fumaric acid esters (FAEs). OBJECTIVE: To evaluate patient-reported outcomes (PROs) in patients treated with risankizumab compared with FAEs. METHODS: Adult patients were randomized 1:1 to receive either risankizumab 150 mg subcutaneous injections at weeks 0, 4 and 16 or FAEs (Fumaderm® ) provided according to the prescribing label. PRO secondary endpoints assessed were Psoriasis Symptom Scale (PSS), Dermatology Life Quality Index (DLQI), 36-Item Short Form Health Survey, version 2 (SF-36v2), Patient Benefit Index (PBI), Hospital Anxiety and Depression Scale (HADS), Patient Global Assessment (PtGA) and European Quality of Life 5 Dimensions 5 Level (EQ-5D-5L). PROs were assessed at weeks 0, 16 and 24. RESULTS: Sixty patients each were randomized to receive risankizumab or FAEs. A significant PSS improvement was observed with risankizumab vs. FAEs at weeks 16 and 24 for total and psoriasis-associated redness, itching and burning scores (P < 0.001). DLQI scores were significantly lower (reflecting better health-related quality of life) with risankizumab vs. FAEs, with least squares (LS) mean differences of -7.4 and -7.6 at weeks 16 and 24, respectively (both P < 0.001). Patients randomized to risankizumab also had larger improvements in SF-36 Physical and Mental Component Summary scores, HADS anxiety and depression scores, PtGA, and EQ-5D-5L index and visual analogue scale scores (all P ≤ 0.002) at weeks 16 and 24 compared with FAEs. PBI was significantly higher, indicating greater benefit, with risankizumab vs. FAEs, with an LS mean difference of 1.1 and 1.3 at weeks 16 and 24, respectively (both P < 0.001). CONCLUSIONS: Risankizumab provides significant benefits over FAEs in improving PROs across several dimensions in patients with moderate to severe psoriasis.

A phase 4, randomized, head-to-head trial comparing the efficacy of subcutaneous injections of brodalumab to oral administrations of fumaric acid esters in adults with moderate-to-severe plaque psoriasis (CHANGE).

BACKGROUND: Brodalumab is a fully human monoclonal immunoglobulin IgG2 antibody that binds to the human IL-17 receptor subunit A and by that inhibits the biologic action of IL-17A, IL-17F, IL-17C and IL-17E. Therapy with fumaric acid esters (FAE) is a well established and widely used first-line systemic treatment for subjects with moderate-to-severe plaque psoriasis. OBJECTIVES: To compare brodalumab to FAE in terms of clinical efficacy, patient-reported outcomes and safety in subjects with moderate-to-severe plaque psoriasis who were naïve to systemic treatment. METHODS: Eligible subjects were randomized 1 : 1 to 210 mg brodalumab injections or oral FAE according to product label in this 24-week, open-label, assessor-blinded, multi-centre, head-to-head phase 4 trial. The primary endpoints were having PASI75 and having sPGA score of 0 or 1 (sPGA 0/1). Subjects with missing values for the primary endpoints were considered non-responders. RESULTS: A total of 210 subjects were randomized. 91/105 subjects completed brodalumab treatment and 58/105 subjects completed FAE treatment. At Week 24, significantly more subjects in the brodalumab group compared to the FAE group had PASI75 (81.0% vs. 38.1%, P < 0.001) and sPGA 0/1 (64.8% vs. 20.0%, P < 0.001). In the brodalumab group, the median time to both PASI75 and to PASI90 was significantly shorter than in the FAE group (4.1 weeks vs. 16.4 weeks, and 7.4 weeks vs. 24.4 weeks, respectively, P < 0.0001 for both). The rate of adverse events was lower in subjects treated with brodalumab compared to subjects treated with FAE (616.4 vs. 1195.8 events per 100 exposure years). No new safety signals were detected for brodalumab. CONCLUSIONS: Brodalumab was associated with rapid and significant improvements in signs and symptoms of moderate-to-severe plaque psoriasis, with a superior efficacy profile to what was observed with FAE in systemic-naïve subjects over 24 weeks.

Nemolizumab is associated with a rapid improvement in atopic dermatitis signs and symptoms: subpopulation (EASI ≥ 16) analysis of randomized phase 2B study.

BACKGROUND: Nemolizumab is a humanized anti-IL-31 receptor blocker in phase 3 for atopic dermatitis (AD). OBJECTIVE: Analyse onset of action of nemolizumab 30 mg and compare efficacy and safety vs placebo (SC q4wk plus loading dose) in moderate-to-severe AD. METHODS: Post hoc analysis of patients with Eczema Area and Severity Index (EASI) scores ≥ 16 from a phase 2b trial of moderate-to-severe AD. Endpoints were change in EASI score at week 16, peak pruritus numeric rating scale (PP-NRS), Investigator's Global Assessment (IGA), changes in sleep and responders with ≥ 4-point improvement on PP-NRS. RESULTS: There was a significantly greater itch relief apparent by Day 2 (-22.8% vs -12.3% PP-NRS; P = 0.005) which continued to improve through week 16 (-68.5% vs -30.9% PP-NRS; P < 0.001). At week 16, PP-NRS ≥ 4-point response of itch was observed in 68.0% nemolizumab vs 15.9% placebo patients (P ≤ 0.001). There was also a rapid improvement of sleep disturbance with nemolizumab 30 mg, with a significant separation from placebo by Day 3 (-26.6% vs -9.0%; P < 0.001) which further improved till week 16 (-76.0% vs -36.5%; P < 0.001). Also for the EASI score a separation between groups in favour of nemolizumab was observed by week 1 (P ≤ 0.001), which increased through week 16 (-68.6% vs. -42.6%; P = 0.002). Finally, the degree of response was greater in nemolizumab-treated patients; clinically relevant reductions of 75% EASI were observed in 50.0% of nemolizumab patients versus 15.9% of placebo patients, while 90% reductions were reported for 36.0% and 6.8% of patients, respectively (P < 0.001 for both). IGA success (score of 0/1) was 32.0% for nemolizumab vs 6.8% for placebo (P = 0.002). Nemolizumab was safe and well-tolerated in this population; nasopharyngitis and upper respiratory tract infection were the most common adverse events. CONCLUSIONS: Nemolizumab resulted in very rapid, sustained improvements of inflammation, pruritus and sleep in patients with EASI ≥ 16 at baseline.

[Systemic treatment of moderate/severe hidradenitis suppurativa]. / Systemische Therapie der mittelschweren/schweren Hidradenitis suppurativa.

Systemic treatment together with radical surgical excision is the most important treatment option for all severity grades of hidradenitis suppurativa. Tetracycline in mild-to-moderate forms and clindamycin in combination with rifampicin in moderate-to-severe forms are guideline-compliant first-line therapy with a good clinical response. Other antibiotics such as ertepenem or multiple combinations are recommended as last-line therapy due to a lack of data. Success rate with dapsone and retinoids, on the other hand, are insufficient-only acitretin can be recommended on the basis of the available studies, but with limited success. With the TNF-alpha blocker adalimumab, an effective and safe long-term therapy is available-further biologics are in clinical trials and could significantly expand the treatment portfolio in the future.

A 24-week multicentre, randomized, open-label, parallel-group study comparing the efficacy and safety of ixekizumab vs. fumaric acid esters and methotrexate in patients with moderate-to-severe plaque psoriasis naive to systemic treatment.

BACKGROUND: Interleukin-17 antagonists have received a first-line label for moderate-to-severe plaque psoriasis. OBJECTIVES: We conducted the first head-to-head trial between the two most commonly used first-line therapies in Germany, fumaric acid esters (FAEs) and methotrexate, and the interleukin-17A antagonist, ixekizumab. METHODS: Systemic-naive patients were randomized in this parallel-group, active-comparator, open-label, rater-blinded trial (each group n = 54). The primary outcome was the proportion of patients achieving ≥ 75% improvement in Psoriasis Area and Severity Index (PASI 75) at 24 weeks. Key secondary outcomes included 24-week PASI 90 and 100, static Physician's Global Assessment (sPGA) score of 0 or 1, and Dermatology Life Quality Index (DLQI) score of 0 or 1. Safety events at week 24 were analysed using Fisher's exact test. Missing data were imputed using nonresponder imputation. The trial was registered at ClinicalTrials.gov (NCT02634801) and EudraCT (2015-002649-69). RESULTS: At week 24, more ixekizumab-treated patients achieved PASI 75 [91% vs. 22% FAEs (P < 0·001) and 70% methotrexate (P = 0·014)], PASI 90 [80% vs. 9% FAEs (P < 0·001) and 39% methotrexate (P < 0·001)] and PASI 100 [41% vs. 4% FAEs (P < 0·001) and 13% methotrexate (P = 0·0041)], as well as sPGA (0,1) and DLQI (0,1). CONCLUSIONS: Ixekizumab was superior in inducing PASI 75/90/100, sPGA (0,1) and DLQI (0,1) responses at week 24 compared with methotrexate and FAEs. Safety profiles for all treatments were consistent with prior studies.

Continued treatment with secukinumab is associated with high retention or regain of response.

BACKGROUND: Conventional analyses present aggregate data, masking late responders and efficacy reductions. Secukinumab, a fully human monoclonal antibody that selectively neutralizes interleukin (IL)-17A, shows sustained efficacy in moderate-to-severe psoriasis. OBJECTIVES: To determine stability of response to secukinumab, changes in efficacy were assessed in individual patients. METHODS: This is a post hoc analysis of two phase III randomized controlled trials, FIXTURE (trial registration: NCT01358578) and CLEAR (trial registration: NCT02074982). Patients received secukinumab 300 mg (FIXTURE and CLEAR), etanercept 50 mg (FIXTURE) or ustekinumab 45 or 90 mg (CLEAR) over 52 weeks. Mutually exclusive response categories were defined: ≥ 90% improvement in the Psoriasis Area and Severity Index (PASI 90) ('excellent'), ≥ 75% improvement in PASI (PASI 75) and < PASI 90 ('good') and < PASI 75 ('insufficient'). Reductions in efficacy were defined as shifts from higher to lower response categories between two consecutive visits maintained for a third consecutive visit. Loss of efficacy was defined as a reduction of efficacy resulting in 'insufficient' response. All comparisons are descriptive. RESULTS: At 52 weeks, in CLEAR, 90·2% (303/336) of patients on secukinumab achieved stable efficacy without loss and 77·7% (261/336) showed stable efficacy without any reduction of response [74·3% (252/339) and 59·9% (203/339) of patients for ustekinumab]. In FIXTURE, 83·5% (273/327) and 66·4% (217/327) of patients on secukinumab had stable efficacy without loss or reduction of response [58·3% (190/326) and 42·6% (139/326) for etanercept]. Response was regained by continuing secukinumab treatment in 50% (8/16) of patients in CLEAR and 26% (9/34) in FIXTURE. Similar patterns were observed for other response definitions. CONCLUSIONS: Efficacy with secukinumab was stable over 52 weeks of treatment in most patients. Continued treatment with secukinumab resulted in regain of efficacy in some patients. Persistent loss of response was uncommon. What's already known about this topic? Secukinumab, a fully human monoclonal antibody that selectively neutralizes interleukin (IL)-17A, shows significant and sustained efficacy in the treatment of moderate-to-severe psoriasis. Secondary loss of response may be experienced by a minority of patients treated with secukinumab, as with other biologics, but the extent of this and the potential for regain of efficacy with continued treatment is not well understood. What does this study add? To determine stability of response to secukinumab and inform clinical practice, changes in efficacy were assessed at individual patient level using response categories. Efficacy with secukinumab was stable over 52 weeks of treatment in most patients, and continued treatment with secukinumab resulted in efficacy regain after loss in some patients. Persistent loss of response was uncommon. Patient factors such as body weight may affect the likelihood of loss of efficacy.

Guselkumab is superior to fumaric acid esters in patients with moderate-to-severe plaque psoriasis who are naive to systemic treatment: results from a randomized, active-comparator-controlled phase IIIb trial (POLARIS).

BACKGROUND: Guselkumab, a fully human interleukin-23 antibody, is approved for systemic treatment of patients with moderate-to-severe plaque psoriasis. OBJECTIVES: To compare the efficacy and safety of guselkumab with those of fumaric acid esters (FAE) in patients with moderate-to-severe plaque psoriasis who are naive to systemic treatment. METHODS: Eligible patients were randomized to this multicentre, randomized, open-label, assessor-blinded, active-comparator-controlled phase IIIb study to receive guselkumab 100 mg by subcutaneous injection or oral FAE according to local label guidelines. RESULTS: Through week 24, 56 of 60 patients completed guselkumab treatment and 36 of 59 completed FAE treatment. The primary endpoint (proportion of patients with ≥ 90% improvement from their baseline Psoriasis Area and Severity Index; PASI 90 response) was achieved by significantly more patients receiving guselkumab than FAE at week 24 (82% vs. 14%, P < 0·001). Analysis of the major secondary endpoints confirmed a statistically significant difference between the treatments with regards to PASI 75 response (90% vs. 27%, P < 0·001) and Dermatology Life Quality Index score of 0 or 1 (no effect at all on the patient's quality of life; 62% vs. 17%, P < 0·001). More patients in the guselkumab group achieved completely clear skin (PASI 100 response) than in the FAE group (32% vs. 3%, P < 0·001). The incidence of adverse events was lower with guselkumab than with FAE (73% vs. 98%). Overall, 28% of patients on FAE discontinued due to an adverse event, compared with none receiving guselkumab. No new safety findings were observed for guselkumab. CONCLUSIONS: Guselkumab demonstrated superiority over FAE in systemic-treatment-naive patients with moderate-to-severe plaque psoriasis through 24 weeks.

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.

Effects of secukinumab on metabolic and liver parameters in plaque psoriasis patients.

BACKGROUND: Psoriasis is associated with metabolic, liver and cardiovascular comorbidity. Secukinumab, a fully human monoclonal antibody that selectively neutralizes interleukin-17A, has shown significant and sustained efficacy in the treatment of moderate to severe psoriasis. OBJECTIVES: This was an exploratory post hoc analysis of pooled data from three phase 3 studies in plaque psoriasis patient populations. The objective was to show the course of metabolic and liver parameters under secukinumab, etanercept or placebo treatment over time. A further objective was to assess the impact of selected comorbidities and metabolic characteristics on high-sensitivity C-reactive protein (hs-CRP), as a surrogate marker of systemic inflammation. METHODS: Data from the phase 3 randomized controlled trials [FIXTURE (NCT01358578), ERASURE (NCT01365455) and SCULPTURE (NCT01406938); n = 3010] were included in this analysis. Patients were treated with secukinumab 150 mg or 300 mg, placebo or etanercept 50 mg (FIXTURE only) as active comparator. A set of metabolic and liver parameters was longitudinally assessed over 52 weeks. Multivariate regression analyses assessed the impact of selected comorbidities and metabolic characteristics on hs-CRP levels at baseline and under treatment. RESULTS: Secukinumab treatment reduced hs-CRP levels. Body weight and uric acid levels tended to decrease over 52 weeks with secukinumab. Secukinumab showed a neutral effect on fasting plasma glucose, lipid parameters and liver enzymes. Psoriatic arthritis, metabolic syndrome, obesity, impaired glucose metabolism, and hyperuricemia were each associated with increased hs-CRP levels at baseline. Concomitant obesity attenuated the decline in hs-CRP under treatment. CONCLUSIONS: These analyses suggest neutral to favourable long-term trends in metabolic and liver parameters under secukinumab treatment. Metabolic comorbidities were associated with increased hs-CRP levels, reflecting the role of systemic inflammatory processes in their pathophysiology.

Sustained long-term efficacy and safety of adalimumab in paediatric patients with severe chronic plaque psoriasis from a randomized, double-blind, phase III study.

BACKGROUND: Adalimumab (ADA) (Humira® , AbbVie Inc., U.S.A.) is approved by the European Medicines Agency for children aged ≥ 4 years with severe plaque psoriasis. OBJECTIVES: To evaluate the long-term efficacy and safety of ADA in children with severe plaque psoriasis. METHODS: Results are presented from the 52-week long-term extension (LTE) of the randomized, double-blind, double-dummy, phase III trial, in children with severe plaque psoriasis (results from prior periods have been published). Patients aged ≥ 4 and < 18 years were randomized 1 : 1 : 1 to ADA 0·8 mg kg-1 (40 mg maximum) or 0·4 mg kg-1 (20 mg maximum) every other week or to methotrexate (MTX) 0·1-0·4 mg kg-1 (25 mg maximum) weekly. The 16-week initial treatment (IT) period was followed by a 36-week withdrawal period and a 16-week retreatment period. Patients could enter the LTE at prespecified time points to receive ADA 0·8 mg kg-1 (blinded or open label) or ADA 0·4 mg kg-1 (blinded), or to remain off treatment. Efficacy is reported for patient groups according to doses received in the IT and LTE periods. RESULTS: Of the 114 patients randomized in the IT period, 108 entered the LTE (n = 36 in each group); 93 received ADA 0·8 mg kg-1 . Efficacy (≥ 75% improvement from baseline in Psoriasis Area and Severity Index) was maintained or improved from entry to the end of the LTE: MTX(IT)/ADA 0·8(LTE) 31-86% of patients; ADA 0·4(IT)/0·4 or 0·8(LTE) 28-47%; ADA 0·8(IT)/0·8(LTE) 50-72%. No serious infections occurred in the LTE. CONCLUSIONS: After 52 weeks of long-term ADA treatment in children aged 4-18 years with severe plaque psoriasis, disease severity was reduced and maintained or further improved, as demonstrated by efficacy outcomes. No new safety risks were identified. What's already known about this topic? The results from the first three periods of this phase III trial in children aged 4-18 years with severe plaque psoriasis suggest that adalimumab is a safe and efficacious treatment option in this population. What does this study add? This is the first study to evaluate long-term treatment of adalimumab in children with severe psoriasis, and the first to evaluate switching from methotrexate to adalimumab in this population.

Comparison of ixekizumab with ustekinumab in moderate-to-severe psoriasis: 24-week results from IXORA-S, a phase III study.

BACKGROUND: It has been shown that the interleukin (IL)-23/IL-17 axis is critical in the pathogenesis of psoriasis. OBJECTIVES: To present the primary end point (week 12) and safety and efficacy data up to week 24 from a head-to-head trial (IXORA-S) of the IL-17A inhibitor ixekizumab (IXE) vs. the IL-12/23 inhibitor ustekinumab (UST). METHODS: Randomized patients received IXE (160-mg starting dose, then 80 mg every 2 weeks for 12 weeks, then 80 mg every 4 weeks, n = 136) or UST (45 mg or 90 mg weight-based dosing per label, n = 166). The primary end point was the proportion of patients reaching ≥ 90% Psoriasis Area and Severity Index improvement (PASI 90). Hommel-adjusted key secondary end points at week 12 included PASI 75, PASI 100, static Physician's Global Assessment (sPGA) score of 0 or 1, sPGA score of 0, Dermatology Life Quality Index (DLQI) score of 0 or 1, ≥ 4-point reduction on the itch numerical rating scale (NRS) and changes in itch NRS and skin pain visual analogue scale. RESULTS: At week 12, IXE (n = 99, 72·8%) was superior to UST (n = 70, 42·2%) in PASI 90 response (response difference 32·1%, 97·5% confidence interval 19·8-44·5%, P < 0·001). Response rates for PASI 75, PASI 100 and sPGA (0,1) were significantly higher for IXE than for UST (adjusted P < 0·05). At week 24, IXE-treated patients had significantly higher response rates than UST-treated patients for PASI, sPGA and DLQI (unadjusted P < 0·05). No deaths were reported, and the treatments did not differ with regard to overall incidences of adverse events (P = 0·299). CONCLUSIONS: The superior efficacy of IXE demonstrated at week 12 persisted up to week 24. The safety profiles were consistent with those previously reported for both treatments.