Tildrakizumab efficacy and safety in patients with psoriasis and concomitant metabolic syndrome: post hoc analysis of 5-year data from reSURFACE 1 and reSURFACE 2.

BACKGROUND: Limited data are available on long-term efficacy and safety of biologics in patients with psoriasis and metabolic syndrome (MetS), a common comorbidity. OBJECTIVES: This analysis updates tildrakizumab efficacy and safety for up to 5 years in patients with and without MetS. METHODS: This was a post hoc analysis of the double-blind, randomized, placebo-controlled, phase 3 reSURFACE 1 (NCT01722331) and reSURFACE 2 (NCT01729754) trials in adult patients with moderate to severe chronic plaque psoriasis. Analyses included data through Week 244 from patients who continuously received tildrakizumab 100 (TIL100) or 200 mg (TIL200) and entered the extension studies, stratified by baseline MetS status. Efficacy was assessed via Psoriasis Area and Severity Index (PASI) scores. Safety was evaluated from exposure-adjusted incidence rates (EAIRs) of treatment-emergent adverse events (TEAEs). RESULTS: reSURFACE 1 and reSURFACE 2 analyses included 26 and 44 TIL100-treated patients with MetS, 98 and 167 TIL100-treated patients without MetS, 34 and 30 TIL200-treated patients with MetS, and 111 and 130 TIL200-treated patients without MetS, respectively. There were no clinically relevant differences in PASI 75/90/100 response rates at Week 244 between patients with vs without MetS. The proportion of patients with vs without MetS achieving absolute PASI score <3 at Week 244 was 53.8% vs 69.4% and 77.3% vs 80.8% in reSURFACE 1 and 2, respectively, for TIL100-treated patients and 58.8% vs 72.1% and 63.3% vs 72.3%, respectively, for TIL200-treated patients. In both studies, median reduction from baseline PASI score at all time points in patients with vs without MetS was >83% vs >89% for TIL100 and >85% vs >90% for TIL200. Pooled EAIRs of TEAEs, serious TEAEs, and TEAEs of special interest were similar in patients with and without MetS. CONCLUSIONS: Tildrakizumab maintains efficacy and a favorable safety profile over 5 years in patients with psoriasis regardless of MetS status.

Long-term efficacy and safety of risankizumab for the treatment of moderate-to-severe plaque psoriasis: interim analysis of the LIMMitless open-label extension trial beyond 3 years of follow-up.

BACKGROUND: Psoriasis is a chronic inflammatory skin disease requiring prolonged treatment. New biologic therapies require long-term evaluation to assess the durability of their efficacy and safety profiles over time. OBJECTIVES: To evaluate the long-term efficacy and safety of risankizumab (RZB) for the treatment of psoriasis. METHODS: LIMMitless is an ongoing, phase III, open-label extension study evaluating the long-term efficacy and safety of RZB in adults with moderate-to-severe plaque psoriasis following multiple phase II/III studies. This analysis assessed efficacy through 172 weeks of continuous RZB treatment by examining the proportion of patients achieving ≥ 90% or 100% improvement in Psoriasis Area and Severity Index (PASI 90 and PASI 100), static Physician's Global Assessment of clear or almost clear (sPGA 0/1) and Dermatology Life Quality Index of no effect on quality of life (DLQI 0/1). Safety was assessed by recording adverse events (AEs) through the data cutoff date. The study is registered at ClinicalTrials.gov (identifier: NCT03047395). RESULTS: Of 955 patients randomized to RZB 150 mg in the base studies, 897 patients continued into LIMMitless; 799 patients were still receiving treatment in LIMMitless at the time of data cutoff for this analysis. After 172 weeks of continuous RZB treatment, 85·5% of patients achieved PASI 90, 54·4% achieved PASI 100, 85·2% achieved sPGA 0/1, and 78·4% achieved DLQI 0/1 using modified nonresponder imputation. Rates of AEs leading to discontinuation and AEs of safety interest were low with long-term treatment and comparable with those identified in the base studies. CONCLUSIONS: Overall, long-term continuous RZB was well tolerated and showed high and durable efficacy over 172 weeks.

Network meta-analysis of biologic treatments for psoriasis using absolute Psoriasis Area and Severity Index values ≤1, 2, 3 or 5 derived from a statistical conversion method.

BACKGROUND: In practice, the goal of treatment for patients with psoriasis is to achieve almost clear or clear skin and maintain disease control, regardless of baseline disease severity. However, identifying absolute Psoriasis Area and Severity Index (PASI) values for new treatment goals is challenging, as most clinical trials report relative PASI 50, 75, 90 or 100 improvements but rarely absolute PASI values achieved. OBJECTIVE: Our objective was to illustrate a statistical conversion method that was developed to derive absolute PASI values from available clinical trial data on relative PASI improvements. The results of network meta-analyses (NMAs) based on these derived data were then compared with those of NMAs based on the corresponding relative PASI improvement data for selected biologics for moderate-to-severe psoriasis. METHODS: The PASI statistical conversion method was applied to relative PASI improvement data for 11 biologic treatment regimens and placebo at 12 weeks using data from 50 published studies. The respective proportions of patients reaching absolute PASI values ≤1, 2, 3 or 5 were then calculated. Frequentist NMAs (Rücker method) were subsequently used to compare efficacy results across relative and absolute PASI data. RESULTS: The ranking of included treatment regimens for patients achieving absolute PASI 0 to 8 was aligned with results for relative PASI scores (from 100 to 60) at end of induction therapy. Across the range of PASI scores considered, the most effective treatment regimens based on both absolute and relative PASI NMAs were brodalumab 210 mg every 2 weeks and ixekizumab 80 mg every 2 weeks, followed by guselkumab 100 mg every 8 weeks and risankizumab 150 mg every 12 weeks. CONCLUSION: Data generated using this mathematical model will be useful to inform ongoing scientific discussions on treatment goals in the absence of primary absolute PASI data for all available treatments for moderate-to-severe plaque psoriasis.

Long-term efficacy of certolizumab pegol for the treatment of plaque psoriasis: 3-year results from two randomized phase III trials (CIMPASI-1 and CIMPASI-2).

BACKGROUND: Certolizumab pegol (CZP) is an Fc-free, PEGylated anti-tumour necrosis factor biologic. OBJECTIVES: To report the 3-year efficacy of CZP in plaque psoriasis, pooled from the CIMPASI-1 (NCT02326298) and CIMPASI-2 (NCT02326272) phase III trials. METHODS: Adults with moderate-to-severe psoriasis for ≥ 6 months were randomized 2 : 2 : 1 to CZP 200 mg, CZP 400 mg or placebo, every 2 weeks (Q2W) for up to 48 weeks. Patients entering the open-label period (weeks 48-144) from double-blinded CZP initially received CZP 200 mg Q2W. Patients not achieving ≥ 50% improvement in Psoriasis Area and Severity Index (PASI 50) at week 16 entered an open-label CZP 400 mg Q2W escape arm (weeks 16-144). Dose adjustments based on PASI response were permitted during open-label treatment. Outcomes included PASI 75, PASI 90 and Physician's Global Assessment (PGA) 0/1 responder rates, based on a logistic regression model (missing data imputed using Markov Chain Monte Carlo methodology). RESULTS: In total, 186 patients were randomized to CZP 200 mg Q2W and 175 to CZP 400 mg Q2W. At week 48, PASI 75/90 was achieved by 72·7%/51·3% of patients randomized to CZP 200 mg and 84·4%/62·7% randomized to CZP 400 mg. Patients entering the open-label period at week 48, from blinded treatment, received CZP 200 mg Q2W. At week 144, PASI 75/90 was achieved by 70·6%/48·7% patients randomized to CZP 200 mg and 72·9%/42·7% randomized to CZP 400 mg. At week 16, 72 placebo-randomized patients entered the CZP 400 mg Q2W escape arm; 75.7%/58.5% achieved PASI 75/90 at week 144. CONCLUSIONS: Both CZP 200 mg and 400 mg Q2W demonstrated sustained, durable efficacy, with numerically higher responses for some outcomes with 400 mg Q2W.

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.

Long-term efficacy and safety of brodalumab in psoriasis through 120 weeks and after withdrawal and retreatment: subgroup analysis of a randomized phase III trial (AMAGINE-1).

BACKGROUND: Brodalumab is efficacious for the treatment of moderate-to-severe plaque psoriasis through 52 weeks. OBJECTIVES: To evaluate the efficacy and safety of brodalumab through 120 weeks, including following withdrawal and retreatment. METHODS: At baseline, patients were randomized to brodalumab (n = 222) or placebo (n = 220). At week 12, patients achieving a static Physician's Global Assessment (sPGA) score of 0 or 1 (sPGA 0/1) with brodalumab were rerandomized to brodalumab (n = 83) or placebo (n = 84; later re-treated with brodalumab if sPGA ≥ 3 occurred), and patients receiving placebo switched to brodalumab (n = 208). Safety was assessed by exposure-adjusted rates of treatment-emergent adverse events. RESULTS: Among those who achieved sPGA 0/1 at week 12 and were rerandomized to brodalumab, 96% and 80% using observed data, respectively, and 74% and 61% using nonresponder imputation, respectively, achieved 75% improvement in Psoriasis Area and Severity Index (PASI 75) and PASI 100 at week 120. Following withdrawal from brodalumab, return of disease occurred after a mean ± SD duration of 74·7 ± 50·5 days. Among those who switched from brodalumab to placebo at week 12, PASI 75 rates using observed data and nonresponder imputation were 55% and 51% at week 20, respectively and 94% and 75% at week 120, respectively; PASI 100 rates at week 120 were 75% and 60%, respectively. Efficacy was maintained through week 120 in those receiving brodalumab after placebo. No new safety signals were observed. CONCLUSIONS: These findings indicate that brodalumab is efficacious and safe for continuous long-term treatment of psoriasis, and support the potential for response after discontinuation and retreatment.

Efficacy of risankizumab in patients with moderate-to-severe plaque psoriasis by baseline demographics, disease characteristics and prior biologic therapy: an integrated analysis of the phase III UltIMMa-1 and UltIMMa-2 studies.

BACKGROUND: Risankizumab is a humanized IgG monoclonal antibody that selectively inhibits interleukin-23 through binding the p19 subunit. In Phase 3 trials, risankizumab demonstrated superior efficacy compared with adalimumab and ustekinumab in patients with moderate-to-severe plaque psoriasis. Here, we evaluated the impact of baseline characteristics on efficacy of risankizumab compared with ustekinumab in patients with moderate-to-severe plaque psoriasis. METHODS: This analysis included all patients initially randomized to risankizumab or ustekinumab from the replicate, double-blinded, randomized, placebo-controlled phase 3 trials, UltIMMa-1 (NCT02684370) and UltIMMa-2 (NCT02684357). Patients received either risankizumab (150 mg) or ustekinumab (weight-based; 45 or 90 mg per label) at weeks 0, 4, 16, 28 and 40. Efficacy was assessed as the proportion of patients achieving ≥90% improvement in Psoriasis Area and Severity Index (PASI 90) at weeks 16 and 52 by baseline patient demographics, disease characteristics and prior biologic exposure. Mean per cent improvement in PASI was calculated by body weight and body mass index at week 52. Missing efficacy data were imputed as non-responders for categorical variables and last observation carried forward for continuous variables. Logistic regression analyses assessed for interactions between treatment and five independent variables (age, sex, weight, baseline PASI score and presence of psoriatic arthritis) at both weeks 16 and 52. RESULTS: Baseline patient demographics, disease characteristics and prior biologic exposure were similar between patients randomized to risankizumab (n = 598) and ustekinumab (n = 199). At weeks 16 and 52, risankizumab demonstrated superior efficacy compared with ustekinumab across these patient characteristics (P < 0.01). Logistic regression analyses demonstrated that risankizumab was superior to ustekinumab at weeks 16 and 52 in all models tested (P < 0.0001 for all). CONCLUSIONS: Risankizumab demonstrated consistent and superior efficacy compared with ustekinumab regardless of patient demographics, disease characteristics or prior biologic exposure.

Immediate breast reconstruction with latissimus dorsi flap for patients with local recurrence of breast cancer.

BACKGROUND: Ipsilateral breast cancer recurrence (IBTR) occurs in about 7% of patients with primary invasive breast tumor. Salvage mastectomy and breast reconstruction are often discussed and latissimus dorsi (LD) flap is frequently proposed. METHODS: We retrospectively investigated 111 consecutive locally relapsing patients who underwent salvage mastectomy and immediate LD reconstruction. All included patients with IBTR previously underwent conserving surgery for BC, and received a postoperative irradiation. Primary endpoints were disease free survival and overall survival. Secondary endpoints were surgical complications and re-interventions. RESULTS: Invasive ductal cancer was the most frequent histotype (60.4%) of breast cancer reappearance. rpT1, rpT2 and rpT3 were observed respectively in 50.5%, 20,7% and 3,6% of the patients. rpTis occurred in 11,7% of cases. Positive axillary nodes were observed in 9,9% of patients at reappearance. Post-operative complication other than seroma occurred in 17,1% of patients, while seroma at the donor site was observed in 61.3% of cases. At 5-year after surgery overall survival was 92% (95% CI: 85%-96%) and disease free survival was 78% (95% CI: 69%-85%). CONCLUSIONS: Immediate latissimus dorsi flap reconstruction in selected patients with isolated breast tumor recurrence, which occurred after breast irradiation, provides an effective treatment with a satisfactory outcome.

Long-term safety of secukinumab in patients with moderate-to-severe plaque psoriasis, psoriatic arthritis, and ankylosing spondylitis: integrated pooled clinical trial and post-marketing surveillance data.

BACKGROUND: Secukinumab, a fully human immunoglobulin G1-kappa monoclonal antibody that directly inhibits interleukin (IL)-17A, has been shown to have robust efficacy in the treatment of moderate-to-severe psoriasis (PsO), psoriatic arthritis (PsA), and ankylosing spondylitis (AS) demonstrating a rapid onset of action and sustained long-term clinical responses with a consistently favorable safety profile in multiple Phase 2 and 3 trials. Here, we report longer-term pooled safety and tolerability data for secukinumab across three indications (up to 5 years of treatment in PsO and PsA; up to 4 years in AS). METHODS: The integrated clinical trial safety dataset included data pooled from 21 randomized controlled clinical trials of secukinumab 300 or 150 or 75 mg in PsO (14 Phase 3 trials and 1 Phase 4 trial), PsA (3 Phase 3 trials), and AS (3 Phase 3 trials), along with post-marketing safety surveillance data with a cut-off date of June 25, 2017. Adverse events (AEs) were reported as exposure-adjusted incident rates (EAIRs) per 100 patient-years. Analyses included all patients who received ≥ 1 dose of secukinumab. RESULTS: A total of 5181, 1380, and 794 patients from PsO, PsA, and AS clinical trials representing secukinumab exposures of 10,416.9, 3866.9, and 1943.1 patient-years, respectively, and post-marketing data from patients with a cumulative exposure to secukinumab of ~ 96,054 patient-years were included in the analysis. The most frequent AE was upper respiratory tract infection. EAIRs across PsO, PsA, and AS indications were generally low for serious infections (1.4, 1.9, and 1.2, respectively), Candida infections (2.2, 1.5, and 0.7, respectively), inflammatory bowel disease (0.01, 0.05, and 0.1, respectively), and major adverse cardiac events (0.3, 0.4, and 0.6, respectively). No cases of tuberculosis reactivation were reported. The incidence of treatment-emergent anti-drug antibodies was low with secukinumab across all studies, with no discernible loss of efficacy, unexpected alterations in pharmacokinetics, or association with immunogenicity-related AEs. CONCLUSIONS: Secukinumab demonstrated a favorable safety profile over long-term treatment in patients with PsO, PsA, and AS. This comprehensive assessment demonstrated that the safety profile of secukinumab was consistent with previous reports in patients with PsO, PsA, and AS, supporting its long-term use in these chronic conditions.

Efficacy and safety of mirikizumab (LY3074828) in the treatment of moderate-to-severe plaque psoriasis: results from a randomized phase II study.

BACKGROUND: Inhibiting interleukin (IL)-23 in patients with psoriasis has demonstrated high levels of skin clearance. OBJECTIVES: To investigate, in a phase II (AMAF; NCT02899988), multicentre, double-blind trial, the efficacy and safety of three doses of mirikizumab (LY3074828), a p19-directed IL-23 antibody, vs. placebo in patients with moderate-to-severe plaque psoriasis. METHODS: Adult patients were randomized 1 : 1 : 1 : 1 to receive placebo (n = 52), mirikizumab 30 mg (n = 51), mirikizumab 100 mg (n = 51) or mirikizumab 300 mg (n = 51) subcutaneously at weeks 0 and 8. The primary objective was to evaluate the superiority of mirikizumab over placebo in achieving a 90% improvement in the Psoriasis Area and Severity Index (PASI 90) response at week 16. Comparisons were done using logistic regression analysis with treatment, geographical region and previous biological therapy in the model. Missing data were imputed as nonresponses. RESULTS: Ninety-seven per cent of patients completed the first 16 weeks of the study. The primary end point was met for all mirikizumab dose groups vs. placebo, with PASI 90 response rates at week 16 of 0%, 29% (P = 0·009), 59% (P < 0·001) and 67% (P < 0·001) for patients receiving placebo, and mirikizumab 30 mg, 100 mg and 300 mg, respectively. There were two (1%) serious adverse events in mirikizumab-treated patients vs. one (2%) in a placebo-group patient. CONCLUSIONS: At week 16, 67% of patients treated with mirikizumab 300 mg at 8-week intervals achieved PASI 90. The percentage of patients reporting at least one treatment-emergent adverse event was similar among patients treated with placebo or mirikizumab.

Comprehensive long-term safety of adalimumab from 18 clinical trials in adult patients with moderate-to-severe plaque psoriasis.

BACKGROUND: Adalimumab (Humira® , AbbVie Inc., North Chicago, IL, U.S.A.) is a fully human monoclonal antibody specific for tumour necrosis factor-α that is approved to treat adults with moderate-to-severe chronic plaque psoriasis. OBJECTIVES: To assess long-term safety for patients with psoriasis receiving adalimumab in clinical studies. METHODS: Adalimumab safety data from adults with psoriasis who received at least one adalimumab dose in 18 clinical trials were evaluated. Adalimumab was delivered subcutaneously in all treatment regimens. Treatment-emergent adverse events (AEs) were collected from the first dose to 70 days after the last dose or cut-off date (31 December 2015). AE incidence rates were expressed as events per 100 patient-years (E/100 PYs) of adalimumab exposure. Standardized incidence ratios (SIRs) for malignancies and standardized mortality ratios (SMRs) were calculated. RESULTS: Cumulative exposure was 5429·7 PYs in 3727 patients. Overall, there were 16 536 AEs (304·6 E/100 PYs). The most common AEs were nasopharyngitis, upper respiratory infection and headache (23·7, 12·9 and 7·9 E/100 PYs, respectively). Incidence rates for serious infections, tuberculosis and opportunistic infections were 1·8, 0·3 and 0·02 E/100 PYs, respectively. Incidence of malignancy excluding nonmelanoma skin cancer (NMSC) was 0·8 E/100 PYs [SIR 0·86, 95% confidence interval (CI) 0·58-1·23]. Incidences of NMSC and melanoma were 0·6 and 0·2 E/100 PYs, respectively. The SIR was 1·55 (95% CI 1·10-2·13) for NMSC and 3·04 (95% CI 1·11-6·62) for melanoma. The SMR was 0·34 (95% CI 0·16-0·65). CONCLUSIONS: AE rates remained stable in this analysis of patients with psoriasis receiving adalimumab; no new safety signals were identified compared with earlier analyses.

Systematic review of the real-world evidence of adalimumab safety in psoriasis registries.

Long-term safety of adalimumab in psoriasis clinical studies has been established. The objective of this research was to review real-world evidence of adalimumab safety from registries of adult patients with psoriasis treated in clinical practice. Databases (BIOSIS Previews, Current Contents Search, Derwent Drug File, EMBASE, EMBASE Alert, EMCare, MEDLINE, SciSearch) were searched for psoriasis registries with adalimumab safety data. Eligible papers were English language manuscripts (conference abstracts excluded) from psoriasis registries presenting safety data for adult patients with psoriasis receiving adalimumab. The incidence and rate (events/100 patient-years [PY]) of adverse events (AEs), serious AEs (SAEs) and AEs of special interest are reported. Abstracts of 425 publications were screened, and 401 publications excluded (208 conference abstracts; 193 papers). Remaining manuscripts were fully screened; 14 were excluded (no adalimumab data, n = 10; no safety data, n = 2; no on-treatment data, n = 1; not English, n = 1), and 10 selected. Overall rates of AEs (4273 [22.2/100PY]) and SAEs (827 [4.3/100PY]) were reported in the ESPRIT registry (N = 6059). Rates of infections (7.7-14.7/100PY) and serious infections (<0.6-2.0/100PY) were reported in four studies. Cardiovascular-related events were reported in three studies: ≤0.1/100PY per major cardiac event in ESPRIT, <0.5/100PY major cardiac events in PsoBest and serious cardiovascular events in two patients (<1%) in DERMBIO. Malignancies were reported in three studies (any malignancy, 0.9/100PY; malignancies excluding non-melanoma skin cancer [NMSC], <0.6/100PY; NMSC, 0.6-<0.5/100PY). These findings suggest that real-world safety of adalimumab is consistent across different psoriasis registries, which supports the existing long-term safety profile of adalimumab from clinical studies.

Phase III randomized study of the proposed adalimumab biosimilar GP2017 in psoriasis: impact of multiple switches.

BACKGROUND: Adalimumab is used to treat several inflammatory diseases, including plaque psoriasis. GP2017 is a proposed adalimumab biosimilar. OBJECTIVES: To assess the impact of multiple switches between GP2017 and reference adalimumab (ref-ADMB) following the demonstration of equivalent efficacy and similar safety and immunogenicity, in adult patients with active, clinically stable, moderate-to-severe plaque psoriasis. METHODS: This 51-week double-blinded, phase III study randomly assigned patients to GP2017 (n = 231) or ref-ADMB (n = 234) 80 mg subcutaneously at week 0, then 40 mg biweekly from week 1. At week 17, patients were rerandomized to switch (n = 126) or continue (n = 253) treatment. The primary end point was patients achieving ≥ 75% improvement in Psoriasis Area and Severity Index (PASI 75) at week 16, with equivalence confirmed if the 95% confidence interval (CI) for the difference in PASI 75 between treatments was ± 18%. The key secondary end point was the change from baseline to week 16 in continuous PASI. Other end points were PASI over time; PASI 50, 75, 90 and100; pharmacokinetics; safety; tolerability and immunogenicity for the switched and continued treatment groups. RESULTS: Equivalent efficacy between GP2017 and ref-ADMB was confirmed for the primary (66·8% and 65·0%, respectively; 95% CI -7·46 to 11·15) and key secondary end points (-60·7% and -61·5%, respectively; 95% CI -3·15 to 4·84). PASI improved over time and was similar between treatment groups at week 16, and the switched and continued groups from weeks 17 to 51. There were no relevant safety or immunogenicity differences between GP2017 and ref-ADMB at week 16, or the switched and continued groups from weeks 17 to 51. No hypersensitivity to adalimumab was reported upon switching. CONCLUSIONS: Following the demonstration of GP2017 biosimilarity to ref-ADMB, switching up to four times between GP2017 and ref-ADMB had no detectable impact on efficacy, safety or immunogenicity.

Long-term optimization of outcomes with flexible adalimumab dosing in patients with moderate to severe plaque psoriasis.

BACKGROUND: The recently updated dosing recommendation for adalimumab for moderate to severe plaque psoriasis states that patients with inadequate response to adalimumab every other week (EOW) after 16 weeks may benefit from an increase in dosing frequency to 40 mg every week (EW). OBJECTIVE: To determine the long-term efficacy of adalimumab in patients with psoriasis with flexibility to escalate and de-escalate between EOW and EW dosing. METHODS: Data from an open-label study in patients with psoriasis who had received adalimumab in phase 2/3 studies and their extensions were included. Patients initially received 40 mg adalimumab EOW for 24 weeks. From weeks 24-252, patients whose Psoriasis Area and Severity Index response was <50% (PASI 50) could have their dose-escalated to 40 mg EW and were re-evaluated at 6 and 12 weeks and then every 12 weeks thereafter. Patients who had their dose-escalated and achieved a PASI 75 response were de-escalated to EOW and could re-escalate to EW if response fell below PASI 50 again; no further de-escalation was allowed. Changes in PASI scores were reported at the last visit before dose escalation or de-escalation. RESULTS: By week 24, 64.1% of patients in the overall population (n = 1256) achieved ≥PASI 75 response, 40.3% ≥PASI 90 response and 21.7% PASI 100 response. Patients who had a

The gambling disorder: family styles and cognitive dimensions.

OBJECTIVE: In this study we present data from a research carried out on a population of people with gambling disorder (GD). SUBJECTS AND METHODS: This research investigated the representation of family styles for subjects with gambling disorder, using the Family Adaptability and Cohesion Evaluation Scale (FACES-IV), their cognitive distortions through Gambling Related Cognitions Scale (GRCS-I), and the relation between these two dimensions. RESULTS: People with GD represent families with emotional detachment, while in the area of management of relational rules and roles, they reveal a perception of disorganization. Concerning their cognitive bias, GD people show the illusion of being able to control and predict the winnings and the perception of being unable to quit playing. CONCLUSIONS: Overall, these data provide specific directions for both the prevention and the therapeutic treatment of GD, highlighting the importance of a family therapeutic approach for the prevention of cognitive distortions.

Secukinumab demonstrates high sustained efficacy and a favourable safety profile in patients with moderate-to-severe psoriasis through 5 years of treatment (SCULPTURE Extension Study).

BACKGROUND: Secukinumab, a fully human monoclonal antibody that selectively neutralizes IL-17A, has been shown to have significant efficacy and a favourable safety profile in the treatment of moderate-to-severe psoriasis and psoriatic arthritis. OBJECTIVE: To assess the efficacy and safety of secukinumab through 5 years of treatment in moderate-to-severe psoriasis. METHODS: In the core SCULPTURE study, Psoriasis Area and Severity Index (PASI) 75 responders at Week 12 continued receiving subcutaneous secukinumab until Year 1. Thereafter, patients entered the extension phase and continued treatment as per the core trial. Treatment was double-blinded until the end of Year 3 and open-label from Year 4. Here, we focus on the 300 mg fixed-interval (every 4 weeks) treatment, the recommended per label dose. Efficacy data are primarily reported as observed, but multiple imputation (MI) and last observation carried forward (LOCF) techniques were also undertaken as supportive analyses. RESULTS: At Year 1, 168 patients entered the extension study and at the end of Year 5, 126 patients completed 300 mg (every 4 weeks) treatment. PASI 75/90/100 responses at Year 1 (88.9%, 68.5% and 43.8%, respectively) were sustained to Year 5 (88.5%, 66.4% and 41%). PASI responses were consistent regardless of the analysis undertaken (as observed, MI, or LOCF). The average improvement in mean PASI was approximately 90% through 5 years compared with core study baseline. DLQI (dermatology life quality index) 0/1 response also sustained through 5 years (72.7% at Year 1 and 65.5% at Year 5). The safety profile of secukinumab remained favourable, with no cumulative or unexpected safety concerns identified. CONCLUSION: Secukinumab 300 mg treatment delivered high and sustained levels of skin clearance and improved quality of life through 5 years in patients with moderate-to-severe psoriasis. Favourable safety established in the secukinumab phase 2/3 programme was maintained through 5 years.

Ixekizumab treatment for psoriasis: integrated efficacy analysis of three double-blinded, controlled studies (UNCOVER-1, UNCOVER-2, UNCOVER-3).

BACKGROUND: Ixekizumab, a high-affinity monoclonal antibody that selectively targets interleukin (IL)-17A, is approved for the treatment of moderate-to-severe psoriasis. OBJECTIVES: This analysis represents an overview of the efficacy outcomes from three phase III psoriasis studies. METHODS: Data were integrated from the 12-week induction period of three studies in which patients received ixekizumab 80 mg every 2 weeks (IXE Q2W; n = 1169) or every 4 weeks (IXE Q4W; n = 1165) after an initial 160-mg dose for both; etanercept (50 mg biweekly; n = 740; two studies) or placebo (n = 792). The coprimary end points were the percentages of patients with response of static Physician's Global Assessment (sPGA; score 0 or 1) and ≥ 75% improvement in baseline Psoriasis Area and Severity Index (PASI 75) at week 12. Response rates were compared between treatments using the Cochran-Mantel-Haenszel test stratified by study. Treatment comparisons with placebo included data from three studies, whereas etanercept comparisons were based on two studies. RESULTS: Ixekizumab treatment was superior to placebo (P < 0·001) and etanercept (P < 0·001) on sPGA (0, 1) and PASI 75, with significant differences in PASI improvement at week 1. With IXE Q2W, at week 12, the frequencies of patients achieving PASI 75, 90 and 100 were nearly 90%, 70% and 40%, respectively. Ixekizumab-treated patients showed significantly greater improvement vs. placebo and etanercept in percentage body surface area involvement and fingernail psoriasis. IXE Q2W was superior to IXE Q4W on all treatment outcomes. CONCLUSIONS: Ixekizumab therapy at both dosing regimens demonstrated rapid onset and superior efficacy to placebo and etanercept, with IXE Q2W providing better outcomes than IXE Q4W during the first 12 weeks of treatment.

Efficacy of colostrum replacer versus maternal colostrum on immunological status, health, and growth of preweaned dairy calves.

Commercially available colostrum replacers (CR) are commonly used when maternal colostrum (MC) is unavailable, for managerial convenience, to ensure quality consistency at first feeding, or in disease control and eradication programs. The objective of this study was to determine the efficacy of feeding First Day Formula (Accelerated Genetics, Baraboo, WI) CR versus pooled MC on immunological status, growth, and health of preweaned dairy calves. A total of 1,220 Jersey and Jersey × Holstein calves born on a California Central Valley dairy farm were assigned after birth to receive either CR or MC following a systematic allocation procedure. Calves assigned to MC were tube fed 2.8 L of MC, and calves assigned to CR were tube fed a total of 500 g of CR (150 g of immunoglobulin G; IgG) mixed into 1.9 L of water at 1 h ± 5 min after the calf was born. A subset of calves was selected for passive transfer (n = 592) and growth (n = 268) analyses. Although both coliform count and total bacteria count were low for MC and CR fed to calves during the study, the predicted probability of calves receiving contaminated liquid feed (coliform count >10,000 cfu/mL) at first feeding was reduced for calves fed CR (1.5%) compared with calves fed MC (6.1%). The mean blood concentration of IgG was lower for calves fed CR than for calves fed MC (19.6 vs. 23.4 mg/mL). However, the apparent efficiency of absorption of IgG did not differ between treatments (34.4 and 35.9% for CR and MC, respectively). Total proteins were lower in calves fed CR compared with MC at 24 h (5.16 vs. 5.84 g/dL, respectively). Calves fed CR were 1.5 kg lighter at weaning and gained 0.03 kg less per day (0.30 vs. 0.33 kg/d, respectively) than calves fed MC before weaning. Height at weaning did not differ between the 2 treatment groups. Calves fed CR tended to have a higher predicted probability of not being treated for diarrhea than calves fed MC (0.142 vs. 0.110, respectively). However, when the disease was present, CR had a higher number of treatment days compared with MC (11.6 vs. 10.8 d, respectively). The hazard ratio of dying did not differ between MC and CR; however, CR calves had a numerically higher risk (hazard ratio = 1.347) of dying compared with calves that received MC. In conclusion, IgG absorption and serum concentration of calves were adequate when calves were fed either CR or MC. The CR-fed calves had a lower probability of receiving contaminated liquid feed and performed similar in terms of health compared with calves receiving high-quality MC, although they were slightly lighter at weaning. Therefore, the CR evaluated in this study is a valid alternative to high-quality (>50 mg of IgG/mL) MC.

Effect of hoof trimmer intervention in moderately lame cows on lameness progression and milk yield.

The objective of this study was to evaluate the effect of hoof trimmer intervention (HTI) in moderately lame cows on lameness progression and milk yield. Two freestall Holstein herds were enrolled. Cows were milked 2 (herd A: 2,374 cows) or 3 (herd B: 2,800 cows) times a day. Within each dairy, moderately lame cows [locomotion score (LS) = 3 on a 5-point scale] were randomly assigned to control group (CON; herd A = 66, herd B = 84) or treatment group (HTI; evaluated and treated by the hoof trimmer under researchers' supervision; herd A = 73; herd B = 75). Enrollment criteria were <350 d in milk, <180 d pregnant, >10 kg/d of milk yield, not selected for therapeutic trimming 2 mo before enrollment, and >14 observations of daily milk yield during the study period. Biweekly lameness scoring (LS ≤2, LS = 3, LS ≥4) was conducted up to 6 wk post-intervention. Lesion type and severity records were collected at intervention from HTI cows and up to 6 wk post-intervention from all enrolled cows identified as lame by farm employees. Daily milk yield data were collected from -1 to 6 wk relative to intervention using Afifarm (Afimilk Ltd., Kibbutz Afikim, Israel) records. No treatment effect was detected on the predicted probability of locomotion score, but the predicted probability of LS ≥3 decreased over time in herd B, whereas in herd A, it initially decreased but later increased. A tendency for a treatment by time interaction was observed in herd A; at 2 wk post-intervention, the predicted probability for LS ≥3 was higher for HTI (0.69) than for CON (0.43), but similar at 4 wk (0.41 HTI, 0.49 CON) and 6 wk (0.77 HTI, 0.73 CON). At intervention, most study cows had no lesions (41.2%), sole hemorrhages (28.4%), thin soles (8.8%), or vertical fissure (6.8%). During the 6 wk following intervention, a similar proportion of cows were identified as lame in CON (8.7%) and HTI (6.7%) groups. In herd A, milk yield (least squares means ± standard error) was similar for CON (42.0 ± 0.77 kg/d) and HTI (42.3 ± 0.75 kg/d) cows, whereas in herd B, it tended to be lower for HTI (43.7 ± 0.61 kg/d) than for CON (45.2 ± 0.59 kg/d) cows. A significant effect of time was detected on both dairies, with milk yield decreasing over the study period. In our study, implementing HTI on moderately lame cows resulted in no improvement in gait or milk yield. The low presence of severe lesions amenable to therapy may partially explain our findings.

Extension of ustekinumab maintenance dosing interval in moderate-to-severe psoriasis: results of a phase IIIb, randomized, double-blinded, active-controlled, multicentre study (PSTELLAR).

BACKGROUND: Phase III studies showed that some patients maintained response for ≥ 6 months following ustekinumab discontinuation. OBJECTIVES: To assess clinical responses with extended ustekinumab maintenance dosing intervals. METHODS: Adults with moderate-to-severe plaque psoriasis received ustekinumab at weeks 0, 4 and 16 during open-label treatment. Patients achieving a week-28 Physician's Global Assessment (PGA) score of cleared/minimal (PGA = 0/1) were randomized 1 : 4 to group 1 [approved every 12 weeks (q12 wk) maintenance] or group 2 (q12-24 wk; response-based dosing determined by time to loss of PGA = 0/1). Key end points included the number of visits with PGA = 0/1 (primary end point) and ≥ 75% improvement in Psoriasis Area and Severity Index (PASI 75) between weeks 88 and 112, and PGA/PASI responses between weeks 28 and 112. RESULTS: Overall, 378 patients achieved PGA = 0/1 at week 28 and were randomized to group 1 (n = 76) or group 2 (n = 302). Patients in group 1 had numerically greater mean numbers of visits with PGA = 0/1 than group 2 and also with PASI 75 from week 88 to 112. A higher proportion of patients in group 1 (55%) than group 2 (39%) had PGA = 0/1 at all seven visits from week 88 to 112. Maintenance of response was observed with dose-interval extension beyond q12 wk in a subset of patients. Extending the dosing interval did not affect antibody development or safety. CONCLUSIONS: Efficacy was better maintained among week-28 PGA responders randomized to continue q12 wk ustekinumab vs. extending maintenance dosing based on clinical response, although some patients maintained high levels of efficacy with up to q24 wk dosing.