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Altres ajuts: The AMAGINE-1, AMAGINE-2 and AMAGINE- 3 trials were sponsored by Amgen and AstraZeneca; this analysis was performed by LEO Pharma. Medical writing support was provided by Ian Eustace from Adelphi Communications Ltd, Bollington, UK, funded by LEO Pharma. Background: Modern biologics achieve complete skin clearance [100% improvement in psoriasis area and severity index (PASI 100)] in 30-45% of psoriasis patients. Cumulative benefit considering rapidity, frequency and sustainability of response has not been thoroughly investigated. Objectives: Compare the frequency, rapidity and sustainability of PASI 90 and 100 response in patients with moderate-to-severe psoriasis treated with brodalumab or ustekinumab. Methods: Integrated analyses of the brodalumab Phase III AMAGINE-2 (NCT01708603) and -3 (NCT01708629) trials were performed to determine proportion of patients achieving PASI response per visit; corresponding odds ratios (OR) were calculated. Cumulative clinical benefit of treatment was determined with area-under-the-curve (AUC) analysis. Cumulative incidence of response was analysed using a competing risk model of PASI response or rescue. Sustained response was evaluated by time to inadequate response using Kaplan-Meier methods. Proportion of time spent in different response states was descriptively analysed. Association between PASI response and health-related quality of life [Dermatology Life Quality Index (DLQI)] was assessed using data from all treatment groups from AMAGINE-1, -2 and -3. Results: A significantly higher proportion of patients treated with brodalumab achieved PASI 100 vs. ustekinumab (Week 52: 51% vs. 28%; OR [95% CI] 2.8 [2.1, 3.7]; P < 0.0001), with significant differences observed from Week 4. Cumulative benefit through 52 weeks was 69% higher with brodalumab (AUC ratio: 1.69; P < 0.001). Brodalumab patients were also significantly more likely to achieve a PASI 100 at least once over 52 weeks vs. ustekinumab (76% vs. 52%; P < 0.0001). Once response was achieved, brodalumab patients had a low likelihood of failure or need for rescue. There was significant positive association between PASI response level and DLQI0/1 achievement (P < 0.0001). Conclusion: Brodalumab treatment resulted in significantly higher levels of skin clearance, longer sustained response and greater cumulative treatment benefit vs. ustekinumab.

Altres ajuts: Amgen; AstraZeneca. Background: The pathway for treatment of psoriasis is partly dependent upon disease severity, and patients may experience inadequate response at any point along the treatment pathway. Patients who repeatedly fail therapy represent a population in whom effective and well-tolerated treatment options are limited. Objectives: To investigate and describe patients achieving Psoriasis Area and Severity Index (PASI) 100 and cumulative treatment benefit over time in patients with moderate-to-severe psoriasis receiving brodalumab or ustekinumab by prior treatment. Methods: We conducted a post hoc analysis of data from two phase 3, randomized, controlled, 52-week AMAGINE trials of brodalumab to describe patients who achieved complete clearance as measured by PASI 100 by prior treatment subgroup (naïve to systemic and biologic treatment, systemic-treated but biologic-naïve, biologic-treated without failure, and biologic-treated with failure). A competing risk model was used to assess cumulative incidence over a 52-week period with outcomes of PASI 100 or inadequate response. Cumulative clinical benefit of treatment was determined with an area under the curve analysis. Results: The 52-week cumulative incidence of patients achieving PASI 100 was consistently higher for brodalumab vs. ustekinumab across treatment pathway subgroups (76% vs. 58% in systemic/biologic-naïve patients, 78% vs. 55% in systemic-treated/biologic-naïve patients, 75% vs. 41% in biologic-treated patients without failure, and 70% vs. 30% in biologic-treated patients with failure). Rates of inadequate response were lower with brodalumab compared with ustekinumab across all subgroups. Cumulative treatment benefit was also higher for all subgroups treated with brodalumab compared with those treated with ustekinumab. Conclusion: Treatment with brodalumab was associated with higher levels of complete clearance and greater cumulative benefit over time compared with ustekinumab, in patients with moderate-to-severe psoriasis, regardless of prior treatment experience.

BACKGROUND: Patients with plaque psoriasis treated with biologic therapies need more efficacious, safe, and convenient treatments to improve quality of life. Risankizumab and secukinumab inhibit interleukin (IL)-23 and IL-17A, respectively, and are effective in adult patients with moderate-to-severe plaque psoriasis but have different dosing regimens.OBJECTIVES: Directly compare efficacy and safety of risankizumab vs. secukinumab over 52 weeks.METHODS: IMMerge was an international, phase 3, multicentre, open-label, efficacy assessor-blinded, active-comparator study, in which adult patients with chronic, moderate-to-severe plaque psoriasis were randomised in a 1:1 ratio to treatment with risankizumab 150mg or secukinumab 300mg. Primary efficacy end points were proportions of patients achieving ≥90% improvement from baseline in Psoriasis Area Severity Index (PASI 90) at week 16 (noninferiority comparison with margin of 12%) and week 52 (superiority comparison).RESULTS: A total of 327 patients from nine countries were treated with risankizumab (n=164) or secukinumab (n=163). Risankizumab was noninferior to secukinumab in proportion of patients achieving PASI 90 at week 16 [73∙8% vs. 65∙6%; difference of 8∙2% [96∙25% confidence interval (CI) -2∙2, 18∙6] within 12% noninferiority margin], and superior to secukinumab at week 52 [86∙6% vs. 57∙1%; difference of 29∙8% (95% CI 20∙8, 38∙8); PCONCLUSIONS: At week 52, risankizumab demonstrated superior efficacy and similar safety with less frequent dosing compared with secukinumab.

BACKGROUND: Tildrakizumab is a specific anti-interleukin-23p19 monoclonal antibody approved for the treatment of plaque psoriasis.OBJECTIVES: To evaluate the long-term efficacy and safety of tildrakizumab treatment for patients with moderate-to-severe psoriasis for up to 148 weeks.METHODS: Pooled analysis from two double-blind, randomized controlled trials: reSURFACE 1 and reSURFACE 2. Efficacy was assessed for responders (≥ 75% improvement in Psoriasis Area and Severity Index; PASI 75) and partial responders (PASI 50-75) to tildrakizumab 100 mg and 200 mg at week 28 who were maintained on the same dose (administered every 12 weeks), and for partial responders or nonresponders (PASI < 50) to etanercept 50 mg at week 28 who, after a 4-week washout, were switched to tildrakizumab 200 mg (administered at weeks 32 and 36, and every 12 weeks thereafter). Safety was assessed in the all-patients-as-treated population. Three different methods of imputing missing data were used: nonresponder imputation (NRI), multiple imputation and observed cases. The Clinicaltrials.gov numbers are NCT01722331 (reSURFACE 1) and NCT01729754 (reSURFACE 2).RESULTS: At week 148 (NRI), 72·6%, 53·8% and 28·9% of tildrakizumab 100-mg responders and 80·2%, 59·9% and 32·6% of tildrakizumab 200-mg responders had PASI 75, 90 and 100 responses, respectively. For partial responders to tildrakizumab 100 mg and 200 mg, the proportions of patients achieving PASI 75, 90 and 100 responses were 32·5%, 25·0% and 10·0%; and 47·1%, 27·5% and 12·8%, respectively. For patients who were partial responders or nonresponders to etanercept, the proportions of patients achieving PASI 75, 90 and 100 responses were 66·9%, 43·8% and 14·9% at week 148. Rates of discontinuations due to adverse events [tildrakizumab 100 mg: 1·7 per 100 patient-years (PYs); tildrakizumab 200 mg: 1·2 per 100 PYs] and exposure-adjusted rates of serious adverse events (5·9 per 100 PYs; 5·5 per 100 PYs), severe infections (1·1 per 100 PYs; 1·1 per 100 PYs), malignancies (0·6 per 100 PYs; 0·4 per 100 PYs) and major adverse cardiovascular events (0·4 per 100 PYs; 0·5 per 100 PYs) were low.CONCLUSIONS: Tildrakizumab was well tolerated and efficacy was well maintained in week 28 responders who continued tildrakizumab treatment through 3 years, or improved among etanercept partial responders or nonresponders who switched to tildrakizumab.

BackgroundPatients with psoriasis are often concerned about the risk of serious infection associated with systemic psoriasis treatments.ObjectivesTo develop and externally validate a prediction model for serious infection in patients with psoriasis within 1 year of starting systemic therapies.MethodsThe risk prediction model was developed using the British Association of Dermatologists Biologic Interventions Register (BADBIR), and the German Psoriasis Registry PsoBest was used as the validation dataset. Model discrimination and calibration were assessed internally and externally using the C‐statistic, the calibration slope and the calibration in the large.ResultsOverall 175 (1·7%) out of 10 033 participants from BADBIR and 41 (1·7%) out of 2423 participants from PsoBest developed a serious infection within 1 year of therapy initiation. Selected predictors in a multiple logistic regression model included nine baseline covariates, and starting infliximab was the strongest predictor. Evaluation of model performance showed a bootstrap optimism‐corrected C‐statistic of 0·64 [95% confidence interval (CI) 0·60–0·69], calibration in the large of 0·02 (95% CI −0·14 to 0·17) and a calibration slope of 0·88 (95% CI 0·70–1·07), while external validation performance was poor, with C‐statistic 0·52 (95% CI 0·42–0·62), calibration in the large 0·06 (95% CI −0·25 to 0·37) and calibration slope 0·36 (95% CI −0·24 to 0·97).ConclusionsWe present the first results of the development of a multivariable prediction model. This model may help patients and dermatologists in the U.K. and the Republic of Ireland to identify modifiable risk factors and inform therapy choice in a shared decision‐making process.

BackgroundPatients with psoriasis and clinicians are concerned that infliximab may be associated with a risk of serious infections.ObjectivesTo compare the risk of serious infections associated with infliximab in patients with chronic plaque psoriasis against a cohort on nonbiologic systemic therapies.MethodsA prospective cohort study was performed using data from the British Association of Dermatologists Biologic Interventions Register (BADBIR). Infliximab was compared with nonbiologic systemic therapies, inclusive of any exposure to methotrexate, ciclosporin, acitretin, fumaric acid esters, psoralen‐ultraviolet A or hydroxycarbamide. Serious infections were those associated with hospitalization, the use of intravenous antimicrobial therapy and/or those that led to death. Propensity score inverse probability treatment weights were used to adjust for potential confounding from a priori identified covariates. Cox proportional hazards models were calculated to obtain hazard ratios (HRs).ResultsIn total, 3843 participants were included for analysis up to October 2016. The incidence rates were significantly higher in the infliximab cohort (47·8 per 1000 person‐years) [95% confidence interval (CI) 35·7–64·0], compared with 14·2 per 1000 person‐years (95% CI 11·5–17·4) in the nonbiologic systemic cohort. Infliximab was associated with an overall increase in the risk of serious infection compared with nonbiologics [adjusted HR (adjHR) 1·95, 95% CI 1·01–3·75] and methotrexate only (adjHR 2·96, 95% CI 1·58–5·57) and a higher risk of serious infection in the first 6 months of therapy (adjHR 3·49, 95% CI 1·14–10·70).ConclusionsInfliximab is associated with an increased risk of serious infections compared with nonbiologic systemic therapies in patients with psoriasis in the U.K. and the Republic of Ireland.

BACKGROUND: Adalimumab (Humira® ; AbbVie Inc., USA) is a fully human monoclonal antibody specific for tumour necrosis factor-α approved to treat adults with moderate-to-severe chronic plaque psoriasis.OBJECTIVE: To assess long-term safety for patients with psoriasis receiving adalimumab in clinical studies METHODS: Adalimumab safety data from adults with psoriasis who received ≥1 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 last dose or cutoff date (December 31, 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). 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 non-melanoma skin cancer (NMSC) was 0.8 E/100 PYs (SIR=0.86; 95% CI, 0.58-1.23). Incidences of NMSC and melanoma were 0.6 and 0.2 E/100 PYs, respectively. SIR was 1.55 (95% CI, 1.10-2.13) for NMSC and 3.04 (95% CI, 1.11-6.62) for melanoma. 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. This article is protected by copyright. All rights reserved.

BACKGROUND: Patients with psoriasis and clinicians are concerned that infliximab may be associated with a risk of serious infections.OBJECTIVES: To compare the risk of serious infections associated with infliximab in patients with chronic plaque psoriasis against a cohort on non-biologic systemic therapies.METHODS: A prospective cohort study was performed using data from BADBIR. Infliximab was compared to non-biologic systemic therapies, inclusive of any exposure to methotrexate, ciclosporin, acitretin, fumaric acid esters, psoralen-ultraviolet A or hydroxycarbamide. Serious infections were those associated with hospitalisation; the use of intravenous antimicrobial therapy; and/or led to death. Propensity-score inverse probability treatment weights were used to adjust for potential confounding from a priori identified covariates. Cox proportional hazards models were calculated to obtain hazard ratios.RESULTS: 3843 participants were included for analysis up to October 2016. The incidence rates were significantly higher in the infliximab cohort (47.8 per 1000 person-years (95% confidence interval (CI) 35.7, 64.0) compared to 14.2 per 1000 person-years (95% CI 11.5, 17.4) in the non-biologic systemic cohort. Infliximab was associated with an overall increase in the risk of serious infection against non-biologics (adjusted hazard ratio (adjHR) 1.95, 95% CI 1.01, 3.75) and methotrexate only (adjHR 2.96, 95% CI 1.58, 5.57) and a higher risk of serious infection in the first 6 months of therapy (adjHR 3.49, 95% CI 1.14, 10.70).CONCLUSIONS: Infliximab is associated with an increased risk of serious infections compared with non-biologic systemic therapies in patients with psoriasis in the United Kingdom and the Republic of Ireland. This article is protected by copyright. All rights reserved.

BACKGROUND: The British Association of Dermatologists Biologic Interventions Register (BADBIR) is a prospective, observational cohort designed to assess the long-term safety of biologic and conventional systemic therapies used for adults with moderate-severe psoriasis in the UK and Republic of Ireland. OBJECTIVES: To describe the demographics, disease severity and co-morbidities of psoriasis patients on enrolment into BADBIR, and to highlight differences in those commencing biologic compared to conventional systemic therapies. METHOD: Baseline data were collected from 151 Dermatology departments in the UK and Republic of Ireland. Descriptive analysis was conducted.RESULTS: As of August 2014, 8399 patients were registered with BADBIR; 5065(60%) received biologics of whom 52.8% received adalimumab, 24.6% etanercept, 18.7% ustekinumab and 3.9% infliximab. In the comparator cohort 44.1% received methotrexate, 23.1% ciclosporin, 18.0% acitretin and 7.6% fumaric acid esters. 4897(58%) were male. Patients on biologics had a higher mean (±SD) age and disease duration than patients on conventional systemic therapies (46.3±12.7vs.44.3±14.3 years; 23.0±12.6vs.19.0±13.4 years, respectively; p1 co-morbidity. The most frequent co-morbidities were obesity (42.1%), hypertension (25.7%), depression (22.1%) and psoriatic arthritis (17.1%). CONCLUSION: BADBIR is an invaluable resource to study the safety and effectiveness of both biologic and conventional systemic therapies. Understanding differences in baseline characteristics between cohorts is crucial in undertaking future pharmacovigilance studies. This article is protected by copyright. All rights reserved.

BackgroundChronic pustular dermatoses are severe and debilitating autoinflammatory conditions that can have a monogenic basis. Their clinical features are, however, complex with considerable overlap. Null and missense mutations in the genes encoding interleukin (IL)‐1 family (IL‐1 and IL‐36) anti‐inflammatory receptor antagonist (Ra) cytokines can underlie the development of severe pustular dermatoses.ObjectiveWe present a clinical and genetic study of four children of Pakistani descent with similar clinical presentations and treatment course, each of whom suffers from a severe pustular dermatosis, initially described as a pustular variant of psoriasis. We use DNA sequencing to refine the diagnosis of two of the children studied.MethodsBidirectional Sanger sequencing was performed on the coding regions of the IL‐1Ra and IL‐36Ra genes (IL1RN and IL36RN, respectively), for the four affected children and their parents.ResultsWe identified a novel homozygous missense mutation in IL36RN in two siblings, and showed the molecular basis of the condition to be both distinct from psoriasis and distinct between the two families studied.ConclusionsWe describe a novel mutation which underpins the diagnosis of childhood pustular dermatosis. Molecular diagnostics can be used to aid the clinical diagnosis and potential treatment of autoinflammatory conditions.

The era of genome-wide association studies has revolutionized the search for genetic susceptibility loci in complex genetic conditions such as psoriasis. There are currently 16 loci with confirmed evidence for association with psoriasis susceptibility but there is the potential for more to be discovered as the genetic heritability of the disease has not yet been fully explained. Many of the associated loci overlap with those for psoriatic arthritis. In contrast to psoriasis susceptibility, few studies have been performed to identify predictors of drug response in psoriasis. As large-scale collaborations and registries for psoriasis and psoriatic arthritis are established, it is likely that a genome-wide approach may be used as a more effective method of searching for genetic predictors of treatment response. However, candidate gene studies will still have a role; for example, it is likely that some disease susceptibility genes will also be markers of treatment response, based on evidence from other diseases. This review summarizes recent advances in investigating the role genetics plays in psoriasis susceptibility and contrasts these to advances made in psoriatic arthritis. Further, it describes the genetics of treatment response in the two diseases and indicates how susceptibility loci could be used to identify drug response in the future. © 2011 The Authors. BJD © 2011 British Association of Dermatologists.