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Background: Certolizumab pegol (CZP) is an Fc‐free, PEGylated anti‐tumor necrosis factor biologic. Objectives: To report 3‐year outcomes from the CIMPACT (NCT02346240) phase 3, CZP in moderate to severe plaque psoriasis, randomized controlled trial. Methods: Adults were randomized 3:3:3:1 to CZP 200 mg every other week (Q2W), CZP 400 mg Q2W, etanercept biweekly or placebo. At Week 16, CZP‐ and etanercept‐treated PASI 75 responders were re‐randomized to CZP 200 mg Q2W, CZP 400 mg Q4W, CZP 400 mg Q2W or placebo for maintenance treatment; PASI 75 non‐responders entered an open‐label escape CZP 400 mg Q2W arm. Patients entering the open‐label extension (OLE; Weeks 48–144) from blinded treatment received CZP 200 mg Q2W. Results: Double‐blinded results have been reported previously. 261 patients received 200 mg Q2W upon OLE entry. PASI 75 response was maintained in patients continuing 200 mg Q2W treatment through Weeks 16–144 (Week 144: 96.2%). In patients dosed down at Week 48 (double‐blinded 400 mg to 200 mg Q2W), PASI 75 decreased (Week 48: 98.7%; Week 144: 85.9%). In patients who received placebo through Weeks 16–48, PASI 75 response decreased (Week 48: 60.4%), then increased following Week 48 switch to 200 mg Q2W (Week 144: 95.1%). 48 and 36 patients initially randomized to 200 and 400 mg Q2W, respectively, were Week 16 PASI 75 non‐responders and entered the escape arm; at Week 144, 71.8% and 78.2% achieved PASI 75. No new safety signals were identified. Conclusions: Response to CZP was durable over three years; no new safety signals were identified. [ABSTRACT FROM AUTHOR]

Abstract: Fumaric acid esters (FAEs) are a group of small molecules that were first investigated for the treatment of psoriasis in 1959. The first fumarate‐based drug – Fumaderm® – was approved in Germany in 1994 for severe psoriasis and then in 2008, the label was expanded to include moderate psoriasis. Fumaderm is a combination of different FAEs: dimethyl fumarate (DMF), which is regarded as the main active component, plus calcium, magnesium and zinc salts of monoethyl fumarate (MEF). FAEs are the most frequently used first‐line systemic psoriasis treatment in Germany, with an overall treatment experience comprising more than 220 000 patient‐years. FAEs have demonstrated good, sustained clinical efficacy with an acceptable safety profile for the long‐term treatment of patients with moderate‐to‐severe psoriasis. Indeed, the European S3‐Guideline on the systemic treatment of Psoriasis vulgaris recommends FAEs for induction and long‐term treatment. Until recently, FAEs were only licensed (for the psoriasis indication) in Germany, but were imported to many other European countries, such as The Netherlands, UK, Ireland, Austria and Italy, for the treatment of psoriasis. In 2017, the European Medicines Agency (EMA) approved Skilarence®, a new oral formulation of DMF, for the treatment of adult patients with moderate‐to‐severe chronic plaque psoriasis in need of systemic therapy. Skilarence only contains DMF and is the first FAE for the treatment of psoriasis that has been approved by the EMA. This approval has given rise to a new oral treatment option for patients with moderate‐to‐severe plaque psoriasis across Europe. Here, we report the results of an expert meeting which was convened to deliver clinician‐agreed consensus and real‐world guidance on the clinical use of DMF in moderate‐to‐severe chronic plaque psoriasis. Guidance on appropriate patient selection, DMF dosage considerations, monitoring and side‐effect management is offered based upon available evidence and collective real‐world clinical experience. [ABSTRACT FROM AUTHOR]

Abstract: Background: Many patients with psoriasis have undiagnosed psoriatic arthritis. Low specificity is found with many PsA screening tools. A new instrument, the CONTEST questionnaire, was developed utilizing the most discriminative items from existing instruments. Objective: The aim of this study was to compare the CONTEST and PEST screening tools. Methods: People attending secondary care clinics with psoriasis, but not PsA, completed the questionnaires, were assessed for function and quality of life, and had a physical examination. Patients thought to have PsA were compared to those without. The performance of CONTEST and PEST was compared using area under the receiver operating curve (AUC), and sensitivity and specificity at the previously published cut‐offs. Results: A total of 451 dermatology patients were approached, 35% were reviewed and 27 (17%, 95% CI 12.3–21.7) had unidentified psoriatic arthritis. The sensitivity and specificity (95% CI) of PEST were 0.60 (0.42–0.78)/0.76 (0.69–0.83) and for CONTEST 0.53 (0.34–0.72)/0.71 (0.63–0.79). The confidence limits for the AUC overlapped (AUC for PEST 0.72 (0.61–0.84), for CONTEST 0.66 (0.54–0.77). Conclusions: PEST and CONTEST questionnaires performed equally well, with no superiority of the new CONTEST tool. [ABSTRACT FROM AUTHOR]

Experts in psoriasis, hepatology, pharmacokinetics and pharmacogenetics convened to discuss the safety and monitoring of methotrexate with respect to hepatotoxicity when used in the treatment of psoriasis. Methotrexate is an efficacious and cost-effective treatment for psoriasis, but is associated with significant safety issues, particularly relating to hepatotoxicity. Current British, Dutch, German, EU and US guidelines for baseline evaluations, monitoring and prevention of hepatotoxicity in patients with psoriasis receiving methotrexate were evaluated. Liver safety monitoring is currently reliant upon multiple methods, including biopsy, serological tests for biomarkers such as type III procollagen amino terminal propeptide (PIIINP), and liver function tests based on liver enzymes. Monitoring of patients receiving long-term therapy is expected to be improved by the utilization of serum biomarkers currently in development such as the Enhanced Liver Fibrosis (ELF) panel and other non-invasive tests of hepatic architecture, such as fibroelastography, microbubbles and magnetic resonance imaging. Appropriate studies to determine optimal dosing to maximize efficacy and minimize toxicity, potentially utilizing pharmacogenetic principles, are clearly needed. Key questions for future research are identified including needs for optimal screening and monitoring, identification of appropriate biomarkers, assessment of relationships between dosing and safety, utility of liver biopsy, optimal dosing regimens (including route of administration), methods to measure methotrexate levels in blood, and use of methotrexate as a standardized active comparator in trials of experimental drugs used to treat psoriasis. [ABSTRACT FROM AUTHOR]

Psoriasis is commonly associated with a co-existent arthritis known as psoriatic arthritis (PsA). Although there is some treatment overlap for psoriasis and psoriatic arthritis, it is possible that dermatologists may not diagnose or treat appropriately patients who are developing psoriatic arthritis at an early stage of the disease process when joint damage may be preventable. In this article we review the criteria for diagnosis of this sero-negative arthritis, look at the clinical indications for referral to a rheumatologist and discuss evolving treatment options relevant to both conditions. [ABSTRACT FROM AUTHOR]

Psoriasis is associated with significant physical and psychological burden affecting all facets of a patient’s life – relationships, social activities, work and emotional wellbeing. The cumulative effect of this disability may be self-perpetuating social disconnection and failure to achieve a ‘full life potential’ in some patients. Health-related quality of life studies have quantified the burden of psoriasis providing predominantly cross-sectional data and point-in-time images of patients’ lives rather than assessing the possible cumulative disability over a patient’s lifetime. However, social and economic outcomes indicate there are likely negative impacts that accumulate over time. To capture the cumulative effect of psoriasis and its associated co-morbidities and stigma over a patient’s life course, we propose the concept of ‘Cumulative Life Course Impairment’ (CLCI). CLCI results from an interaction between (A) the burden of stigmatization, and physical and psychological co-morbidities and (B) coping strategies and external factors. Several key aspects of the CLCI concept are supported by data similar to that used in health-related quality of life assessments. Future research should focus on (i) establishing key components of CLCI and determining the mechanisms of impairment through longitudinal or retrospective case–control studies, and (ii) assessing factors that put patients at increased risk of developing CLCI. In the future, this concept may lead to a better understanding of the overall impact of psoriasis, help identify more vulnerable patients, and facilitate more appropriate treatment decisions or earlier referrals. To our knowledge, this is a first attempt to apply and develop concepts from ‘Life Course Epidemiology’ to psoriasis research. [ABSTRACT FROM AUTHOR]

Tuberculosis (TB), caused by Mycobacterium tuberculosis, is a significant global health problem. In immunocompetent individuals, the microorganism can remain in a latent, non‐contagious form, however, it may become active under conditions of immunosuppression. Tumour necrosis factor (TNF) inhibitors, which are frequently used for the management of immune‐mediated disorders like psoriasis, have been associated with a significantly increased risk of reactivating latent TB. Consequently, international guidelines recommend TB screening and preventive treatment before starting anti‐TNF therapy. These recommendations have extended to IL‐12/23, IL‐17, IL‐23 and TYK2 inhibitors under a caution principle, despite their different mechanisms of action. However, current evidence suggests that some of these agents are arguably not associated with an increased risk of TB reactivation or development of TB disease after infection, which calls for a critical reassessment of these guidelines. We have conducted a literature search evaluating the risk of TB reactivation associated with these innovative therapies, integrating findings from both randomized clinical trials and real‐world evidence. The identified evidence is limited but the low number of identified cases of reactivation with IL‐17 and IL‐23 inhibitors prompts reconsidering the need for preventive treatment for latent TB in all cases, regardless of biologic class or individual patient's risk of TB reactivation or drug toxicity. This review, along with the clinical insight of a panel of experts on behalf of the SPIN‐FRT, led to the development of these consensus recommendations for managing psoriasis treatment in patients with latent TB infection or at risk of TB infection, who are receiving or are intended to receive biologic and non‐biologic targeted therapies. These recommendations highlight the need for updates to the existing guidelines, aiming to provide a more differentiated approach that reflects the evolving landscape of psoriasis treatment and its implications for TB management. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented which discusses the reaction of recalcitrant necrobiosis lipoidica when treated with combined immunosuppression therapy.

Porokeratotic eccrine ostial and dermal duct nevus is a rare disorder characterized by distinctive histopathology. We describe a 6-year-old boy who had the typical palmar involvement and small discrete areas involving the midline of his back. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article on the impact of the major life changing decisions (MLCDs) to the cumulative impairment of disease.

Background: Brodalumab is a monoclonal antibody that blocks multiple interleukin (IL)-17 family cytokines by binding to the shared A subunit of the IL-17 receptor. In Phase 3 trials, brodalumab provided high levels of skin clearance through 52 weeks in patients with moderate-to-severe psoriasis and was generally well tolerated., Objectives: To assess efficacy response rates and safety outcomes through 120 weeks for patients with moderate-to-severe psoriasis who received brodalumab., Methods: Safety and efficacy data were pooled for patients from AMAGINE-2 and -3 who received continuous brodalumab 210 mg every 2 weeks, or brodalumab 210 mg every 2 weeks after receiving either brodalumab 140 mg or placebo through Week 12. Efficacy data are presented using observed data, non-responder imputation (NRI) and a combination of NRI and missing at random assumption to account for missing data. Absolute PASI scores are presented using mixed-effect model repeated measure modelling and multiple imputation., Results: Based on observed data at Week 120, 86% of the continuous brodalumab 210 mg group achieved PASI 90 and 74% achieved PASI 100. At Week 12, 58% of this group achieved absolute PASI ≤1; this proportion increased to approximately 80% at Week 52 and persisted through Week 120. Among patients receiving continuous brodalumab 210 mg, median duration of brodalumab exposure was 747 days and the overall exposure-adjusted event rate of treatment emergent adverse events per 100 patient-years was 329. Safety through 120 weeks was comparable to the results of the primary AMAGINE-2 and -3 studies. Patients who switched to brodalumab 210 mg after receiving either brodalumab 140 mg or placebo through Week 12 showed similar skin clearance and safety profiles., Conclusions: Brodalumab treatment was well tolerated and resulted in high levels of skin clearance that were rapidly achieved and maintained through Week 120, supporting its long-term efficacy and safety profile., (© 2022 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology.)

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., (© 2022 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology.)

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., (© 2021 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology.)

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., (© 2021 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology.)

Background: As treatment interruptions occur during psoriasis management in clinical practice, it is important to know the duration of clinical response after treatment withdrawal., Objectives: To report time to and predictors of relapse in patients who were tildrakizumab 100 and 200 mg responders (≥75% improvement in Psoriasis Area and Severity Index, PASI 75) at week 28 re-randomized to placebo from reSURFACE 1 trial., Methods: Post hoc analysis of adult patients with moderate-to-severe plaque psoriasis from a 64-week phase 3 trial. Relapse was primarily defined as loss of PASI 75 response. Both relapses defined as loss of PASI 90 and loss of absolute PASI < 2 response were included as sensitivity analyses. PASI 75, PASI 90 and PASI < 2 responders re-randomized to placebo at week 28 and followed up until week 64 were included. The Kaplan-Meier (KM) estimates of the 64-week relapse rate were calculated. The log-rank test to compare KM curves from responders to tildrakizumab 100 and 200 mg was used. Independent predictors of relapse were explored., Results: Median time to loss of PASI 75/PASI 90/PASI < 2 response from week 28 was 142/111/112 days with tildrakizumab 100 mg and 172/140/113 days with tildrakizumab 200 mg, respectively (all not significant). Around 20% of patients did not relapse (either maintained a PASI 75 response or were lost to follow-up) during the 36-week period. Increase in body mass index (BMI) (hazard ratio, HR [95% confidence interval, CI] for loss of PASI 75 response: 1.0345 [1.0112-1.0582]) and increase in disease duration (HR [95% CI]: 1.0151 [1.0028-1.0275] for loss of PASI 75 response) were associated with an increased risk of relapse, regardless of the relapse definition., Conclusions: When treatment is interrupted, tildrakizumab provides durable maintenance of efficacy with a median time to loss of PASI 75 response of 5-6 months, irrespective of the dose. Interventions on modifiable risk factors for relapse, such as BMI, may improve personalized long-term psoriasis management., (© 2020 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology.)

Tuberculosis is an infectious disease with a major global impact, ranked in the top 10 mortality causes worldwide. In an immunocompetent individual, the host defence mechanisms control Mycobacterium tuberculosis infection and induce the latent form of the disease. However, in the presence of diseases or therapies, which exert an immunosuppressive effect, latent tuberculosis can be re-activated. Psoriasis is an immune-mediated, inflammatory disease, and its treatment has rapidly evolved over the last few years. It has long been recognized that the tumour necrosis factor (TNF)-α inhibitors are associated with increased risk of reactivation of latent tuberculosis infection. Thus, international guidelines have been suggesting tuberculosis screening before starting the treatment with all biological agents since then. In addition, the institution of chemoprophylaxis in the presence of latent tuberculosis and the annual screening for tuberculosis thereafter have also been indicated. However, anti-tuberculosis treatments can have significant side-effects and there are currently several contraindications to their use. The risk benefit of starting anti-tuberculous treatment should be carefully weighed up. The emergence of new biological drugs for the treatment of psoriasis, such as interleukin (IL)-17 and IL-23 inhibitors, has reignited the subject of tuberculosis reactivation as it is possible that IL-17 and 23 blockade do not carry the same risk of TB reactivation as TNF-α inhibitors. Although preclinical studies have shown that cytokines IL-17 and IL-23 have a possible role against infection with M. tuberculosis, data from clinical trials and post-marketing surveillance with drugs that inhibit these cytokines appear to suggest that they are not crucial to this response. In this article, we review the available data on tuberculosis reactivation after the treatment of psoriasis with IL-17 and IL-23 inhibitors, and its possible impact on the way we currently manage latent tuberculosis infection before or after starting treatment with these new drugs., (© 2020 European Academy of Dermatology and Venereology.)

The majority of patients with psoriasis vulgaris (chronic plaque psoriasis) can be treated successfully with short-term topical therapies. However, long-term management of psoriasis with topicals is challenging and tends to take a reactive approach to disease relapse, rather than a proactive approach aimed at maintaining disease remission. Patients are often dissatisfied with the delay in treatment response and inconvenience of applying topical treatments, and therefore frequently discontinue treatment leading to poor outcomes. Relapse is common, particularly with reactive management, as underlying residual disease can remain following initial skin clearance; some patients find that their disease at relapse may be worse than their initial symptoms. This can have a detrimental effect on patient quality of life (QoL) and increase the risk of psoriasis-associated depression. A long-term proactive management approach, with maintenance treatment following initial treatment success, could help sustain disease remission and improve clinical and QoL outcomes for patients. Treatment with fixed-dose calcipotriol 50 µg/g betamethasone dipropionate 0.5 mg/g cutaneous foam (Cal/BD foam) is effective in the short term, providing a fast onset of action and improvements in disease at 4 weeks. Results from the Phase III PSO-LONG study demonstrated that long-term proactive management was superior to reactive management in prolonging time to first relapse, reducing number of relapses and increasing days in remission in adults with psoriasis vulgaris. Furthermore, Cal/BD foam was well tolerated in PSO-LONG. No new safety concerns were identified over 52 weeks; the safety profile was consistent with that described previously. Given this, Cal/BD foam should be considered when prescribing topicals for the long-term proactive management for patients with psoriasis., (© 2021 European Academy of Dermatology and Venereology.)

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., (© 2020 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology.)

Alterations in the innate and adaptive immunity underpin psoriasis pathophysiology, with the Th17 cells subset now recognized as the fundamental cells in the key controlling pathway involved in its pathogenesis. Since psoriasis is a systemic disease with important comorbidity, further knowledge on the interleukin (IL)-23/Th17 axis led to the hypothesis that there may be shared pathogenic pathways between primary skin disease and comorbidity. Psoriasis has been identified as a risk factor for cardiovascular and metabolic disease, and increasing evidence gives support to this epidemiological observation from the clinical-pathologically field. As an example, increased levels of IL-23 and IL-23R have been found in human atherosclerotic plaque, and levels correlated with symptom duration and mortality. Also, upregulation of IL-23/IL-17 seems to play an important role in both myocardial damage and stroke, with interesting reports on deleterious effect neutralization after administration of related anti-bodies in both associated conditions. In diabetic patients, increased levels of IL-23/IL-17 have also been observed and available data support a synergistic role of IL-23/IL-17 in β-cells damage. In obesity, signs of an expansion of Th17 subset in adipose tissue have been reported, as well as elevated concentrations of IL-23 in obese patients. In non-alcoholic fatty liver disease, closely related to metabolic syndrome, but also in other mentioned cardiometabolic disorders, a predominance of IL-23 and other related pro-inflammatory factors has been identified as participating in their pathogenesis. Thus, the involvement of the IL-23/Th17 axis in these shared psoriasis-cardiometabolic pathogenic mechanisms is reviewed and discussed in the light of the existing preclinical and clinical evidence, including that from comorbid psoriasis patients., (© 2020 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology.)

The use of biologic therapies for the treatment of chronic plaque psoriasis has been linked to the development of atopic eczema, amongst other cutaneous adverse events. This can cause diagnostic confusion and create difficulty in the management of patients with plaque psoriasis. The main objective of this systematic review was to review all cases of eczema, including atopic eczema, reported in patients treated with biologics for chronic plaque psoriasis. PubMed, Medline and Embase databases were used to identify studies reporting eczema in patients treated with biologic therapy for chronic plaque psoriasis. A total of 92 patients were identified from 24 studies, with patients treated with either: adalimumab; etanercept; infliximab; ixekizumab; secukinumab; or ustekinumab. Factors common to some reported cases include: a prior history of atopy; eosinophilia; raised serum immunoglobulin E. Twenty-three had documented treatment outcomes; 14 had biologic therapy discontinued or switched. Management strategies included topical or oral corticosteroids, and treatment with alternative systemic agents such as ciclosporin or apremilast. This adverse event occurred in 1.0-12.1% of patients within trial data and observational studies. This review demonstrates that there are consistent reports of a switch to an atopic eczema phenotype from psoriasis in patients taking biologics inhibiting tumour necrosis factor alpha and the interleukin (IL)-17/IL-23 axis. The majority stopped the implicated biologic, but conservative management was successful in some cases. Those with an atopic diathesis may be more at risk. Elucidation of mechanisms and risk factors would contribute to optimal therapy selection for individual patients., (© 2020 European Academy of Dermatology and Venereology.)

Psoriatic disease is a multifaceted disorder, which develops in the skin, its appendages and joints. Though characterized by different pathogenic background and clinical manifestations, skin plaque psoriasis (PsO), psoriatic arthritis (PsA) and ankylosing spondylitis (AS) are related, sharing key inflammatory mechanisms and hence mode of management. Secukinumab is a fully human monoclonal antibody that selectively binds and neutralizes interleukin-17A. It has been approved for use as a subcutaneous injection for the treatment of moderate-to-severe PsO, PsA and AS. The current review highlights the long-term efficacy and safety profile of secukinumab in the treatment of plaque psoriasis and its multiple manifestations from its phase 3 clinical trial programme. The long-term extension of pivotal trials has shown sustainable efficacy and safety of secukinumab up to 5 years in PsO, PsA and AS and up to 2.5 years in moderate-to-severe nail and palmoplantar PsO through dedicated randomized controlled trials. The effect of secukinumab therapy in all these indications has corresponding effects on improvement in quality-of-life and daily activities. Overall, secukinumab is an effective and safe treatment choice for patients suffering from psoriatic disease in its multiple clinical variants., (© 2019 European Academy of Dermatology and Venereology.)

Background: The cardiovascular safety profile of biologic therapies used for psoriasis is unclear., Objectives: To compare the risk of major cardiovascular events (CVEs; acute coronary syndrome, unstable angina, myocardial infarction and stroke) in patients with chronic plaque psoriasis treated with adalimumab, etanercept or ustekinumab in a large prospective cohort., Methods: Prospective cohort study examining the comparative risk of major CVEs was conducted using the British Association of Dermatologists Biologics and Immunomodulators Register. The main analysis compared adults with chronic plaque psoriasis receiving ustekinumab with tumour necrosis-α inhibitors (TNFi: etanercept and adalimumab), whilst the secondary analyses compared ustekinumab, etanercept or methotrexate against adalimumab. Hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated using overlap weights by propensity score to balance baseline covariates among comparison groups., Results: We included 5468 biologic-naïve patients subsequently exposed (951 ustekinumab; 1313 etanercept; and 3204 adalimumab) in the main analysis. The secondary analyses also included 2189 patients receiving methotrexate. The median (p25-p75) follow-up times for patients using ustekinumab, TNFi, adalimumab, etanercept and methotrexate were as follows: 2.01 (1.16-3.21), 1.93 (1.05-3.34), 1.94 (1.09-3.32), 1.92 (0.93-3.45) and 1.43 (0.84-2.53) years, respectively. Ustekinumab, TNFi, adalimumab, etanercept and methotrexate groups had 7, 29, 23, 6 and 9 patients experiencing major CVEs, respectively. No differences in the risk of major CVEs were observed between biologic therapies [adjusted HR for ustekinumab vs. TNFi: 0.96 (95% CI 0.41-2.22); ustekinumab vs. adalimumab: 0.81 (0.30-2.17); etanercept vs. adalimumab: 0.81 (0.28-2.30)] and methotrexate against adalimumab [1.05 (0.34-3.28)]., Conclusions: In this large prospective cohort study, we found no significant differences in the risk of major CVEs between three different biologic therapies and methotrexate. Additional studies, with longer term follow-up, are needed to investigate the potential effects of biologic therapies on incidence of major CVEs., (© 2019 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology.)

Psoriasis is a chronic disease that requires long-term treatment. Consequently, understanding the safety and tolerability of any potential treatment over time is critical to effective prescribing. The biologic agents currently available for the treatment of psoriasis target a number of different inflammatory cytokines involved in psoriasis disease pathogenesis. The monoclonal antibodies tildrakizumab, guselkumab and risankizumab target the p19 subunit that is specific to interleukin (IL)-23. This article reviews published data on the safety of these IL-23p19 inhibitors in patients with psoriasis compared with other currently available biologic therapies. Data from randomized, placebo- and active-controlled phase 3 clinical trials show tildrakizumab, guselkumab and risankizumab to have a favourable risk-benefit profile in patients with moderate to severe psoriasis. No significant safety concerns have been observed for any of these IL-23p19 inhibitors in the data published to date. The most commonly reported adverse events (AEs) associated with these agents in phase 3 studies were upper respiratory tract infections. No increase was seen in rates of serious infections, malignancies or major adverse cardiovascular events, with no signals suggestive of an elevated risk of opportunistic infections, active tuberculosis or reactivation of latent tuberculosis infection, mucocutaneous Candida infections, triggering or worsening of inflammatory bowel disease, demyelinating disorders or suicidal ideation. Selectively targeting IL-23p19 may help avoid AEs that have been associated with biologic agents with other mechanisms of action. Data from long-term extension studies and patient registries will further establish the safety profile of IL-23p19 inhibitors for the treatment of moderate to severe psoriasis in routine practice., (© 2019 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology.)

Background: Therapeutic advances have made the achievement of clear/almost clear skin possible for many patients with moderate-to-severe plaque psoriasis., Objective: To determine patient perceptions of the impact of psoriasis and of attaining clear/almost clear skin., Methods: Global survey of patients with moderate-to-severe psoriasis., Results: A total of 8338 patients from 31 countries participated. The majority (57%) had not achieved self-assessed clear/almost clear skin with their current therapy, and 56% of those who had not met this goal believed it would be impossible to do so. Among the patients who had clear/almost clear skin, 73% had not initiated their current treatment until >1 year after psoriasis diagnosis, and 28% had to wait >5 years. Eighty-four percent of all respondents experienced discrimination and/or humiliation due to psoriasis, and many reported negative effects on work, intimate relationships, sleep and mental health. Patients without clear/almost clear skin reported that such achievement would open new possibilities, such as swimming (58%), a wider choice of clothing (40%), and meeting new people (26%). A limitation of this study, as with any survey-based research, is that selection and recall bias may have been present. Additionally, respondent definitions of clear/almost clear skin were subjective and may have varied., Conclusion: Despite the importance of clear/almost clear skin to psoriasis patients, most are still not achieving it, and many are unaware it is possible., (© 2018 European Academy of Dermatology and Venereology.)

Background: Psoriasis causes work productivity impairment that increases with disease severity. Whether differential treatment efficacy translates into differential indirect cost savings is unknown., Objective: To assess work hours lost and indirect costs associated with secukinumab versus ustekinumab and etanercept in the United Kingdom (UK)., Methods: This was a post hoc analysis of work impairment data collected in the CLEAR study (secukinumab vs. ustekinumab) and applied to the FIXTURE study (secukinumab vs. etanercept). Weighted weekly and annual average indirect costs per patient per treatment were calculated from (i) overall work impairment derived from Work Productivity and Activity Impairment data collected in CLEAR at 16 and 52 weeks by Psoriasis Area and Severity Index (PASI) response level; (ii) weekly/annual work productivity loss by PASI response level; (iii) weekly and annual indirect costs by PASI response level, based on hours of work productivity loss; and (iv) weighted average indirect costs for each treatment. In the primary analysis, work impairment data for employed patients in CLEAR at Week 16 were used to compare secukinumab and ustekinumab. Secondary analyses were conducted at different time points and with patient cohorts, including FIXTURE., Results: In CLEAR, 452 patients (67%) were employed at baseline. At Week 16, percentages of weekly work impairment/mean hours lost decreased with higher PASI: PASI < 50: 22.8%/7.60 h; PASI 50-74: 13.3%/4.45 h; PASI 75-89: 6.4%/2.14 h; PASI ≥ 90: 4.9%/1.65 h. Weighted mean weekly/annual work hours lost were significantly lower for secukinumab than ustekinumab (1.96/102.51 vs. 2.40/125.12; P = 0.0006). Results were consistent for secukinumab versus etanercept (2.29/119.67 vs. 3.59/187.17; Ρ<0.0001). Average annual indirect cost savings with secukinumab were £355 vs. ustekinumab and £1061 versus etanercept. Results at 52 weeks were similar., Conclusions: Secukinumab significantly reduced work impairment and associated indirect costs of psoriasis compared with ustekinumab and etanercept at Week 16 through 52 in the United Kingdom., (© 2018 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology.)

Background: Psoriasis symptoms may decrease quality of life for patients. Skin-related personal relationship difficulties in psoriasis patients are common, under-reported and poorly understood., Objective: To assess the effect of ixekizumab (IXE) treatment on skin-related personal relationship difficulties in patients with moderate-to-severe psoriasis., Methods: Pooled data (N = 2570) on skin-related relationship problems were obtained from two large phase 3 trials (UNCOVER-2 and UNCOVER-3) in patients with moderate-to-severe plaque psoriasis randomized to subcutaneous placebo (PBO, N = 361), etanercept (ETN; 50 mg twice weekly, N = 740), or 80 mg IXE as one injection every 4 (IXEQ4W, N = 733) or 2 weeks (IXEQ2W, N = 736) for 12 weeks, following a 160-mg initial dose. The Dermatology Life Quality Index (DLQI) Personal Relationships Domain (PRD) (Items 8 and 9) was used to assess how much the skin caused any personal relationship difficulties at weeks 0, 2, 4 and 12. Improvement was compared for IXE vs PBO and ETN using logistic models. Factors associated with improvement were assessed using multiple linear regressions. DLQI Item 9, assessing sexual difficulties, was also analysed separately., Results: PRD scores (mean ± standard deviation) at baseline were similar across all treatment groups (PBO: 1.8 ± 1.9; ETN: 1.7 ± 1.8; IXEQ4W: 1.6 ± 1.8; IXEQ2W: 1.7 ± 1.8). Treatment with IXE rapidly and significantly improved the mean PRD score compared to PBO and ETN (P < 0.001 at all time points). Baseline PRD score was the strongest negative predictor of improvement. IXE enabled significantly more patients with moderate-to-severe plaque psoriasis to reduce their skin-related sexual difficulties at Week 12 compared to PBO (P < 0.001) or ETN (P < 0.001)., Conclusion: Ixekizumab improves patient-reported skin-related PRD difficulties in patients with moderate-to-severe psoriasis., (© 2017 European Academy of Dermatology and Venereology.)

Background: Palmoplantar psoriasis has significant physical and emotional impact on patients and can be difficult to treat., Objective: To evaluate the efficacy of ixekizumab in the treatment of patients with moderate-to-severe plaque psoriasis and moderate-to-severe non-pustular palmoplantar involvement., Methods: In three phase 3, double-blind, placebo-controlled trials, patients with moderate-to-severe non-pustular plaque psoriasis [UNCOVER-1 (N = 1296), UNCOVER-2 (N = 1224), UNCOVER-3 (N = 1346)] were randomized to subcutaneous 80 mg ixekizumab every 2 or 4 weeks (Q2W, Q4W), after a 160-mg starting dose, or placebo through week 12. Additional UNCOVER-2 and UNCOVER-3 cohorts were randomized to 50 mg etanercept biweekly. Patients entering the open-label long-term extension (UNCOVER-3) received ixekizumab Q4W weeks 12-60. Moderate-to-severe palmoplantar involvement was defined as Palmoplantar Psoriasis Area and Severity Index (PPASI) ≥8., Results: Twenty-eight percent of UNCOVER-1, UNCOVER-2 and UNCOVER-3 patients had baseline palmoplantar involvement (PPASI ≥0, n = 1092) and 9.1% (n = 350) had moderate-to-severe involvement, with mean baseline PPASI ~20, PASI ~24, and most (>60%) had static Physician's Global Assessment ≥4. Higher percentages of patients treated with ixekizumab vs. placebo or etanercept achieved PPASI 50 (approximately 80% vs. 32.9%, 67.8%; ixekizumab, placebo, etanercept, respectively) and PPASI 75 (approximately 70% vs. 18.8%, 44.1%; ixekizumab, placebo, etanercept, respectively) at week 12 (all P < 0.05). PPASI 100 was achieved by higher percentages of ixekizumab-treated patients vs. placebo (approximately 50% vs. 8.2%, P < 0.001) and ixekizumab Q2W-treated patients vs. etanercept (51.8% vs. 32.2%, P < 0.05). Outcomes were maintained or improved in patients continuing on ixekizumab Q4W through week 60. Differences between ixekizumab and placebo or etanercept were statistically significant as early as week 1., Conclusion: In a subpopulation analysis of patients from phase 3 trials with moderate-to-severe non-pustular palmoplantar involvement and moderate-to-severe plaque psoriasis, ixekizumab treatment resulted in greater and more rapid improvements than placebo and etanercept at week 12; improvements were sustained with continued treatment., (© 2017 European Academy of Dermatology and Venereology.)

Background: Chronic 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., Objective: We 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., Methods: Bidirectional 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., Results: We 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., Conclusions: We 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., (© 2015 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology.)

Background: There is limited evidence as to whether biologic therapy should be stopped or continued in patients with psoriasis and/or psoriatic arthritis (PsA) who are undergoing surgical procedures. Current guidelines of care recommend a planned break from biologic therapy in those undergoing major surgical procedures., Objective: To audit current practice of managing biologic therapy peri-operatively in a tertiary referral psoriasis clinic against guidelines of care and to investigate the effects of continuing/stopping biologic therapy in psoriasis and PsA patients., Methods: A retrospective audit of psoriasis and PsA patients who had a surgical procedure whilst on biologic therapy. A proforma was used to collect information on the biologics used, whether they were stopped peri-operatively and whether patients developed post-operative complications and/or disease flare., Results: A total of 42 patients who had 77 procedures were identified. Procedures ranged from skin surgery to orthopaedic and cardiothoracic surgery. Biologic therapy was continued in the majority of procedures (76%). There was no significant difference in post-operative risk of infection and delayed wound healing between those patients who continued and those who stopped biologic therapy, including those undergoing major surgery. Interrupting biologic therapy peri-operatively was associated with a significant (P = 0.003) risk of flare of psoriasis or PsA., Conclusion: Continuing biologic therapy in psoriasis and PsA patients peri-operatively did not increase the risk of post-operative complications. Interrupting biologic therapy peri-operatively significantly increased the risk of disease flare. This study is limited by cohort size and requires replication, ideally in a prospective randomized controlled manner., (© 2015 European Academy of Dermatology and Venereology.)

Background: Psoriasis is a common, chronic, inflammatory skin disease with the majority of individuals having limited disease, treated with topical medication. However, special attributes of topical treatments like galenic/cosmetic properties or an inconvenient treatment schedule may result in low preference for topical treatments. Hence, there is strong medical need for a topical medication, which is highly efficacious, easy-to-use and preferred by both physicians and patients., Objective: Blinded interim analysis with the purpose to assess efficacy of (both from the physician's and patient's perspective) and the patients' preference with a highly efficacious and easy-to-use fixed combination of calcipotriol/betamethasone dipropionate topical gel after 8 weeks of once daily treatment in a large patient population., Methods: In this phase IV, international, multicentre, randomized, controlled, prospective, parallel group study, adult patients with active, mild to moderate psoriasis despite previous topical psoriasis treatment, i.e. unsuccessful in the 8 weeks preceding study participation, are followed over 64 weeks. During the first 8 weeks the patients apply their medication once a day followed by a 56-weeks maintenance period according to SmPC. Blinded interim analysis of all patients included demographics, Physician's Global Assessment, the novel Patient's self Global Assessment (PsGA) and Patient Preference Questionnaire (PPQ)., Results: 1795 patients were analysed. At week 8, 36.5% of the physicians rated the patients' psoriasis as clear/almost clear. Similarly, based on the patients' self-assessment, 34.2% had a clear/almost clear score of PsGA in week 8. Analysis of the PPQ showed that the vast majority of the patients judged their 8-week treatment to be preferable compared with their previous treatments., Conclusion: Results of this blinded interim analysis indicate that the fixed combination of calcipotriol/betamethasone dipropionate gel is highly efficacious and preferred by the majority of analysed patients., (© 2014 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology.)

Background: There is limited information on systemic and biological treatment optimization and transitioning in routine clinical practice., Objective: To provide practical guidance on treatment optimization and transitioning for moderate-to-severe plaque psoriasis., Methods: Dermatologists from 33 countries contributed to the Transitioning Therapies programme. Fourteen questions were identified. Answers were drafted based on systematic literature reviews (7/14 questions) and expert opinion (7/14 questions). Using a modified Delphi procedure, dermatologists from 30 countries voted on their level of agreement with each draft answer (scale: 1-9, strong disagreement to strong agreement). Consensus was defined as ≥75% of participants scoring within the 7-9 range., Results: Consensus was achieved on the answers to all questions. Recommendations for the use of cyclosporine and methotrexate were agreed. Transitioning from a conventional systemic therapy to a biological agent may be done directly or with an overlap (if transitioning is required because of lack of efficacy) or potentially with a treatment-free interval (if transitioning is required for safety reasons). Combination therapy may be beneficial. Continuous therapy for patients on biologicals is strongly recommended. However, during successful maintenance with biological monotherapy, a dosage reduction may be considered to limit drug exposure, although this may carry the risk of decreased efficacy. Switching biologicals for reasons of efficacy should be done without a washout period, but switching for reasons of safety may require a treatment-free interval., Conclusion: This consensus provides practical guidance on treatment optimization and transitioning for moderate-to-severe plaque psoriasis, based on literature reviews and the expert opinion of dermatologists from across the globe., (© 2013 The Authors Journal of the European Academy of Dermatology and Venereology © 2013 European Academy of Dermatology and Venereology.)