Quality of life and patient-perceived symptoms in patients with psoriasis undergoing proactive or reactive management with the fixed-dose combination Cal/BD foam: A post-hoc analysis of PSO-LONG.

BACKGROUND: Psoriasis has important physical and psychosocial effects that extend beyond the skin. Understanding the impact of treatment on health-related quality of life (HRQoL) and patient-perceived symptom severity in psoriasis is key to clinical decision-making. OBJECTIVES: This post hoc analysis of the PSO-LONG trial data assessed the impact of long-term proactive or reactive management with fixed-dose combination calcipotriene 50 µg/g and betamethasone dipropionate 0.5 mg/g (Cal/BD) foam on patient-reported outcomes (PROs) in patients with psoriasis vulgaris. METHODS: Five hundred and twenty-one patients from the Phase 3, randomized, double-blind PSO-LONG trial were included. An initial 4-week, open-label phase of fixed-dose combination Cal/BD foam once daily (QD) was followed by a 52-week maintenance phase, at the start of which patients were randomized to a proactive management arm (Cal/BD foam twice weekly) or reactive management arm (vehicle foam twice weekly). Patient-perceived symptom severity and HRQoL were assessed using the Psoriasis Symptom Inventory (PSI), the Dermatology Life Quality Index (DLQI) and the EuroQol-5D for psoriasis (EQ-5D-5L-PSO). RESULTS: Statistically and clinically significant improvements were observed across all PRO measures. The mean difference (standard deviation) from baseline to Week 4 was -8.97 (6.18) for PSI, -6.02 (5.46) for DLQI and 0.11 (0.15) for EQ-5D-5L-PSO scores. During maintenance, patients receiving reactive management had significantly higher DLQI (15% [p = 0.007]) and PSI (15% [p = 0.0128]) and a numerically lower EQ-5D-5L-PSO mean area under the curve score than patients receiving proactive management (1% [p = 0.0842]). CONCLUSIONS: Cal/BD foam significantly improved DLQI, EQ-5D-5L-PSO and PSI scores during the open-label and maintenance phases. Patients assigned to proactive management had significantly better DLQI and PSI scores and numerically better EQ-5D-5L-PSO versus reactive management. Additionally, baseline flare was associated with worse PROs than the start of a relapse, and patients starting a relapse also had worse PROs than patients in remission.

The novel AKT inhibitor afuresertib suppresses human Merkel cell carcinoma MKL-1 cell growth.

Merkel cell carcinoma (MCC) is a highly aggressive neuroendocrine neoplasm of the skin, which has an exceedingly poor prognosis. The AKT/mammalian target of rapamycin (mTOR) signalling pathway, which plays a pivotal role in the modulation of protein synthesis and cell survival, has been shown to be extremely important for Merkel cell carcinogenesis. In the current study, we found that AKT has important regulatory functions in MCC cells and that inhibition of AKT with the novel ATP-competitive AKT inhibitor, afuresertib, has widespread effects on proliferative pathways. In particular, we found that treatment of MCC cells with afuresertib led to deactivation of mTOR and glycogen synthase kinase 3 pathway proteins while increasing activation of proapoptotic pathways through the upregulation of p16 expression and phosphomodulation of the B-cell lymphoma-2-associated death promoter. Overall, afuresertib treatment led to significant and robust inhibition of MCC cell proliferation, thus raising intriguing questions regarding the potential efficacy of AKT inhibition for the future clinical management of MCC.

Tildrakizumab efficacy and impact on quality of life up to 52 weeks in patients with moderate-to-severe psoriasis: a pooled analysis of two randomized controlled trials.

BACKGROUND: Two randomized controlled trials (reSURFACE 1 and 2) have demonstrated the effectiveness of tildrakizumab, a high-affinity, humanized, IgG1κ, anti-interleukin-23 monoclonal antibody, for treating moderate-to-severe plaque psoriasis in the first 28 weeks. OBJECTIVES: To examine the efficacy of tildrakizumab and its impact on quality of life (QoL) in patients with different levels of week-28 Psoriasis Area and Severity Index (PASI) improvement. METHODS: Patients treated with tildrakizumab 100 mg or 200 mg from baseline to week 28 were pooled from reSURFACE 1 and reSURFACE 2 and classified into five mutually exclusive week-28 PASI improvement groups for each dose: PASI 0-49, 50-74, 75-89, 90-99 and 100. Mean PASI improvement and Dermatology Life Quality Index (DLQI) 0/1 over time were examined for each group. RESULTS: Of 1156 patients, 575 were in the 100-mg and 578 in the 200-mg cohorts, respectively. At week 28, 8.3%, 14.3%, 23.8%, 30.4% and 23.1% in the 100-mg and 4.0%, 18.1%, 19.6%, 29.1% and 29.3% in the 200-mg cohort achieved PASI < 50, 50-74, 75-89, 90-99 and 100, respectively. Patients with PASI < 50 at week 28 could be identified as early as week 8, and those with week-28 PASI ≥ 90 had approximately 50% PASI improvement by week 4. Among patients achieving PASI > 50 at week 28 who continued the same dose of tildrakizumab to week 52, mean PASI improvement was maintained or improved over time. Similar results were observed for both doses. Higher proportions of patients achieved DLQI 0/1 in higher week-28 PASI groups, and DLQI 0/1 was maintained or improved to week 52. However, not all patients with PASI 100 had DLQI 0/1. CONCLUSION: Patients unlikely to respond to tildrakizumab could be identified by week 8, and those likely to achieve a PASI ≥ 90 response could be identified as early as week 4. Week-28 PASI improvement level correlated with QoL improvement.

Efficacy of tildrakizumab for moderate-to-severe plaque psoriasis: pooled analysis of three randomized controlled trials at weeks 12 and 28.

BACKGROUND: Efficacy of tildrakizumab for plaque psoriasis was demonstrated in randomized, placebo-controlled trials. OBJECTIVE: To consolidate tildrakizumab efficacy results by pooling data. METHODS: Data (N = 2081) from tildrakizumab 100 mg, tildrakizumab 200 mg and placebo groups in three trials were pooled. RESULTS: Proportions of Psoriasis Area and Severity Index (PASI) 75 responders at week 12 were better with tildrakizumab 100 mg (62.3%) and tildrakizumab 200 mg (64.8%) vs. placebo (5.6%; P < 0.0001) and for PASI 90, PASI 100 and Physician's Global Assessment (PGA) 'clear' or 'minimal' vs. placebo (P < 0.0001). Responses increased from weeks 12 to 28. Week 12 PASI and PGA responses to tildrakizumab vs. placebo were numerically greater in patients with lower vs. higher bodyweight and were better with tildrakizumab 200 mg than tildrakizumab 100 mg for patients with higher bodyweight. Week 12 PASI 75 responses vs. placebo with tildrakizumab 100 mg were similar between patients with (55.0%) or without (56.7%) prior biologics. PASI 90, PASI 100 and PGA responses were generally higher in patients without prior biologics. Week 8 PASI 50 response predicted PASI 90 response. CONCLUSION: Pooled data confirmed the efficacy of tildrakizumab for moderate-to-severe plaque psoriasis.

The oral Janus kinase/spleen tyrosine kinase inhibitor ASN002 demonstrates efficacy and improves associated systemic inflammation in patients with moderate-to-severe atopic dermatitis: results from a randomized double-blind placebo-controlled study.

BACKGROUND: ASN002 is an oral dual inhibitor of Janus kinase and spleen tyrosine kinase, which are involved in the pathogenesis of atopic dermatitis (AD) through their regulatory role on T helper (Th)1, Th2 and Th17/Th22 pathways. OBJECTIVES: The objectives of this study were to evaluate the efficacy, safety, pharmacokinetics and effects on systemic biomarkers of ASN002 in patients with moderate-to-severe AD. Methods A total of 36 patients with moderate-to-severe AD were randomized (3 : 1) to ASN002 or placebo in the phase Ib study. Three dosage cohorts were studied over a 28-day period (20 mg, 40 mg and 80 mg once daily). RESULTS: ASN002 was superior to placebo for the proportion of patients achieving Eczema Area and Severity Index (EASI) 50 (20 mg 20%, P = 0·93; 40 mg 100%, P = 0·003; 80 mg 83%, P = 0·03; placebo 22%), EASI 75 (20 mg 0%, P = 0·27; 40 mg 71%, P = 0·06; 80 mg 33%, P = 0·65; placebo 22%) and in change from baseline in pruritus (20 mg -1·3 ± 2·1, P = 0·81; 40 mg -3·1 ± 2·7, P = 0·27; 80 mg -4·7 ± 2·1, P = 0·01; placebo -1·6 ± 1·8). Adverse events were generally mild and similar across all groups. ASN002 showed dose-dependent plasma exposure with low interpatient variability, significantly downregulated several serum biomarkers involved in Th1, Th2 and Th17/Th22 immunity, and decreased the atherosclerosis-associated biomarker E selectin/SELE. CONCLUSIONS: In patients with moderate-to-severe AD, ASN002 showed strong efficacy with rapid onset of action and associated improvements in systemic inflammation.

Efficacy and safety of brodalumab in patients with psoriasis who had inadequate responses to ustekinumab: subgroup analysis of two randomized phase III trials.

BACKGROUND: Brodalumab, a fully human anti-interleukin-17 receptor A monoclonal antibody, has demonstrated superior efficacy and safety over ustekinumab as induction therapy for moderate-to-severe psoriasis. OBJECTIVES: To evaluate the efficacy and safety of brodalumab through week 52 in patients who had inadequate responses to ustekinumab. METHODS: A subgroup analysis of the phase III AMAGINE-2/-3 double-blind randomized controlled trials was performed. Participants were aged 18-75 years and had a Psoriasis Area and Severity Index (PASI) ≥ 12, static Physician's Global Assessment score ≥ 3 and involvement of ≥ 10% body surface area. The studies were registered at ClinicalTrials.gov: AMAGINE-2, NCT01708603; AMAGINE-3, NCT01708629. RESULTS: At baseline, patients with or without prior biologic experience who had an adequate response at week 16 on ustekinumab or brodalumab had lower rates of involved body surface area, PASI, prior biologic use, psoriatic arthritis and body mass index than patients who experienced inadequate response at or after week 16. Among patients who experienced inadequate response to ustekinumab, those rescued with brodalumab had PASI ≥ 75%, ≥ 90% and 100% improvement response rates of 72·6%, 58·1% and 36·3%, respectively, at week 52 compared with 61·7%, 25·5% and 5·4%, respectively, in patients who continued ustekinumab. Exposure-adjusted rates of treatment-emergent adverse events were similar among patients rescued with brodalumab (377·3 adverse events per 100 patient-years) and those who remained on ustekinumab (389·9 adverse events per 100 patient-years). CONCLUSIONS: Among patients who experienced inadequate responses to ustekinumab, rescue with brodalumab improved skin clearance outcomes compared with continuing ustekinumab.

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.

Polyomaviruses of the skin: integrating molecular and clinical advances in an emerging class of viruses.

BACKGROUND: Human polyomaviruses (HPyVs) are small, nonenveloped, double-stranded DNA viruses that express tumour antigen proteins. Fourteen species of polyomaviruses have been discovered in humans, and since the 2008 discovery of the first cutaneous polyomavirus - Merkel cell polyomavirus (MCPyV) - six more species have been detected in the skin: trichodysplasia spinulosa-associated polyomavirus (TSPyV), HPyV6, HPyV7, HPyV9, HPyV10 and HPyV13. Of these cutaneous species, only MCPyV, TSPyV, HPyV6 and HPyV7 have been definitively associated with diseases of the skin, most commonly in immunocompromised individuals. MCPyV is a predominant aetiology in Merkel cell carcinomas. TSPyV is one of the aetiological factors of trichodysplasia spinulosa. HPyV6 and HPyV7 have been recently linked to pruritic skin eruptions. The roles of HPyV9, HPyV10 and HPyV13 in pathogenesis, if any, are still unknown, but their molecular features have provided some insight into their functional biology. RESULTS: In this review, we summarize the known molecular mechanisms, clinical presentation and targeted therapies of each of the eight cutaneous HPyVs. CONCLUSIONS: We hope that heightened awareness and clinical recognition of HPyVs will lead to increased reports of HPyV-associated diseases and, consequently, a more robust understanding of how to diagnose and treat these conditions.

Safety of tildrakizumab for moderate-to-severe plaque psoriasis: pooled analysis of three randomized controlled trials.

BACKGROUND: Short-term interleukin-23p19 inhibition by tildrakizumab improves plaque psoriasis and appears to be well tolerated. OBJECTIVES: Safety and tolerability were assessed for up to 64 weeks of tildrakizumab therapy using pooled data from three randomized controlled trials for moderate-to-severe psoriasis. METHODS: Data pools for the placebo-controlled (up to 16 weeks) and full trial periods (up to 64 weeks) were analysed (n = 2081). RESULTS: In the placebo-controlled period, frequencies of treatment-emergent adverse events (TEAEs; range 47·9-54·0%), serious TEAEs (range 1·4-2·3%), discontinuations due to AEs (range 0·6-1·9%), major adverse cardiovascular events (MACEs; range 0·0-0·1%) and severe infections (range 0·0-0·3%) were comparable between tildrakizumab 100 mg, tildrakizumab 200 mg, placebo and etanercept. In the full trial period, exposure-adjusted rates (patients per 100 patient-years) for TEAEs, serious TEAEs and discontinuations due to AEs with tildrakizumab 100 mg and 200 mg were lower than or comparable with the placebo rates, and lower than with etanercept. Exposure-adjusted rates of MACEs (range 0·0-0·5) and severe infections (range 0·9-2·0) were comparable among groups. No TEAEs of inflammatory bowel disease or suicide were reported. Candida skin infections were infrequent at frequencies of 0·1%, 0·3%, 0·0% and 0·0% for the tildrakizumab 100 mg, tildrakizumab 200 mg, placebo and etanercept groups, respectively, in the placebo-controlled period, and exposure-adjusted rates of 0·2, 0·7, 0·0 and 0·0, respectively, in the full trial period. Oral candidiasis was also infrequent. CONCLUSIONS: Up to 64 weeks of tildrakizumab was well tolerated, with low rates of serious TEAEs, discontinuations due to AEs, and AEs of clinical interest.

Dupilumab for Moderate-to-Severe Atopic Dermatitis.

Atopic dermatitis (AD) is the most common chronic inflammatory disease affecting 2-10% of adults and up to 15-30% of children. Despite a rising prevalence, effective and safe therapeutics for patients with moderate-to-severe AD are limited due to toxicity and side effects. Dupilumab, an interleukin (IL)-4 and IL-13 antagonist that limits type 2 T helper (Th2) driven inflammatory activity, is a promising therapeutic option. In clinical trials, it has demonstrated efficacy by reducing clinical activity and symptoms, and showed improvement in the AD genomic phenotype, including a significant reduction in Th2 chemokines and reversal of key epidermal markers of AD. It also has a favorable safety profile. This review discusses the role of dupilumab in treating Th2 related inflammation, and its efficacy and safety, as demonstrated in clinical trials. Dupilumab (Dupixent®) recently gained US FDA approval for patients with moderate-to-severe AD, and is poised to revolutionize the management of this chronic, relapsing condition.

Novel TMC8 splice site mutation in epidermodysplasia verruciformis and review of HPV infections in patients with the disease.

BACKGROUND: Epidermodysplasia verruciformis (EV) is a genodermatosis leading to infections with cutaneous HPV, persistent plane warts and a high rate of non-melanoma skin cancer (NMSC). Biallelic loss-of-function mutations in TMC6 and TMC8 are known to be causative. OBJECTIVE: The aim of this study was to report EV-causing mutations in four patients with EV and to give an overview of all described patients with EV. PATIENTS AND METHODS: We investigated four patients with classical features of EV from two families. All patients were affected by plane warts with typical EV histology since early childhood, and ß-HPVs were detected on their skin. One patient had recurring cutaneous squamous cell carcinomas (cSCC) and carcinomas in situ (Bowen type). We sequenced both TMC6/8 for disease-causing mutations and quantified levels of gene expression. We also performed a systematic literature review to discuss these patients in the context of previously reported cases, mutations already identified, as well as HPV types. RESULTS: Three patients of one family carried a homozygous splice site mutation in TMC8 resulting in aberrantly spliced transcripts that were not degraded. By contrast, no TMC6/8 mutation was detected in the patient from the other family. A systematic literature review revealed 501 described patients with EV. Around 40% of patients with EV analysed for genetic alterations carried no mutation in TMC6/8. While ß-HPVs were identified in the majority of cases, α-HPVs were detected in several individuals. CONCLUSION: The relatively high proportion of EV patients without mutation in TMC6/8 indicates the existence of EV-causing mutations in additional, presently unknown gene(s). However, a homozygous TMC8 splice site mutation in our patients resulted in aberrant transcripts which cannot retain the healthy phenotype. The literature review revealed that HPV-5 is the most commonly identified HPV in patients with EV, but HPV-3, HPV-14 and HPV-20 were unexpectedly identified more frequently than HPV-8.

Secukinumab demonstrates greater sustained improvements in daily activities and personal relationships than ustekinumab in patients with moderate-to-severe plaque psoriasis: 52-week results from the CLEAR study.

BACKGROUND: Psoriasis can greatly impact patients' lives by influencing clothing worn as well as by impairing sexual functioning. Secukinumab, a human monoclonal antibody selectively neutralizing interleukin-17A, has demonstrated good efficacy and safety in the treatment of moderate-to-severe psoriasis and psoriatic arthritis with a rapid onset of action and sustained response. OBJECTIVE: This analysis using the CLEAR study, a phase 3b double-blind study comparing the efficacy and safety of secukinumab vs. ustekinumab in adults with moderate-to-severe plaque psoriasis, evaluated the treatment effects on patient's daily activities and personal relationships. METHODS: Impact on daily activities (interference with home/shopping/garden, and influence on clothes worn) and impact on personal relationships (problems with partner/others, and sexual difficulties) as well as their corresponding subscales were selected from the Dermatology Life Quality Index scale and evaluated for patients treated with secukinumab vs. ustekinumab from the CLEAR study. Treatment differences in mean scores and proportions of responders (score = 0, indicating no impact) were evaluated through 52 weeks. Time to response was evaluated through Week 16. RESULTS: Significant differences between secukinumab and ustekinumab were observed for daily activities and personal relationships at Week 16 and sustained through Week 52 (Week 52 response rates for daily activities: 82.9% vs. 73.5%, including interference with home/shopping/garden: 88.5% vs. 78.2%, and influence on clothes worn: 85.6% vs. 74.4%; personal relationships: 86.1% vs. 73.7%, including problems with partner/others: 86.6% vs. 74.8%, and sexual difficulties: 88.5% vs. 74.3%; all P < 0.01). The median time to response was 4 weeks for secukinumab vs. 8 weeks for ustekinumab for daily activities and personal relationships (both P < 0.05). CONCLUSION: Secukinumab treatment helps patients with moderate-to-severe plaque psoriasis have a more normal life faster when compared to ustekinumab, by providing greater and sustained improvement in clothing choice and sexual functioning.

Dysregulation of the MEK/ERK/MNK1 signalling cascade by middle T antigen of the trichoydsplasia spinulosa polyomavirus.

BACKGROUND: Trichodysplasia spinulosa (TS) is a disfiguring folliculocentric cutaneous disease caused by infection with the trichodysplasia spinulosa polyomavirus (TSPyV). The TSPyV genome contains splice variants encoding the middle tumour (mT) antigen, although the potential role for TSPyV mT antigen in disease development remains unknown. OBJECTIVE: The current study was designed to investigate the mechanistic properties of TSPyV mT antigen, which may further our understanding of TS pathogenesis and provide insight into potential therapies. METHODS: A lentiviral packaging system was used to create an inducible cell line expressing TSPyV mT antigen. Proteins were extracted, separated by SDS-PAGE and subjected to Western blot analysis. Co-immunoprecipitation experiments and mutational analyses were also performed to evaluate protein-protein interactions of mT antigen. RESULTS: We describe a novel mechanism of action for mT antigen that involves hyperactivation of MEK, ERK and MNK1. Our findings suggest that dysregulation of these key signalling molecules depends upon TSPyV mT antigen interaction with protein phosphatase 2A (PP2A) via intact Zn binding motifs. CONCLUSION: Given that PP2A interaction and MEK/ERK/MNK1 phosphorylation are associated with high levels of cell proliferation and inflammation, our findings provide new evidence that TSPyV mT antigen may contribute to the pro-proliferative conditions that lead to TS development.

A Review of Guselkumab, an IL-23 Inhibitor, for Moderate-to-Severe Plaque Psoriasis.

Psoriasis is a chronic inflammatory skin disorder that affects 2% of the population. Evidence suggests that interleukin (IL)-23 plays a pivotal role in the pathogenesis of psoriasis. Guselkumab is a subcutaneously administered, humanized anti-IL23 monoclonal antibody indicated for the treatment of moderate-to-severe plaque psoriasis. Data from Phase I-III trials in this patient population reveal that guselkumab has proven to be superior to placebo or adalimumab based on achieving a Psoriasis Area and Severity Index (PASI) 90% reduction, or a static Physician Global Assessment (sPGA) score of 0 or 1 from baseline. This article reviews the current status of guselkumab as a therapy for moderate-to-severe plaque psoriasis.