Effectiveness of systemic treatments on pruritus associated with atopic dermatitis: A systematic review in pediatric patients.

BACKGROUND/OBJECTIVES: Itch is one of the hallmarks of atopic dermatitis (AD), which has a significant impact on the quality of life of pediatric patients with AD and their caregivers. We aimed to conduct a systematic review and meta-analysis to evaluate the antipruritic effects of systemic AD treatments in pediatric patients with AD. METHODS: PubMed, EMBASE, Cochrane, and Web of Science databases were searched, including studies providing original data on the effects of systemic treatment on pruritus in pediatric patients (<18 years) with AD. Placebo-controlled trials reporting a Peak Pruritus Numerical Rating Scale 4 (PP-NRS4) response were included in a meta-analysis. RESULTS: A total of 30 studies were included, with most evidence available for dupilumab. Overall, marked improvements of pruritus (50% or greater reduction in pruritus outcome measurements) were found for treatment with cyclosporin A (2-16 years), dupilumab (6 months-17 years), abrocitinib, and upadacitinib (both 12 and 17 years). Nemolizumab (12-17 years) may be promising in reducing pruritus in pediatric patients; however, data are limited. Only five randomized controlled trials could be included in our meta-analysis, in which dupilumab, abrocitinib, and upadacitinib showed a significantly higher probability of achieving a PP-NRS4 response compared with placebo. Our study was limited by a lack of homogeneity of included studies. CONCLUSIONS: Cyclosporin A, dupilumab, abrocitinib, and upadacitinib are all effective in decreasing pruritus and, therefore, in improving the quality of life in children with AD. As more systemic treatments for AD become available, it will be imperative to incorporate patient-oriented treatment goals such as reduction of pruritus into therapeutic decision-making.

Predictors of surgical treatment burden, outcomes, and overall survival in older adults with basal cell carcinoma: Results from the prospective, multicenter BATOA cohort.

BACKGROUND: Incorporating patient-related factors associated with treatment outcomes could improve personalized care in older patients with basal cell carcinoma (BCC). OBJECTIVE: To evaluate and identify predictors of treatment burden, treatment outcomes, and overall survival in patients aged ≥70 years, surgically treated for BCC in the head and neck area. METHODS: The data from the prospective, multicenter Basal Cell Carcinoma Treatment in Older Adults (BATOA) cohort study were extracted to evaluate the experienced treatment burden (visual analog scale, 0-10 cm; lower scores indicating higher treatment burden), treatment outcomes, and mortality. RESULTS: A total of 539 patients were included (median age, 78 years). The patients experienced a low overall treatment burden (median, 8.6) and good cosmetic results. The predictors of higher treatment burden were instrumental activities of daily living (iADL) dependency, female sex, complications, larger tumor diameter, and polypharmacy. Thirty-five patients (6.5%) died (none of the deaths were due to BCC) within the follow-up period; the predictors of mortality were increasing comorbidity index and iADL dependency. No difference in these outcomes was seen between Mohs micrographic surgery and conventional excision after correction for covariates. Age was not significantly associated with any outcome. LIMITATIONS: A selection bias may exist owing to the observational design. CONCLUSION: BCC management decisions based on chronological age alone should be avoided, whereas more attention is recommended for patient-related factors. Based on these data, early BCC intervention is beneficial for robust and fit patients or those experiencing symptoms.

Safety Assessment of Conventional and Biological Systemic Therapy in Older Adults with Psoriasis, a Real-world Multicentre Cohort Study.

Optimal selection of systemic therapy in older adults with psoriasis can be challenging, due to sparse evidence-based guidance. This multicentre retrospective study investigated the safety of systemic therapy with causality assessment in a real-world cohort of older adults (≥ 65 years) with psoriasis. Data from 6 hospitals on (serious) adverse events were collected, causality assessment performed and incidence rate ratios calculated. Potential predictors for adverse events-occurrence were studied using multivariable logistic regression analysis. In total, 117 patients with 176 treatment episodes and 390 patient-years were included, comprising 115 (65.3%) and 61 (34.7%) treatment episodes with conventional systemic therapy and biologics/apremilast, respectively. After causality assessment, 232 of 319 (72.7%) adverse events remained and were analysed further, including 12 serious adverse events. No significant differences in incidence rate ratios were found between the systemic treatment types. In regression analysis, increasing age was associated with causality assessed adverse events-occurrence (odds ratio 1.195; p=0.022). Comorbidity, polypharmacy, and treatment type were not associated with causality assessed adverse events-occurrence. In conclusion, increasing age was associated with a higher causality assessed adverse events-occurrence. Causality assessed serious adverse events were rare, reversible and/or manageable in clinical practice. In conclusion, the safety profile of systemic antipsoriatic therapy within this population is reassuring.

An Analysis of Patient-reported Outcomes in IXORA-S: Comparing Ixekizumab and Ustekinumab over 52 Weeks in Moderate-to-severe Psoriasis.

Patient-reported outcomes are valuable for assessing new psoriasis therapies. This study investigated patient-reported outcomes in patients with moderate-to-severe plaque psoriasis treated with ixekizumab or ustekinumab, dosed according to their respective labels, for 52 weeks (IXORA-S-NCT02561806). Patient-reported outcomes investigated included patient global assessment, pruritus, skin pain, health-related quality of life, and work productivity. Ixekizumab-treated patients reported greater improvements in patient-reported outcomes sooner after treatment compared with ustekinumab-treated patients, and maintained greater improvements in patient global assessment scores (ixekizumab 0.72, ustekinumab 1.19; p < 0.001), rates of Dermatology Life Quality Index (0, 1) (ixekizumab 71.3%, ustekinumab 56.6%, p < 0.01), and 36-item Short-form Health survey physical component summary score change from baseline (ixekizumab 5.53, ustekinumab 3.28; p < 0.05) at week 52. While clinically meaningful improvements in patient-reported outcomes resulted with either treatment, ixekizumab provided more rapid improvements in patient-reported outcomes and superior outcomes for some assessments through one year of treatment, while maintaining statistically superior improvements in skin severity, as assessed by either physicians or patients.

Disease and Treatment Characteristics in Geriatric Psoriasis: A Patient Survey Comparing Age Groups.

Little is known about psoriasis in geriatric patients, whereas treating this growing population can be challenging due to comorbidities, comedication and physical impairments. To compare disease and treatment characteristics of psoriasis patients ≥ 65 years old with patients < 65 years old, a self-assessment survey was sent to all members of the Dutch Psoriasis Association (n = 3,310). In total, 985 (29.7%) patients returned the survey, 414 (43.6%) respondents were ≥ 65 years old. Patients ≥ 65 years old had experienced erythrodermic psoriasis significantly more frequently than patients < 65 years old, other disease characteristics were highly comparable. Despite a significantly higher prevalence of comorbidities and comedication use in patients ≥ 65 years old, no difference was seen between the age groups regarding systemic antipsoriatic treatment (38.3% in ≥ 65 years old vs 42.3% in < 65 years old; p = 0.219). Remarkably, treatment-related side-effects were reported more frequently by patients < 65 years old. In conclusion, age alone should not be a limiting factor in psoriasis management, and proper attention must be paid to additional patient-related factors.

Psoriasis and Mental Health Workshop Report: Exploring the Links between Psychosocial Factors, Psoriasis, Neuroinflammation and Cardiovascular Disease Risk.

Psoriasis is a systemic, relapsing, inflammatory disease associated with serious comorbidities including mood problems and/or unhealthy lifestyle behaviours. Cutaneous and systemic abnormalities in innate and acquired immunity play a role in its pathogenesis. The exact pathogenetic mechanism remains elusive. Evidence is accumulating that TNF-alpha, IL-17 and IL-23 signalling are highly relevant as targeting these pathways reduces disease activity. Evidence suggests a strong link between psoriasis and depression in adults. The International Psoriasis Council (IPC) held a roundtable event, "Psoriasis and Mental Health", in Barcelona, Spain which focused on the presence of depression and suicidality, plus the role of neuroinflammation in psoriasis, sleep disruption and the impact of depression on cardiovascular disease outcomes. We summarize here the expert presentations to provide additional insight into the understanding of psychiatric comorbidities of psoriasis and of the impact of chronic, systemic inflammation on neuro- and cardiovascular outcomes. the associations between psoriasis and other psychiatric comorbidities are still controversial and warrant further attention.

Health Economic Consequences of a Tightly Controlled Dose Reduction Strategy for Adalimumab, Etanercept and Ustekinumab Compared with Standard Psoriasis Care: A Cost-utility Analysis of the CONDOR Study.

A dose reduction strategy for adalimumab, etanercept and ustekinumab in patients with psoriasis who have stable and low disease activity has recently been compared with usual care in the CONDOR study (CONtrolled DOse Reduction) of biologics in patients with psoriasis with low disease activity. The aim of the current study was to perform a cost-utility analysis with a 12-month time horizon alongside this trial, using prospectively measured healthcare costs and quality-adjusted life years, based on Short-Form Six-Dimension utilities. Bootstrap analys-es were used to calculate the decremental cost-utility ratio and the incremental net monetary benefit. The dose reduction strategy resulted in a mean cost saving of €3,820 (95th percentile -€3,099 to -€4,509) per patient over a period of 12 months. There was an 83% chance that dose reduction would result in a reduction in quality adjusted life years (mean -0.02 (95th percentile -0.06 to 0.02). In conclusion, dose reduction of biologics resulted in substantial cost savings with an acceptable reduction in quality of life.

Ixekizumab provides superior efficacy compared with ustekinumab over 52 weeks of treatment: Results from IXORA-S, a phase 3 study.

BACKGROUND: Biologics targeting interleukin 17A (IL-17A) allow for rapid clearance of psoriatic plaques, with a clinically favorable safety profile. OBJECTIVES: To compare the safety and efficacy of ixekizumab, an IL-17A antagonist, with the safety and efficacy of the IL-12/23 inhibitor ustekinumab through 52 weeks of treatment in the head-to-head trial IXORA-S. METHODS: Patients were randomized to ixekizumab (n = 136) or ustekinumab (n = 166) and dosed per the approved labels. After 1 year, efficacy was assessed via improvements in Psoriasis Area and Severity Index (PASI) score (with PASI 90 indicating a 90% or greater improvement from baseline PASI score) and a static Physician's Global Assessment (sPGA) response of either 0 or 0 or 1, with dropouts counted as nonresponders. Safety analyses included treatment-emergent adverse events (AEs). RESULTS: At week 52, significantly more ixekizumab-treated patients (P < .01) reported PASI 90 (104 [76.5%]), an sPGA response of 0 (72 [52.9%]), or an sPGA response of 0 or 1 (110 [82.1%]) responses than did ustekinumab-treated patients (PASI 90, 98 [59.0%]; sPGA response of 0, 60 [36.1%]; and sPGA response of 0 or 1, 108 [65.1%]). Treatment-emergent AEs, serious AEs, and discontinuation rates were not different between the treatment groups. Injection site reactions occurred more frequently in the ixekizumab-treated group (ixekizumab, 22 [16.3%]; ustekinumab, 2 [1.2%]) (P < .001). LIMITATIONS: This study was not designed to compare safety end points related to rare events. CONCLUSIONS: Compared with ustekinumab, ixekizumab showed superior efficacy and comparable safety outcomes through 52 weeks of treatment.

Use of Systemic Treatment in Patients with Chronic Pruritus: A Survey of Dermatologists in the Netherlands.

Treatment of chronic pruritus can be a challenge for clinicians. Several systemic treatments have been suggested to reduce itch, such as gabapentinoids and antidepressants. The aim of this study was to assess the current practice of dermatologists regarding systemic treatment in patients with chronic pruritus, and to identify possible barriers in the prescription of these treatments. An online survey was sent to all dermatologists and dermatology residents in the Netherlands between July 2017 and April 2018. A total of 193 physicians completed the questionnaire (response rate 27.0%). Overall, 61.7% prescribed gabapentinoids or antidepressants in patients with chronic pruritus. Amitriptyline was prescribed most frequently, followed by gabapentin, doxepin and mirtazapine. Reasons not to prescribe systemic treatment included lack of knowledge or experience, risk of side-effects, and lack of available evidence. As only a minority of respondents felt comfortable prescribing these drugs, more education on effective and safe dosing is needed.

Nail Involvement as a Predictor of Disease Severity in Paediatric Psoriasis: Follow-up Data from the Dutch ChildCAPTURE Registry.

Little is known about the relationship between nail psoriasis and psoriasis severity in children, and there has been no longitudinal assessment of psoriasis severity related to nail psoriasis. The aim of this study was to assess whether nail psoriasis could serve as a predictor for a more severe disease course. De-identified data were obtained from the ChildCAPTURE registry, a daily clinical practice cohort of children with psoriasis, from September 2008 to November 2015. Cross-sectional analyses were performed at baseline. Longitudinal data until 2-year follow-up were analysed by linear mixed models. Nail psoriasis was present in 19.0% of all 343 patients at baseline and cross-sectionally associated with higher Psoriasis Area and Severity Index (PASI) (p = 0.033). Longitudinal analysis demonstrated higher PASI (p <0.001) during 2-year follow-up in patients with nail involvement at baseline. These findings suggest that nail psoriasis is a potential clinical predictor for more severe disease course over time in paediatric psoriasis.

Beliefs About Medicines in Patients with Psoriasis Treated with Methotrexate or Biologics: A Cross-sectional Survey Study.

Methotrexate (MTX) and biologics are frequently used treatments for psoriasis. Exploring patients' beliefs about their treatment may help to elucidate patients' attitudes towards these therapies. A cross-sectional survey was conducted using the Beliefs about Medicines Questionnaire-Specific (BMQ-Specific) in patients treated with methotrexate or biologics. BMQ-Specific scores (Necessity and Concerns scales) were calculated and patients were classified as "accepting", "indifferent", "ambivalent" or "sceptical" towards their treat-ment. Biologics users scored higher on the Necessity scale than did methotrexate users. Both groups had lower Concerns scores than Necessity scores. A high Necessity scale was associated with a low Psoriasis Area and Severity Index score in both groups and long treatment duration in the methotrexate group. Although this study cannot make a direct comparison, it was observed that most patients on biologics could be classified as "accepting" (59%), and most patients on MTX could be classified as "indifferent" (47%). In conclusion, the BMQ-Specific is useful to identify patients with a sceptical, ambivalent or indifferent profile. These profiles may negatively influence patient's attitude towards their medication.

Development of a Novel Approach to Studying Corneodesmosomes and Stratum Corneum Adhesion: Extending Knowledge on the Pathophysiology of Sensitive Skin.

BACKGROUND/AIMS: Aberrant skin barrier and intercorneocyte adhesion are potential contributors to the pathomechanism of sensitive skin (SS). Here we aimed to develop a novel and easy-to-apply method to analyze corneodesmosomes and to interrogate potential differences between corneocytes of subjects with SS and non-SS (NSS). METHODS: Corneocytes of the volar forearm and upper outer quadrant of the left buttock of SS (n = 10) and NSS (n = 8) subjects were extracted as a function of depth using adhesive tape and stained with anti-desmoglein 1 (DSG1) antibody. The total area of corneocytes and the number and average size of cells per tape was estimated using image processing. RESULTS: The total area of extracted corneocytes and the quantity of DSG1 decreased with depth. The level of decrease, total area of corneocytes, and average area of individual cells differed between anatomical locations. In SS, a larger total area of extracted corneocytes and a larger average cell size per tape was found at all inspected depths. CONCLUSION: The developed novel and easy-to-apply approach allows investigation of corneodesmosome components. We confirm a role of altered corneocytes in the pathomechanism of SS. The disclosed protocol can further be optimized in studies of skin conditions with strongly affected corneodesmosomes.

Nocebo Effects and Scratching Behaviour on Itch.

Nocebo effects, i.e. reduced treatment effects due to patients' negative expectations, play a role in itch. Recent studies have shown that nocebo effects can be induced experimentally on itch and also be minimized and even turned into the opposite direction, i.e. placebo effects. It is not known whether these effects generalize to itch-associated scratching behaviour. The aim of this study was to determine whether induction and reversal of nocebo effects on itch evoked by electrical and histamine stimuli generalized to scratching. Ninety-seven healthy participants were included in the study. The manipulation was successful, as during the nocebo learning phase, increased scratching responses were found for higher intensity compared with lower intensity itch stimuli. During the testing phase of induction or reversal of the nocebo effects, however, no significant nocebo effects or reversed nocebo effects, were found in scratching. Thus, no straightforward generalization of nocebo effects from itch to scratching was found in this laboratory setting. Further investigation into possible generalization is needed in different settings and in patients with chronic itch.

Tailored Therapist-guided Internet-based Cognitive-behavioural Treatment for Psoriasis and Rheumatoid Arthritis: Two Case Reports.

Chronic somatic conditions, such as psoriasis, arthritis psoriatica and rheumatoid arthritis, have a large impact on patients' lives. Tailored therapist-guided internet-based cognitive-behavioural therapy (ICBT) has been shown to be effective in improving physical and psychological well-being in these patients. Two cases are presented here, in order to provide an in-depth illustration of the course and content of this novel treatment and to investigate the therapeutic alliance in an online treatment. After face-to-face intakes, both patients received therapist-guided ICBT tailored to their specific problems and treatment goals. The treatment resulted in improved physical and psychological well-being and these clinically significant improvements were maintained at 6-month follow-up. In addition, the therapeutic relationship was evaluated positively by both patients and increased further during treatment, indicating an adequate therapeutic working alliance in this online treatment. These case reports show that tailored ICBT may contribute to improved care for patients with chronic somatic conditions.

Nail Involvement in Alopecia Areata: A Questionnaire-based Survey on Clinical Signs, Impact on Quality of Life and Review of the Literature.

Alopecia areata (AA) is an immune-mediated disease causing temporary or permanent hair loss. Up to 46% of patients with AA also have nail involvement. The aim of this study was to determine the presence, types, and clinical implications of nail changes in patients with AA. This questionnaire-based survey evaluated 256 patients with AA. General demographic variables, specific nail changes, nail-related quality of life (QoL), and treatment history and need were evaluated. Prevalence of nail involvement in AA was 64.1%. The specific nail signs reported most frequently were pitting (29.7%, p = 0.008) and trachyonychia (18.0%). Red spots on the lunula were less frequent (5.1%), but very specific for severe AA. Nail-related QoL was only minimally affected by nail changes. In conclusion, nail involvement is common in patients with AA and presents mostly with pitting and trachyonychia. The presence of these nail changes reflects the severity of the disease, with red spots on the lunula as a predictor for severe alopecia.

Initial Results of Secukinumab Drug Survival in Patients with Psoriasis: A Multicentre Daily Practice Cohort Study.

Interleukin 17-antagonist secukinumab demonstrated high efficacy for treatment of psoriasis in randomized controlled trials. However, performance in daily practice may differ from trials. Drug survival is a comprehensive outcome covering effectiveness and safety, suitable for analyses of daily practice. The aim of this study was to evaluate drug survival of secukinumab in a daily practice psoriasis cohort. Data were collected from 13 hospitals. Drug survival was analysed using Kaplan-Meier survival curves, split for reason of discontinuation. In total, 196 patients were included (83% biologic experienced). Overall, 12 and 18 months drug survival of secukinumab was 76% and 67%, respectively, and was mostly determined by ineffectiveness. There was a trend towards shorter drug survival in women and in biologic experienced patients. Thirteen percent of patients experienced at least one episode of fungal infection. This is one of the first studies of drug survival of secukinumab in patients with psoriasis treated in daily practice.

Effects of blue light on inflammation and skin barrier recovery following acute perturbation. Pilot study results in healthy human subjects.

BACKGROUND/PURPOSE: While growing evidence supports the therapeutic effect of 453 nm blue light in chronic inflammatory skin diseases, data on its effects on acutely perturbed human skin are scarce. In this study, we investigated the impact of 453 nm narrow-band LED light on healthy skin following acute perturbation. METHODS: Tape stripping and histamine iontophoresis were performed on the forearm of 22 healthy volunteers on 2 consecutive weeks. In 1 week, challenges were followed by irradiation for 30 minutes. In the other week (control), no light was administered. Reactions were evaluated up to 72 hours thereafter by transepidermal water loss (TEWL), diffuse reflectance spectroscopy, and skin surface biomarkers. RESULTS: Skin barrier disruption resulted in upregulation of IL-1α at 24 hours after tape stripping (P = .029). In contrast, irradiation abrogated this effect (P > .05). Irradiation also resulted in higher TEWL at 24 hours and in higher b* value at 72 hours after tape stripping compared to the control (P = .034 and P = .018, respectively). At 30 minutes following histamine iontophoresis and irradiation, a trend toward a higher a* value compared to the control was observed (P = .051). CONCLUSION: We provide the first in vivo evidence that blue light at 453 nm exerts biological effects on acutely perturbed healthy human skin.

Use of oral antidepressants in patients with chronic pruritus: A systematic review.

BACKGROUND: Chronic pruritus is a common skin symptom with marked impact on quality of life. Adequate treatment can be challenging for clinicians, demanding the exploration of new treatment options such as oral antidepressants. OBJECTIVE: To evaluate the use of oral antidepressants in chronic pruritus by a systematic overview of the available relevant literature. METHODS: The PubMed, EMBASE, Cochrane, and Web of Science databases were searched. Studies providing original data on the efficacy of oral antidepressants in patients with chronic pruritus were included. We assessed the risk for bias by using the Cochrane Risk of Bias tool for randomized controlled trials and the Newcastle-Ottawa Scale for observational studies. RESULTS: A total of 35 studies evaluating the oral use of fluoxetine, fluvoxamine, paroxetine, sertraline, amitriptyline, nortriptyline, doxepin, and mirtazapine were included. The majority of included articles showed a marked improvement of pruritus during treatment with oral antidepressants. LIMITATIONS: Recommendations are mainly based on open-label trials, case series, and case reports. CONCLUSION: Oral antidepressants should be considered in patients with chronic pruritus that is unresponsive to topical treatment and oral antihistamines, particularly in patients with uremic pruritus, cholestatic pruritus, or paraneoplastic pruritus. More evidence based on randomized-controlled trials is required.

Minimally-invasive Sampling of Interleukin-1α and Interleukin-1 Receptor Antagonist from the Skin: A Systematic Review of In vivo Studies in Humans.

Interleukin-1α (IL-1α) and its receptor antagonist IL-1RA play a pivotal role in skin homeostasis and disease. Although the use of biopsies to sample these cytokines from human skin is widely employed in dermatological practice, knowledge about less invasive, in vivo sampling methods is scarce. The aim of this study was to provide an overview of such methods by systematically reviewing studies in Medline, EMBASE, Web of Science and Cochrane Library using combinations of the terms "IL-1α", IL-1RA", "skin", "human", including all possible synonyms. Quality was assessed using the STrengthening the Reporting of OBservational studies in Epidemiology (STROBE) checklist. The search, performed on 14 October 2016, revealed 10 different sampling methods, with varying degrees of invasiveness and wide application spectrum, including assessment of both normal and diseased skin, from several body sites. The possibility to sample quantifiable amounts of cytokines from human skin with no or minimal discomfort holds promise for linking clinical outcomes to molecular profiles of skin inflammation.