IL-6 levels dominate the serum cytokine signature of severe epidermolysis bullosa: A prospective cohort study.

BACKGROUND: Systemic inflammation is considered a major player in the pathogenesis of epidermolysis bullosa (EB), but its pattern has only been described in small heterogeneous cohorts. There is controversy if and how systemic inflammation should be therapeutically targeted. METHODS: We examined serum proinflammatory, anti-inflammatory, and itch related cytokines in a paediatric cohort of 29 patients with junctional and dystrophic EB. The cytokine that emerged as the most relevant was measured in a validation cohort of 42 patients during follow-up visits over 2 years. RESULTS: IL-6 showed the most consistent and highest aberration dominating systemic inflammation. IL-6 correlated with wound body surface area (BSA) in both, finding and validation cohorts. Patients with less than 3% wound BSA had normal IL-6, while IL-6 levels significantly increased at more than 5% and 10% of wound BSA. TGF-ß was only marginally elevated in patients with severe recessive dystrophic EB, while TNF-α, IFN-γ and IL-1ß varied inconsistently. Patients reporting itch showed elevations in type 2 immunity (IgE, TSLP, IL4 and/or IL-31, respectively). CONCLUSIONS: Our data suggest a dominant skin barrier and wound healing inflammatory pattern in junctional and dystrophic EB that depends on the wound area and not on the EB type. In EB, itch mediators may be similar to other pruritic disorders.

Early disease intervention with guselkumab in psoriasis leads to a higher rate of stable complete skin clearance ('clinical super response'): Week 28 results from the ongoing phase IIIb randomized, double-blind, parallel-group, GUIDE study.

BACKGROUND: Guselkumab is an interleukin (IL)-23 inhibitor with demonstrated efficacy in patients with psoriasis. OBJECTIVES: Evaluate the impact of early disease intervention on clinical responses following 28 weeks of guselkumab treatment in patients with moderate-to-severe plaque psoriasis. Correlate clinical response and disease duration data with serum biomarker data. METHODS: GUIDE is a phase IIIb randomized, double-blind, parallel-group, multicentre study of adults with moderate-to-severe plaque psoriasis. In study part 1, patients with a short disease duration (SDD [≤2 years]) or a long disease duration (LDD [>2 years]) received guselkumab 100 mg at Week (W) 0, 4, 12, and 20. Those achieving complete skin clearance at W20 and W28 were defined as a super responder (SRe). A multivariable logistic regression analysed the association between baseline factors and the likelihood of becoming an SRe. The relationship between clinical response, disease duration and serum biomarker data was assessed at W0 and 4. RESULTS: In total, 880 patients were enrolled (SDD/LDD = 40.6%/59.4% of patients). More SDD than LDD patients achieved absolute Psoriasis Area and Severity Index (PASI) = 0 at W28 (51.8% vs. 39.4%) and were SRes (43.7% vs. 28.1% [overall 34.4%]). SDD patients also achieved PASI = 0 quicker than LDD patients (median 141 vs. 200 days). Disease duration and prior biologic use had the greatest impact on becoming an SRe, with no strong association among these independent variables. At baseline, there were no significant differences in the serum biomarker levels of IL-17A, IL-17F, IL-22 and ß-defensin 2 between SDD and LDD patients, or between SRe and non-SRe patients. Guselkumab rapidly decreased these markers of systemic inflammation across all patient groups analysed at W4. Guselkumab was well tolerated. CONCLUSIONS: Guselkumab efficacy was consistent across subpopulations, on the skin and systemically. The proportion of SRes was higher in SDD than LDD patients, indicating early treatment intervention may improve clinical outcomes.

Direct comparison of risankizumab and fumaric acid esters in systemic therapy-naïve patients with moderate-to-severe plaque psoriasis: a randomized controlled trial.

BACKGROUND: Fumaric acid esters (FAEs; Fumaderm® ) are the most frequently prescribed first-line systemic treatment for moderate-to-severe plaque psoriasis in Germany. Risankizumab (Skyrizi® ) is a humanized IgG1 monoclonal antibody that specifically binds to the p19 subunit of interleukin 23. OBJECTIVES: To compare risankizumab treatment to FAEs in patients with psoriasis. METHODS: This phase III randomized, active-controlled, open-label study with blinded assessment of efficacy was conducted in Germany. Patients were randomized (1 : 1) to subcutaneous risankizumab 150 mg (weeks 0, 4 and 16) or oral FAEs at increasing doses from 30 mg daily (week 0) up to 720 mg daily (weeks 8-24). Enrolled patients were adults naïve to and candidates for systemic therapy, with chronic moderate-to-severe plaque psoriasis. Phototherapy was not allowed within 14 days before or during the study. RESULTS: Key efficacy endpoints were met at week 24 for risankizumab (n = 60) vs. FAEs (n = 60) (P < 0·001): achievement of a ≥ 90% improvement in Psoriasis Area and Severity Index (PASI; primary endpoint 83·3% vs. 10·0%), ≥ 100% improvement in PASI (50·0% vs. 5·0%), ≥ 75% improvement in PASI (98·3% vs. 33·3%), ≥ 50% improvement in PASI (100% vs. 53·3%) and a Static Physician's Global Assessment of clear/almost clear (93·3% vs. 38·3%). The rates of gastrointestinal disorders, flushing, lymphopenia and headache were higher in the FAE group. One patient receiving risankizumab reported a serious infection (influenza, which required hospitalization). There were no malignancies, tuberculosis or opportunistic infections in either treatment arm. CONCLUSIONS: Risankizumab was found to be superior to FAEs, providing earlier and greater improvement in psoriasis outcomes that persisted with continued treatment, and more favourable safety results, which is consistent with the known safety profile. No new safety signals for risankizumab or FAEs were observed.

Addictions in patients with atopic dermatitis: a cross-sectional pilot study in Germany.

BACKGROUND: Atopic dermatitis (AD) is the most common chronic inflammatory skin disease worldwide and displays many atopic, but also non-atopic comorbidities. Among the latter, mental health disorders such as depression have been extensively studied. However, data on addictions are still rare. OBJECTIVES: The aim of this study was to assess the prevalence of different kinds of addictions in adult AD patients using a single-centre approach. METHODS: This non-interventional cross-sectional study was performed from 03/2020 to 05/2020 at the Department of Dermatology of a large German university hospital. Participants with a diagnosis of AD confirmed by a dermatologist answered questions about disease severity (patient-oriented eczema measure, POEM), quality of life (Dermatology Life Quality Index, DLQI) and smoking habits. They were screened for problematic alcohol consumption, drug abuse, internet addiction and pathological gambling using internationally established and validated questionnaires. RESULTS: 157 patients (56.1% female; mean age of 49.9 ± 20.4) with an average POEM of 13.7 ± 7.5 and DLQI of 6.1 ± 5.4 were evaluated. 14.1% were identified as regular smokers, 12.1% screened positive for alcohol dependency, 6.4% for drug use disorders, 4.5% for Internet addiction and 3.2% for pathological gambling. Co-occurrences of different addictions were observed, and a positive correlation was noted between DLQI scores and smoking. CONCLUSIONS: In summary, this study hints at elevated positive screening rates for problematic alcohol consumption, drug use disorders, Internet addiction and problem gambling compared with the general population. Screening routinely for addictions may improve patient-centred health care of AD patients.

Requirements and expectations of high-quality biomarkers for atopic dermatitis and psoriasis in 2021-a two-round Delphi survey among international experts.

BACKGROUND: Chronic inflammatory skin diseases such as atopic dermatitis (AD) and psoriasis (PSO) present major challenges in health care. Thus, biomarkers to identify disease trajectories and response to treatments to improve the lives of affected individuals warrant great research consideration. The requirements that these biomarkers must fulfil for use as practical clinical tools have not yet been adequately investigated. AIM: To identify the core elements of high-quality AD and PSO biomarkers to prepare recommendations for current biomarker research. METHOD: A cross-sectional two-round Delphi survey was conducted from August to October 2019 and October to November 2020. All participants were members of the BIOMAP project, an EU-funded consortium of clinicians, researchers, patient organizations and pharmaceutical industry partners. The first round consisted of three open-ended questions. Responses were qualitatively analysed, and 26 closed statements were developed. For the second round, 'agreement' was assumed when the responses of ≥70% of the participants were ≥5 points on a 7-point Likert scale for each statement. Priority classification was based on mean scores (<20th percentile = low, 20th to 60th percentile = medium, >60th percentile = high). RESULTS: Twenty-one and twenty-six individuals participated in rounds one and two, respectively. From 26 statements that were included in round 2, 18 achieved agreement (8 concerning the performance, 8 for the purpose and 2 on current obstacles). Seven statements were classified as high priority, e.g. those concerning reliability, clinical validity, a high positive predictive value, prediction of the therapeutic response and disease progression. Another seven statements were assigned medium priority, e.g. those about analytical validity, prediction of comorbidities and therapeutic algorithm. Low priority included four statements, like those concerning cost effectiveness and prediction of disease flares. CONCLUSION: The core requirements that experts agreed on being essential for high-quality AD and PSO biomarkers require rapid validation. Biomarkers can therefore be assessed based on these prioritized requirements.

So close, and yet so far away: The dichotomy of the specific immune response and inflammation in psoriasis and atopic dermatitis.

Characterization of the complex interplay between cytokines, chemokines and microorganisms has led to a better understanding of the pathogenesis of both psoriasis and AD and resulted in new therapeutics targeting distinct immune responses. Psoriasis and AD share many characteristics: they are highly prevalent, chronic, cause primarily skin inflammation, but are associated with comorbidities, and come with a devastating quality of life due to itch and stigmatization. However, the pathogenesis of psoriasis and AD is opposing - psoriasis is dominated by a Th17 immune response that causes neutrophil migration, induction of innate immunity and exaggerated epithelial metabolism. Leading cytokines of this Th17 immune response are IL-17A and F, IL-22 and TNF-a. AD is characterized by Th2 immunity characterized by the signature cytokines IL-4 and IL-13 leading to an impaired epidermal barrier, dampened innate immunity and eosinophil migration. This review compares genetics, microbiome and T-cell infiltrate and resulting epithelial response in psoriasis and AD. Whilst the antagonistic course of psoriasis and AD is confirmed by response to specific biologics targeting the key cytokines of inflammation in psoriasis and AD, respectively, clinically overlapping phenotypes are challenging in our daily clinical practice. We conclude this review by summarizing what is known about these mixed phenotypes and how the identification of clinically relevant endotypes and molecular-driven decision-making is the next step in the field of dermato-immunology.

Patient-reported outcomes with risankizumab versus fumaric acid esters in systemic therapy-naïve patients with moderate to severe plaque psoriasis: a phase 3 clinical trial.

BACKGROUND: In a phase 3 clinical study, patients from Germany with moderate to severe psoriasis who were naïve to systemic treatment and received risankizumab had greater and more rapid disease improvements compared with those who received fumaric acid esters (FAEs). OBJECTIVE: To evaluate patient-reported outcomes (PROs) in patients treated with risankizumab compared with FAEs. METHODS: Adult patients were randomized 1:1 to receive either risankizumab 150 mg subcutaneous injections at weeks 0, 4 and 16 or FAEs (Fumaderm® ) provided according to the prescribing label. PRO secondary endpoints assessed were Psoriasis Symptom Scale (PSS), Dermatology Life Quality Index (DLQI), 36-Item Short Form Health Survey, version 2 (SF-36v2), Patient Benefit Index (PBI), Hospital Anxiety and Depression Scale (HADS), Patient Global Assessment (PtGA) and European Quality of Life 5 Dimensions 5 Level (EQ-5D-5L). PROs were assessed at weeks 0, 16 and 24. RESULTS: Sixty patients each were randomized to receive risankizumab or FAEs. A significant PSS improvement was observed with risankizumab vs. FAEs at weeks 16 and 24 for total and psoriasis-associated redness, itching and burning scores (P < 0.001). DLQI scores were significantly lower (reflecting better health-related quality of life) with risankizumab vs. FAEs, with least squares (LS) mean differences of -7.4 and -7.6 at weeks 16 and 24, respectively (both P < 0.001). Patients randomized to risankizumab also had larger improvements in SF-36 Physical and Mental Component Summary scores, HADS anxiety and depression scores, PtGA, and EQ-5D-5L index and visual analogue scale scores (all P ≤ 0.002) at weeks 16 and 24 compared with FAEs. PBI was significantly higher, indicating greater benefit, with risankizumab vs. FAEs, with an LS mean difference of 1.1 and 1.3 at weeks 16 and 24, respectively (both P < 0.001). CONCLUSIONS: Risankizumab provides significant benefits over FAEs in improving PROs across several dimensions in patients with moderate to severe psoriasis.

Characteristics and outcomes of patients treated with apremilast in the real world: results from the APPRECIATE study.

BACKGROUND: APPRECIATE is a multinational, observational, retrospective, cross-sectional study in patients treated for psoriasis with apremilast, an oral phosphodiesterase 4 inhibitor. OBJECTIVES: To describe the characteristics of patients with psoriasis treated with apremilast in the clinical setting, to evaluate real-world outcomes of psoriasis treatment with apremilast and to better understand the perspectives of patients and physicians on treatment outcomes. METHODS: In six European countries, patients with chronic plaque psoriasis treated in clinical practice who could be contacted 6 (±1) months after apremilast initiation were enrolled. Patient characteristics, Dermatology Life Quality Index (DLQI) and Psoriasis Area and Severity Index (PASI) were obtained from medical records when available. Outcomes were evaluated using patient/physician questionnaires. RESULTS: In 480 patients at treatment initiation, mean [median; 95% confidence interval (CI)] PASI and DLQI scores were 12.5 (10.7; 11.6-13.4) and 13.4 (13.0; 11.4-14.2), respectively. At 6 (±1) months, 72.3% of patients (n = 347) continued apremilast treatment [discontinuations: lack of efficacy (13.5%), safety (11.7%), other (2.5%)]. In patients continuing treatment, 48.6% achieved a ≥75% reduction in PASI score; mean (95% CI) DLQI score was 5.7 (4.5-6.9), and mean (SD) Patient Benefit Index score was 2.8 (1.2). Physicians perceived clinical improvement in 75.6% of patients. Physicians' perspective on overall success of apremilast in meeting expectations correlated with patients' perception of treatment benefit (r = 0.691). Most commonly reported adverse events (>5% of patients) were diarrhoea, nausea and headache. CONCLUSIONS: Patients in APPRECIATE reported high disease burden despite more moderate skin involvement than those who enrolled in clinical trials of apremilast. Findings from APPRECIATE demonstrate the real-world value of apremilast for psoriasis treatment, as 7 of 10 patients continued therapy and showed notable improvement in disease severity and quality of life 6 (±1) months after apremilast initiation.

Continued treatment with secukinumab is associated with high retention or regain of response.

BACKGROUND: Conventional analyses present aggregate data, masking late responders and efficacy reductions. Secukinumab, a fully human monoclonal antibody that selectively neutralizes interleukin (IL)-17A, shows sustained efficacy in moderate-to-severe psoriasis. OBJECTIVES: To determine stability of response to secukinumab, changes in efficacy were assessed in individual patients. METHODS: This is a post hoc analysis of two phase III randomized controlled trials, FIXTURE (trial registration: NCT01358578) and CLEAR (trial registration: NCT02074982). Patients received secukinumab 300 mg (FIXTURE and CLEAR), etanercept 50 mg (FIXTURE) or ustekinumab 45 or 90 mg (CLEAR) over 52 weeks. Mutually exclusive response categories were defined: ≥ 90% improvement in the Psoriasis Area and Severity Index (PASI 90) ('excellent'), ≥ 75% improvement in PASI (PASI 75) and < PASI 90 ('good') and < PASI 75 ('insufficient'). Reductions in efficacy were defined as shifts from higher to lower response categories between two consecutive visits maintained for a third consecutive visit. Loss of efficacy was defined as a reduction of efficacy resulting in 'insufficient' response. All comparisons are descriptive. RESULTS: At 52 weeks, in CLEAR, 90·2% (303/336) of patients on secukinumab achieved stable efficacy without loss and 77·7% (261/336) showed stable efficacy without any reduction of response [74·3% (252/339) and 59·9% (203/339) of patients for ustekinumab]. In FIXTURE, 83·5% (273/327) and 66·4% (217/327) of patients on secukinumab had stable efficacy without loss or reduction of response [58·3% (190/326) and 42·6% (139/326) for etanercept]. Response was regained by continuing secukinumab treatment in 50% (8/16) of patients in CLEAR and 26% (9/34) in FIXTURE. Similar patterns were observed for other response definitions. CONCLUSIONS: Efficacy with secukinumab was stable over 52 weeks of treatment in most patients. Continued treatment with secukinumab resulted in regain of efficacy in some patients. Persistent loss of response was uncommon. What's already known about this topic? Secukinumab, a fully human monoclonal antibody that selectively neutralizes interleukin (IL)-17A, shows significant and sustained efficacy in the treatment of moderate-to-severe psoriasis. Secondary loss of response may be experienced by a minority of patients treated with secukinumab, as with other biologics, but the extent of this and the potential for regain of efficacy with continued treatment is not well understood. What does this study add? To determine stability of response to secukinumab and inform clinical practice, changes in efficacy were assessed at individual patient level using response categories. Efficacy with secukinumab was stable over 52 weeks of treatment in most patients, and continued treatment with secukinumab resulted in efficacy regain after loss in some patients. Persistent loss of response was uncommon. Patient factors such as body weight may affect the likelihood of loss of efficacy.

Guselkumab is superior to fumaric acid esters in patients with moderate-to-severe plaque psoriasis who are naive to systemic treatment: results from a randomized, active-comparator-controlled phase IIIb trial (POLARIS).

BACKGROUND: Guselkumab, a fully human interleukin-23 antibody, is approved for systemic treatment of patients with moderate-to-severe plaque psoriasis. OBJECTIVES: To compare the efficacy and safety of guselkumab with those of fumaric acid esters (FAE) in patients with moderate-to-severe plaque psoriasis who are naive to systemic treatment. METHODS: Eligible patients were randomized to this multicentre, randomized, open-label, assessor-blinded, active-comparator-controlled phase IIIb study to receive guselkumab 100 mg by subcutaneous injection or oral FAE according to local label guidelines. RESULTS: Through week 24, 56 of 60 patients completed guselkumab treatment and 36 of 59 completed FAE treatment. The primary endpoint (proportion of patients with ≥ 90% improvement from their baseline Psoriasis Area and Severity Index; PASI 90 response) was achieved by significantly more patients receiving guselkumab than FAE at week 24 (82% vs. 14%, P < 0·001). Analysis of the major secondary endpoints confirmed a statistically significant difference between the treatments with regards to PASI 75 response (90% vs. 27%, P < 0·001) and Dermatology Life Quality Index score of 0 or 1 (no effect at all on the patient's quality of life; 62% vs. 17%, P < 0·001). More patients in the guselkumab group achieved completely clear skin (PASI 100 response) than in the FAE group (32% vs. 3%, P < 0·001). The incidence of adverse events was lower with guselkumab than with FAE (73% vs. 98%). Overall, 28% of patients on FAE discontinued due to an adverse event, compared with none receiving guselkumab. No new safety findings were observed for guselkumab. CONCLUSIONS: Guselkumab demonstrated superiority over FAE in systemic-treatment-naive patients with moderate-to-severe plaque psoriasis through 24 weeks.

Developments and challenges in dermatology: an update from the Interactive Derma Academy (IDeA) 2019.

The 2019 Interactive Derma Academy (IDeA) meeting was held in Lisbon, Portugal, 10-12 May, bringing together leading dermatology experts from across Europe, the Middle East and Asia. Over three days, the latest developments and challenges in relation to the pathophysiology, diagnosis, evaluation and management of dermatological conditions were presented, with a particular focus on acne, atopic dermatitis (AD) and actinic keratosis (AK). Interesting clinical case studies relating to these key topics were discussed with attendees to establish current evidence-based best practices. Presentations reviewed current treatments, potential therapeutic approaches and key considerations in the management of acne, AK and AD, and discussed the importance of the microbiome in these conditions, as well as the provision of patient education/support. It was highlighted that active treatment is not always required for AK, depending on patient preferences and clinical circumstances. In addition to presentations, two interactive workshops on the diagnosis and treatment of sexually transmitted infections/diseases (STIs/STDs) presenting to the dermatology clinic, and current and future dermocosmetics were conducted. The potential for misdiagnosis of STIs/STDs was discussed, with dermoscopy and/or reflectance confocal microscopy suggested as useful diagnostic techniques. In addition, botulinum toxin was introduced as a potential dermocosmetic, and the possibility of microbiome alteration in the treatment of dermatological conditions emphasized. Furthermore, several challenges in dermatology, including the use of lasers, the complexity of atopic dermatitis, wound care, use of biosimilars and application of non-invasive techniques in skin cancer diagnosis were reviewed. In this supplement, we provide an overview of the presentations and discussions from the fourth successful IDeA meeting, summarizing the key insights shared by dermatologists from across the globe.

IL-17C amplifies epithelial inflammation in human psoriasis and atopic eczema.

BACKGROUND: Key pathogenic events of psoriasis and atopic eczema (AE) are misguided immune reactions of the skin. IL-17C is an epithelial-derived cytokine, whose impact on skin inflammation is unclear. OBJECTIVE: We sought to characterize the role of IL-17C in human ISD. METHODS: IL-17C gene and protein expression was assessed by immunohistochemistry and transcriptome analysis. Primary human keratinocytes were stimulated and expression of cytokines chemokines was determined by qRT-PCR and luminex assay. Neutrophil migration towards supernatant of stimulated keratinocytes was assessed. IL-17C was depleted using a new IL-17C-specific antibody (MOR106) in murine models of psoriasis (IL-23 injection model) and AE (MC903 model) as well as in human skin biopsies of psoriasis and AE. Effects on cell influx (mouse models) and gene expression (human explant cultures) were determined. RESULTS: Expression of IL-17C mRNA and protein was elevated in various ISD. We demonstrate that IL-17C potentiates the expression of innate cytokines, antimicrobial peptides (IL-36G, S100A7 and HBD2) and chemokines (CXCL8, CXCL10, CCL5 and VEGF) and the autocrine induction of IL-17C in keratinocytes. Cell-free supernatant of keratinocytes stimulated with IL-17C was strongly chemotactic for neutrophils, thus demonstrating a critical role for IL-17C in immune cell recruitment. IL-17C depletion significantly reduced cell numbers of T cells, neutrophils and eosinophils in murine models of psoriasis and AE and led to a significant downregulation of inflammatory mediators in human skin biopsies of psoriasis and AE ex vivo. CONCLUSION: IL-17C amplifies epithelial inflammation in Th2 and Th17 dominated skin inflammation and represents a promising target for the treatment of ISD.

Variable response to low-dose naltrexone in patients with Darier disease: a case series.

BACKGROUND: Darier disease is a rare autosomal-dominant genodermatosis with a loss of function of a Ca2+ -ATPase pump (SERCA2-pump). Clinically, the disease is characterized by red-brown keratotic papules mainly in seborrhoeic areas and has only limited and unsatisfactory treatment options. Previously, low-dose naltrexone was described as a successful treatment option in Hailey-Hailey disease, a genodermatosis with a genetic mutation coding for a similar loss of function of a Ca2+ -ATPase pump (hSPCA1-pump). OBJECTIVE: To assess the efficacy of low-dose naltrexone as a treatment option in Darier disease. METHODS: Six patients with biopsy-proven Darier disease (four had severe, one had moderate and one mild clinical manifestations). The patients received off-label therapy with naltrexone [5 mg per os (p.o.)] and magnesium [200 mg p.o.]. Patients were followed up every 4 weeks for minimally 12 weeks. Upon clinical presentation, the disease severity and subjective pain and itch scores were assessed, and standardized photographs were obtained. RESULTS: The clinical response to naltrexone varied after 12 weeks. The four patients with severe Darier disease showed worsening after initial improvement during the first 4 weeks, whereas the two patients with a mild to moderate clinical manifestation clearly improved, showing almost full remission after 12 weeks with complete flattening of the keratotic papules. CONCLUSION: Low-dose naltrexone did not have an effect on severe Darier disease compared to Hailey-Hailey disease, but it was beneficial in mild to moderate forms of the disease. Further studies are needed to confirm these observations of variable responses.

Non-invasive imaging in dermatology and the unique potential of raster-scan optoacoustic mesoscopy.

In recent years, several non-invasive imaging methods have been introduced to facilitate diagnostics and therapy monitoring in dermatology. The microscopic imaging methods are restricted in their penetration depth, while the mesoscopic methods probe deeper but provide only morphological, not functional, information. 'Raster-scan optoacoustic mesoscopy' (RSOM), an emerging new imaging technique, combines deep penetration with contrast based on light absorption, which provides morphological, molecular and functional information. Here, we compare the capabilities and limitations of currently available dermatological imaging methods and highlight the principles and unique abilities of RSOM. We illustrate the clinical potential of RSOM, in particular for non-invasive diagnosis and monitoring of inflammatory and oncological skin diseases.

Is the humoral immunity dispensable for the pathogenesis of psoriasis?

BACKGROUND: Imbalances of T-cell subsets are hallmarks of disease-specific inflammation in psoriasis. However, the relevance of B cells for psoriasis remains poorly investigated. OBJECTIVE: To analyse the role of B cells and immunoglobulins for the disease-specific immunology of psoriasis. METHODS: We characterized B-cell subsets and immunoglobulin levels in untreated psoriasis patients (n = 37) and compared them to healthy controls (n = 20) as well as to psoriasis patients under disease-controlling systemic treatment (n = 28). B-cell subsets were analysed following the flow cytometric gating strategy based on the surface markers CD24, CD38 and CD138. Moreover, immunofluorescence stainings were used to detect IgA in psoriatic skin. RESULTS: We found significantly increased levels of IgA in the serum of treatment-naïve psoriasis patients correlating with disease score. However, IgA was only observed in dermal vessels of skin sections. Concerning B-cell subsets, we only found a moderately positive correlation of CD138+ plasma cells with IgA levels and disease score in treatment-naïve psoriasis patients. Confirming our hypothesis that psoriasis can develop in the absence of functional humoral immunity, we investigated a patient who suffered concomitantly from both psoriasis and a hereditary common variable immune defect (CVID) characterized by a lack of B cells and immunoglobulins. We detected variants in three of the 13 described genes of CVID and a so far undescribed variant in the ligand of the TNFRSF13B receptor leading to disturbed B-cell maturation and antibody production. However, this patient showed typical psoriasis regarding clinical presentation, histology or T-cell infiltrate. Finally, in a group of psoriasis patients under systemic treatment, neither did IgA levels drop nor did plasma cells correlate with IgA levels and disease score. CONCLUSION: B-cell alterations might rather be an epiphenomenal finding in psoriasis with a clear dominance of T cells over shifts in B-cell subsets.

Conjunctivitis in atopic dermatitis patients with and without dupilumab therapy - international eczema council survey and opinion.

BACKGROUND: Conjunctivitis is common in patients with atopic dermatitis (AD) in general and a commonly reported adverse event in AD clinical trials with dupilumab. OBJECTIVE: To survey opinions and experience about conjunctivitis occurring in AD, including those during dupilumab treatment in a group of AD experts from the International Eczema Council (IEC). METHODS: Electronic survey and in-person discussion of management strategies. RESULTS: Forty-six (53.5%) IEC members from 19 countries responded to the survey. Consensus was reached for several statements regarding diagnostic workup, referral and treatment. IEC members suggest that patients with AD should (i) routinely be asked about ocular complaints or symptoms, (ii) obtain information about the potential for conjunctivitis before starting dupilumab therapy and (iii) if indicated, be treated with dupilumab despite previous or current conjunctivitis. In cases of new-onset conjunctivitis, there was consensus that dupilumab treatment should be continued when possible, with appropriate referral to an ophthalmologist. LIMITATIONS: The study relies on expert opinion from dermatologists. Responses from few dermatologists without dupilumab access were not excluded from the survey. CONCLUSION: The IEC recommends that dermatologists address conjunctivitis in patients with AD, especially during treatment with dupilumab.

[Personalized medicine in the field of inflammatory skin diseases]. / Personalisierte Medizin im Bereich entzündlicher Hauterkrankungen.

BACKGROUND: For sufficient treatment of patients with chronic inflammatory skin diseases, new concepts need to be established and biomarkers must be identified. OBJECTIVE: Presentation of new markers, their quality and implications for the clinical daily routine. MATERIAL AND METHODS: This article presents a discussion of basic research and a review of current achievements of personalized medicine in the area of chronic inflammatory skin diseases. RESULTS: Promising biomarker for the various entities of chronic inflammatory skin diseases have been proposed; however, they need to be prospectively validated and translated into affordable and feasible tests. CONCLUSION: There is still a long way to go to establish personalized medicine in the field of chronic inflammatory skin diseases and its success is dependent on multicenter collaboration to validate and implement novel biomarkers.

Use of systemic corticosteroids for atopic dermatitis: International Eczema Council consensus statement.

BACKGROUND: Guidelines discourage the use of systemic corticosteroids for atopic dermatitis (AD), but their use remains widespread. OBJECTIVES: To reach consensus among an international group of AD experts on the use of systemic corticosteroids for AD. METHODS: A survey consisting of statements accompanied by visual analogue scales ranging from 'strongly disagree' to 'neutral' to 'strongly agree' was distributed to the International Eczema Council (IEC). Consensus was reached in agreement on a statement if < 30% of respondents marked to the left of 'neutral' towards 'strongly disagree'. RESULTS: Sixty of 77 (78%) IEC members participated. Consensus was reached on 12 statements, including that systemic corticosteroids should generally be avoided but can be used rarely for severe AD under certain circumstances, including a lack of other treatment options, as a bridge to other systemic therapies or phototherapy, during acute flares in need of immediate relief, in anticipation of a major life event or in the most severe cases. If used, treatment should be limited to the short term. Most respondents agreed that systemic corticosteroids should never be used in children, but consensus was not reached on that statement. The conclusions of our expert group are limited by a dearth of high-quality published evidence. If more stringent consensus criteria were applied (e.g. requiring < 20% of respondents marking towards 'strongly disagree'), consensus would have been reached on fewer statements. CONCLUSIONS: Based on expert opinion from the IEC, routine use of systemic corticosteroids for AD is generally discouraged and should be reserved for special circumstances.

Sebocytes contribute to skin inflammation by promoting the differentiation of T helper 17 cells.

BACKGROUND: The main function of sebocytes is considered to be the production of lipids to moisturize the skin. However, it recently became apparent that sebocytes release chemokines and cytokines and respond to proinflammatory stimuli as well as the presence of bacteria. OBJECTIVES: To analyse the functional communication between human sebocytes and T cells. METHODS: Immunofluorescence stainings for CD4 and interleukin (IL)-17 were performed on acne sections and healthy skin. Migration assays and T-cell-stimulation cultures were performed with supernatants derived from unstimulated or prestimulated SZ95 sebocytes. Dendritic cells were generated in the presence of SZ95 supernatant and subsequently used in mixed leucocyte reactions. RESULTS: We showed that CD4+ IL-17+ T cells accumulate around the pilosebaceous unit and are in close contact with sebocytes in acne lesions. By using SZ95 sebocyte supernatant, we demonstrate a chemotactic effect of sebocytes on neutrophils, monocytes and T cells in a CXCL8-dependent manner. Furthermore, sebocyte supernatant induces the differentiation of CD4+ CD45RA+ naive T cells into T helper (Th)17 cells via the secretion of IL-6, transforming growth factor-ß and, most importantly, IL-1ß. No direct effects of sebocytes on the function of CD4+ CD45RO+ memory T cells were detected. Moreover, sebocytes functionally interact with Propionibacterium acnes in the maturation of dendritic cells, leading to antigen-presenting cells that preferentially prime Th17 cells. CONCLUSIONS: Our study provides evidence that human sebocytes actively participate in inflammatory processes in the skin by recruiting and communicating with immune cells. This interaction leads to the generation of Th17 cells, which might contribute to the pathogenesis not only of acne vulgaris, but also of several inflammatory skin diseases.

Immune response patterns in non-communicable inflammatory skin diseases.

Non-communicable inflammatory skin diseases (ncISD) such as psoriasis or atopic eczema are a major cause of global disease burden. Due to their impact and complexity, ncISD represent a major challenge of modern medicine. Dermatology textbooks describe more than 100 different ncISD based on clinical phenotype and histological architecture. In the last decades, this historical description was complemented by increasing molecular knowledge - and this knowledge is now being translated into specific therapeutics. Combining the enormous advances made in lymphocyte immunology and molecular genetics with clinical and histological phenotyping reveals six immune response patterns of the skin - type I immune cells cause the lichenoid pattern characterized by immune-mediated cell death of keratinocytes; type II immune cells underlie the eczematous pattern with impaired epidermal barrier, infection and eosinophils as well as the bullous pattern with loss of epithelial integrity; Th17 cells and ILC3 mediate the psoriatic pattern characterized by acanthosis, high metabolic activity and neutrophils; dysbalance of regulatory T cells causes either the fibrogenic pattern with rarefication of cells and dermal thickening or the granulomatous pattern defined by formation of granulomas. With more and more specific therapeutic agents approved, classifying ncISD also according to their immune response pattern will become highly relevant. This review defines the six immune response patterns of ncISD and highlights therapeutic strategies targeting key lymphocyte mediators.