OBJECTIVES:Identifying which patients with psoriasis (PsO) may develop PsA is a research priority. We have previously shown that elafin, along with IL-36γ, are excellent cutaneous biomarkers for PsO. The protease inhibitor elafin and its target protease, neutrophil elastase (NE), can be detected in both serum and epidermal samples. Our aims were to assess whether known PsO biomarkers are expressed differentially in patients affected by plaque PsO with and without PsA. METHODS:Protein expression of NE and elafin were analysed in matched epidermal samples and serum of PsO, PsA patients and healthy controls. Findings were validated in independent PsA and arthritis cohorts. RESULTS:The ratio between NE and elafin differed significantly between PsO and PsA patients. Expression of elafin was reduced in PsA samples as compared with plaque PsO patients. The ratio of NE to secretory leucocyte protease inhibitor was also increased in PsA as compared with PsO patients with no PsA, healthy controls and other arthritis patients. CONCLUSIONS:PsA patients show a reduced NE inhibitor expression in both the skin and blood compartment compared with those with plaque PsO only. This may suggest differences in the ability to regulated neutrophil activity in PsA patients.

Background Tissue resident memory (TRM) cells are of interest in chronic inflammatory skin diseases as they are believed to facilitate flares in the same anatomical area. IL-15 is an essential growth factor for the survival of TRM in the skin compartment. A main source of IL-15 are tissue-resident cells. Objective The purpose of this study was to explore the role of IL-15 in the chronification process of atopic dermatitis (AD). Methods Primary human keratinocytes and fibroblasts were cultured and exposed to a range of stimuli in order to assess their IL-15 expression and production, which were measured by qPCR and ELISA, respectively. RNAseq and PCR were performed from lesional and non-lesional atopic dermatitis (AD) biopsies. Results We tested a range of type I and type II response-associated cytokines and PAMPs on primary human fibroblasts and keratinocytes. The main inducer for IL-15 in keratinocytes proved to be IFNγ, while fibroblasts showed responsiveness to long-term exposure to IL-4. Transcriptomic analyses of AD skin biopsies confirmed that IL-15 was associated with a higher IFN signature and longer disease duration, and a significant correlation was observed between IL-15 and the TRM molecules CCR8 and CD69. Conclusion The epidermal compartment responds to IFNs with IL-15 expression. Analysis of patient-derived skin biopsies highlights higher expression of IL-15 in the context of a Th1 shift known to occur in chronic AD. These data suggest that flares require prompt intervention to avoid consolidation of an IFNγ-driven tissue memory.

IκBζ, an atypical and largely unknown member of the IκB family, is a transcriptional coactivator of selective immune functions. In this study, we investigated the role of keratinocyte-derived IκBζ upon infection with a multidrug-resistant Staphylococcus aureus strain. Infection of keratinocytes rapidly induced IκBζ expression, leading to an elevated expression of antimicrobial peptides, IL-17/IL-36-responsive genes, and proteins involved in skin barrier function. Conversely, loss of IκBζ resulted in increased S aureus internalization, epidermal tissue damage, and severe skin infections in vivo. This impaired host defense upon IκBζ depletion was characterized by reduced antimicrobial peptide expression and diminished recruitment of neutrophils and CD4+ T cells. Importantly, S aureus-induced IκBζ expression required the internalization of the bacteria and its sensing by the intracellular receptor NOD2, which triggered IκBζ and its target gene expression. Thus, we identified NOD2-IκBζ signaling as a key pathway mediating a protective host defense against pathogenic S aureus infections in the skin.

Background:Atopic dermatitis is a chronic relapsing inflammatory skin condition. One of the most common skin disorders in children, atopic dermatitis typically manifests before the age of 5 years, but it can develop at any age. Atopic dermatitis is characterised by dry, inflamed skin accompanied by intense itchiness (pruritus). Objectives:To appraise the clinical and cost effectiveness of abrocitinib, tralokinumab and upadacitinib within their marketing authorisations as alternative therapies for treating moderate-to-severe atopic dermatitis compared to systemic immunosuppressants (first-line ciclosporin A or second-line dupilumab and baricitinib). Data sources:Studies were identified from an existing systematic review (search date 2019) and update searches of electronic databases (MEDLINE, EMBASE, CENTRAL) to November 2021, from bibliographies of retrieved studies, clinical trial registers and evidence provided by the sponsoring companies of the treatments under review. Methods:A systematic review of the clinical effectiveness literature was carried out and a network meta-analysis undertaken for adults and adolescents at different steps of the treatment pathway. The primary outcome of interest was a combined response of Eczema Area and Severity Index 50 + Dermatology Life Quality Index ≥ 4; where this was consistently unavailable for a step in the pathway, an analysis of Eczema Area and Severity Index 75 was conducted. A de novo economic model was developed to assess cost effectiveness from the perspective of the National Health Service in England. The model structure was informed through systematic review of the economic literature and by consulting clinical experts. Effectiveness data were obtained from the network meta-analysis. Costs and utilities were obtained from the evidence provided by sponsoring companies and standard UK sources. Results:Network meta-analyses indicate that abrocitinib 200 mg and upadacitinib 30 mg may be more effective, and tralokinumab may be less effective than dupilumab and baricitinib as second-line systemic therapies. Abrocitinib 100 mg and upadacitinib 15 mg have a more similar effectiveness to dupilumab. Upadacitinib 30 and 15 mg are likely to be more effective than ciclosporin A as a first-line therapy. Upadacitinib 15 mg, abrocitinib 200 and 100 mg may be more effective than dupilumab in adolescents. The cost effectiveness of abrocitinib and upadacitinib for both doses is dependent on the subgroup of interest. Tralokinumab can be considered cost-effective as a second-line systemic therapy owing to greater cost savings per quality-adjusted life-year lost. Conclusions:The primary strength of the analysis of the three new drugs compared with current practice for each of the subpopulations is the consistent approach to the assessment of clinical and cost effectiveness. However, the conclusions are limited by the high uncertainty around the clinical effectiveness and lack of data for the primary outcome for comparisons with baricitinib and for the adolescent and adult first-line populations. Future work and limitations:The most significant limitation that Eczema Area and Severity Index 50 + Dermatology Life Quality Index ≥ 4 could not be obtained for the adolescent and adult first-line systemic treatment populations is due to a paucity of data for dupilumab and ciclosporin A. A comparison of the new drugs against one another in addition to current practice would be beneficial to provide a robust view on which treatments are the most cost-effective. Study registration:This study is registered as PROSPERO CRD42021266219. Funding:This award was funded by the National Institute for Health and Care Research (NIHR) Evidence Synthesis programme (NIHR award ref: 135138) and is published in full in Health Technology Assessment; Vol. 28, No. 4. See the NIHR Funding and Awards website for further award information.

BackgroundEczema and psoriasis are common diseases. Despite both showing active epidermal contribution to the inflammatory process, their molecular aetiology and pathological mechanisms are different.ObjectiveFurther molecular insight into these differences is therefore needed to enable effective future diagnostic and treatment strategies. The majority of our mechanistic and clinical understanding of psoriasis and eczema is derived from RNA, immunohistology and whole skin biopsy data.MethodsIn this study, non-invasive epidermal sampling of lesional, perilesional and non-lesional skin from diseased and healthy skin was used to perform an in depth proteomic analysis of epidermal proteins.ResultsOur findings confirmed the psoriasis-associated cytokine IL-36 gamma as an excellent protein biomarker for lesional psoriasis. However, ELISA and ROC curve analysis of 53 psoriasis and 42 eczema derived samples showed that the sensitivity and specificity were outperformed by elastase-specific protease inhibitor, elafin. Of note, elafin was also found upregulated in non-lesional psoriatic skin at non-predilection sites demonstrating inherent differences between the non-involved skin of healthy and psoriatic individuals. Mass spectrometry and ELISA analysis also demonstrated the upregulation of the anti-inflammatory molecule IL-37 in psoriatic perilesional but not lesional skin. The high expression of IL-37 surrounding psoriatic plaque may contribute to the sharp demarcation of inflammatory morphology changes observed in psoriasis. This finding was also specific for psoriasis and not seen in atopic dermatitis or autoimmune blistering perilesional skin. Our results confirm IL-36 gamma and add elafin as robust, hallmark molecules distinguishing psoriasis and eczema-associated inflammation even in patients under systemic treatment.ConclusionsOverall, these findings highlight the potential of epidermal non-invasive sampling and proteomic analysis to increase our diagnostic and pathophysiologic understanding of skin diseases. Moreover, the identification of molecular differences in healthy-looking skin between patients and healthy controls highlights potential disease susceptibility markers and proteins involved in the initial stages of disease. Epidermal sampling of lesional, perilesional and non-lesional skin from psoriasis and eczema patients as well as healthy skin was used to perform an in depth proteomic analysis. IL-36 gamma known to be expressed in lesional psoriasis skin was outperformed by the protease inhibitor Elafin as a disease-specific epidermal biomarker. Elafin is a robust marker presents across psoriasis subtypes and under systemic therapy as long as active lesions are present. Mass spectrometry and ELISA analysis also demonstrated the upregulation of the anti-inflammatory molecule IL-37 in psoriatic perilesional but not lesional skin. This anti-inflammatory activity at lesion border may contribute to the sharp demarcation seen in psoriatic plaques.image

Patients suffering from Crohn’s disease often present with skin symptoms, mainly in the perianal area. We here report on a patient with widespread granulomatous skin lesions covering a large body surface. Histology findings together with the clinical presentation led to the diagnosis of “metastatic” Crohn’s disease. This case report is interesting due to the diagnostic challenges this type of skin manifestation presented. Of note, the Crohn’s disease (CD) affecting the Gastro Intestinal (GI) tract presented less severe than the skin symptoms. Extraintestinal manifestations and co-morbidities of Crohn’s disease are often challenging and require interdisciplinary management. We here describe an unusual case of metastatic Crohn’s Disease.

Background: Lichen planopilaris (LPP) is an inflammatory cicatricial alopecia characterized by an irreversible destruction of the hair follicle resulting in its permeant destruction. The clinical presentation of LPP is a progressive patchy scarring alopecia. A variety of systemic agents is used to treat LPP with varying success. The aim of this retrospective, real-life analysis was to evaluate the treatment of hydroxychloroquine for LPP. Method: In this retrospective, single-center study, we analyzed 110 patients with LPP and frontal fibrosing alopecia (FFA) who received treatment over a 12-month period from March 2014 to March 2021 at the Department of Dermatology, University of Mainz Medical Center. Patient records were analyzed for response to treatment, co-morbidities, disease progression-free survival (DPFS), and safety. Clinical parameters associated with treatment response were determined with Cox regression modelling and logistic regression. Results: Overall, 77 of 110 patients were treated with a systemic agent. There was a clear association between LPP and the occurrence of Hashimoto thyroiditis. Topical treatment with corticosteroids did not improve clinical symptoms in the majority of patients (15 out of 101). In 71% of patients treated with systemic cyclosporine A and 62% of patients treated with hydroxychloroquine, we observed a significant resolution of the inflammatory process, which correlated with a robust durable clinical response (p < 0.001). Toxicity was observed in 17% (n = 9) of patients receiving systemic treatment with hydroxychloroquine and correlated with the duration of systemic treatment (p < 0.001). Treatment discontinuation was associated with a flare-up of clinical symptoms (29%), which required the re-initiation of second-line therapy in 13 out of 51 patients. Overall, the initiation of second-line treatment, either hydroxychloroquine or Cyclosporine A (CsA), yielded positive results, especially in the patient cohort treated with hydroxychloroquine (overall response rate, ORR = 100%), who showed disease progression during CsA or retinoids. Conclusions: Our results from this contemporary cohort of patients with LPP and FFA indicate that hydroxychloroquine and cyclosporine are effective systemic agents in decreasing clinical symptoms. However, our data also show that the discontinuation of treatment is often associated with the exacerbation of clinical symptoms. Response rates to second-line treatment were especially favorable in the patient cohort with hydroxychloroquine.

Background:Hand eczema is common and a cause of morbidity and occupational disability. When education, irritant/contact allergen avoidance, moisturisation and topical corticosteroids are insufficient to control chronic hand eczema, ultraviolet therapy or systemic immune-modifying drugs are used. There is no treatment pathway generally accepted by UK dermatologists. Primary objective:Compare alitretinoin and ultraviolet therapy as first-line therapy in terms of disease activity at 12 weeks post planned start of treatment. Design:Prospective, multicentre, open-label, two-arm parallel group, adaptive randomised controlled trial with one planned interim analysis, and an economic evaluation. Setting:UK secondary care dermatology outpatient clinics. Participants:Patients with severe chronic hand eczema unresponsive to at least 4 weeks of treatment with potent topical corticosteroids. Primary end point:Natural logarithm of the Hand Eczema Severity Index + 1, 12 weeks post planned start of treatment. Randomisation:Participants randomised 1 : 1 by minimisation to alitretinoin or ultraviolet therapy for 12 to 24 weeks. Blinding:Blinded primary end-point assessor. Results:Intention-to-treat population: 441 (100.0%) participants; 220 (49.9%) alitretinoin and 221 (50.1%) ultraviolet therapy. At least one dose was received by 212 (96.4%) alitretinoin and 196 (88.7%) ultraviolet therapy participants. Primary outcome:The unadjusted median (interquartile range) relative change in hand eczema severity index at 12 weeks was 30% (10-70%) of that at baseline for alitretinoin compared with 50% (20-100%) for ultraviolet therapy. There was a statistically significant benefit of alitretinoin compared with ultraviolet therapy at 12 weeks, with an estimated fold change or relative difference (95% confidence interval) = 0.66 (0.52 to 0.82), p = 0.0003 at 12 weeks. There was no evidence of a difference at 24 or 52 weeks, with the estimated fold change (95% confidence interval) equal to 0.92 (0.798 to 1.08) and 1.27 (0.97 to 1.67), respectively. Primary analysis results were consistent for secondary end points:Fifty-nine per cent allocated to alitretinoin and 61% allocated to ultraviolet therapy achieved a clear/almost clear assessment during the trial period. Differential treatment compliance observed: 145 (65.9%) alitretinoin and 53 (24.0%) ultraviolet therapy participants confirmed compliance (≥ 80% received, no treatment breaks > 7 days during first 12 weeks). High levels of missing data were observed. Safety:One hundred and thirty-five reportable adverse events across 79 participants, 55 (25.0%) alitretinoin and 24 (10.9%) ultraviolet therapy. Four serious adverse events (two alitretinoin, two ultraviolet therapy). Four pregnancies reported (three alitretinoin, one ultraviolet therapy). No new safety signals were detected. Conclusion:As a first-line therapy, alitretinoin showed more rapid improvement and superiority to ultraviolet therapy at week 12. This difference was not observed at later time points. Alitretinoin is cost-effective at weeks 12 and 52. Ultraviolet therapy is cost-effective after 10 years, with a high degree of uncertainty. Hand eczema severity index may be a useful primary outcome measure for hand eczema trials; ALPHA results will inform future trials. Limitations:Treatment compliance was poor for ultraviolet therapy. Regular twice weekly treatment was not received by most patients. Assessment of long-term effects of randomised treatments was complicated by use of second-line treatments post treatment phase. Further work:Further analysis of substudies and pilot data will provide valuable information for future studies. A clear need for better therapeutic approaches for severe chronic hand eczema remains. Future studies will need to further address long-term benefits of treatments given. Trial registration:This trial is registered as ISRCTN80206075. Funding:This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 12/186/01) and is published in full in Health Technology Assessment; Vol. 28, No. 59. See the NIHR Funding and Awards website for further award information.

Lichen planus (LP) presents with a range of clinical subtypes. It can affect the outer skin, involve the nails and present with alopecia and mucosal symptoms to varying degrees. LP of the outer skin mostly shows a self-limiting course; however, this is not the case for lichen planopilaris and the mucosa-affecting subtypes. The pathogenesis of LP is still incompletely understood. As a result, an effective, targeted therapy is currently lacking and different immunomodulatory approaches are being used in clinical practice. The management of patients with severe oral LP mucosae can be particularly challenging. Although the true risk remains controversial, oral LP is considered a risk factor for the development of squamous cell carcinoma and there is a need for regular screening. The quality of life in patients with LP is significantly impaired because of frequent clinical visits, pain, soreness, inability to eat certain foods, side effects to medication, frustrating therapy attempts and worry regarding cancer risk. We highlight here the advantages of an interdisciplinary dermatology and oral surgery clinic, which can address the domains of tooth status, nutrition, pain and malignant transformation and optimized patient management.

Severe chronic hand eczema resistant to topical corticosteroid treatment is an important cause of morbidity and occupational disability. There is uncertainty regarding the best treatment approach and currently no treatment pathway is generally accepted by UK dermatologists. The primary aim of the ALPHA trial was to compare alitretinoin and immersion psoralen plus ultraviolet A (PUVA) as a first-line therapy in terms of disease activity at 12 weeks after the planned start of treatment. We conducted a prospective, multicentre, open-label, two-arm parallel group, adaptive randomized controlled trial. The natural logarithm of the Hand Eczema Severity Index (HECSI) + 1 at 12 weeks after the planned start of treatment was chosen as the primary endpoint so the relative effect of treatment could be estimated. In total, 514 participants were required to detect a fold change of 1.3 (5% two-sided significance level, 80% power, 20% attrition). Participants were randomized 1 : 1 by minimization to alitretinoin or immersion PUVA for 12–24 weeks. The intention-to-treat population consisted of 441 participants: 220 (49.9%) allocated to alitretinoin and 221 (50.1%) to immersion PUVA. In total, 212 (96.4%) alitretinoin participants and 196 (88.7%) immersion PUVA participants received at least one dose. There was a statistically significant benefit of alitretinoin compared with immersion PUVA at 12 weeks, with an estimated fold change of 0.66 [95% confidence interval (CI) 0.52–0.82; P < 0.001]. There was no evidence of a difference at 24 or 52 weeks. Of those allocated to alitretinoin and immersion PUVA, 59% and 61%, respectively, were observed to achieve a clear/almost clear assessment during the trial period. Alitretinoin was more cost-effective than immersion PUVA. Limitations include differences in treatment compliance and differential missing data levels. In total, 145 (65.9%) alitretinoin participants and 53 (24.0%) immersion PUVA participants were observed to comply (≥ 80% received and no treatment breaks of > 7 days during first 12 weeks). Thus, twice-weekly attendance for PUVA was not received by most participants. However, this represents standard of care with ALPHA run as a pragmatic trial using standard-of-care settings for the interventions. A further limitation was that assessment of long-term effects of randomized treatments was complicated by permitted use of second-line treatments after the treatment phase; therefore, trial conclusions are for randomized treatments as first-line therapies. We conclude that, as a first-line therapy, patients on alitretinoin showed more rapid improvement and superiority than those treated with immersion PUVA at week 12, but this difference was not observed at later time points. Future studies will need to further address the long-term benefits of treatments given and complex treatment pathways.

Journal Article Accepted manuscript Hand eczema leaves systemic traces Get access Lennart M Roesner, Lennart M Roesner Department of Dermatology and Allergy, Hannover Medical School, Hannover, GermanyCluster of Excellence RESIST (EXC 2155), Hannover Medical School, Hannover, Germany Correspondence: Lennart M. Roesner, Email: roesner.lennart@mh-hannover.de Search for other works by this author on: Oxford Academic Google Scholar Miriam Wittmann Miriam Wittmann University Medical Center of the Johannes Gutenberg-University of Mainz, Department of Dermatology, Mainz, Germany Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, ljad178, https://doi.org/10.1093/bjd/ljad178 Published: 24 May 2023 Article history Received: 17 May 2023 Revision received: 22 May 2023 Accepted: 22 May 2023 Published: 24 May 2023

The ALPHA trial was a UK National Institute for Health and Care Research-funded, multicentre, prospective, adaptive, two-arm parallel group randomized controlled trial. Consenting participants with severe chronic hand eczema (CHE) were randomized on a 1 : 1 basis to receive either alitretinoin or immersion psoralen + ultraviolet A in conjunction with concomitant topical corticosteroids, emollients and patient education. Different skin types might respond differently to phototherapy due to different pigmentation, so it was important to recruit an ethnically diverse patient group. This was reflected in the design and analysis of the trial. ALPHA included a substudy where photographs were taken in a subgroup of randomly selected consenting participants and used as a disease-assessment quality-assurance check. Following a discussion with the Trial Steering Committee patient representative, a protocol amendment was implemented so that all consenting participants of an ethnic minority background would be selected for the substudy to assess any differences by skin type. The minimization algorithm was amended to incorporate the skin type as a minimization factor to ensure balance between the treatment groups in terms of skin colour and incorporated as a covariate in the primary analysis. ALPHA recruited 441 participants between October 2015 and June 2021, of which 49 (11.1%) were participants from ethnic minority background (13% was the national average in 2011, and 18% was the national average in 2021). In total, 95.2% (n = 373/392) of White participants and 92% (n = 45/49) of participants from ethnic minority backgrounds provided consent to have photographs taken as part of ALPHA. A total of 113 (30.3%) consenting White participants were selected for the photographic substudy, and 36 (80%) ethnic minority participants were selected. The presentation will report on the agreement between assessors in terms of photographs by skin type. Details of disagreement between photographs will be explored through the use of other disease-assessment measures that provide extra detail on the clinical symptoms that may not be visible on a photograph. Through increased awareness of the importance of different skin types, the trial was adapted to ensure ALPHA recruited a proportion of participants from ethnic minorities similar to the proportion of people from ethnic minority backgrounds in the UK. As a result, the trial was an example of adapting trial design to acknowledge the differences across ethnic groups, and to lead to improved research outcomes for patients from ethnic minority backgrounds. We will conclude the presentation with some practical recommendations for equality, diversity and inclusion in dermatological clinical trials.