Machine learning applied to atopic dermatitis transcriptome reveals distinct therapy-dependent modification of the keratinocyte immunophenotype.

BACKGROUND: Atopic dermatitis (AD) arises from a complex interaction between an impaired epidermal barrier, environmental exposures, and the infiltration of T helper (Th)1/Th2/Th17/Th22 T cells. Transcriptomic analysis has advanced our understanding of gene expression in cells and tissues. However, molecular quantitation of cytokine transcripts does not predict the importance of a specific pathway in AD or cellular responses to different inflammatory stimuli. OBJECTIVES: To understand changes in keratinocyte transcriptomic programmes in human cutaneous disease during development of inflammation and in response to treatment. METHODS: We performed in silico deconvolution of the whole-skin transcriptome. Using co-expression clustering and machine-learning tools, we resolved the gene expression of bulk skin (seven datasets, n = 406 samples), firstly, into keratinocyte phenotypes identified by unsupervised clustering and, secondly, into 19 cutaneous cell signatures of purified populations from publicly available datasets. RESULTS: We identify three unique transcriptomic programmes in keratinocytes - KC1, KC2 and KC17 - characteristic of immune signalling from disease-associated Th cells. We cross-validate those signatures across different skin inflammatory conditions and disease stages and demonstrate that the keratinocyte response during treatment is therapy dependent. Broad-spectrum treatment with ciclosporin ameliorated the KC17 response in AD lesions to a nonlesional immunophenotype, without altering KC2. Conversely, the specific anti-Th2 therapy, dupilumab, reversed the KC2 immunophenotype. CONCLUSIONS: Our analysis of transcriptomic signatures in cutaneous disease biopsies reveals the effect of keratinocyte programming in skin inflammation and suggests that the perturbation of a single axis of immune signal alone may be insufficient to resolve keratinocyte immunophenotype abnormalities.

Supportive care in the acute phase of Stevens-Johnson syndrome and toxic epidermal necrolysis: an international, multidisciplinary Delphi-based consensus.

BACKGROUND: Supportive care is the cornerstone of management of adult and paediatric Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). However, consensus on the modalities of supportive care is lacking. OBJECTIVES: Our aim in this international multicentric Delphi exercise was to establish a multidisciplinary expert consensus to standardize recommendations regarding supportive care in the acute phase of SJS/TEN. METHODS: Participants were sent a survey via the online tool SurveyMonkey, consisting of 103 statements organized into 11 topics: multidisciplinary team composition, suspect drug management, infection prevention, fluid resuscitation and prevention of hypothermia, nutritional support, pain and psychological distress management, management of acute respiratory failure, local skincare, ophthalmological management, management of other mucosa, and additional measures. Participants evaluated the level of appropriateness of each statement on a scale of 1 (extremely inappropriate) to 9 (extremely appropriate). The results were analysed according to the RAND/UCLA Appropriateness Method. RESULTS: Forty-five participants from 13 countries (on three continents) participated. After the first round, a consensus was obtained for 82.5% of the 103 initially proposed statements. After the second round, a final consensus was obtained for 102 statements. CONCLUSIONS: We have reached an international Delphi-based consensus on best supportive care practice for SJS/TEN. Our expert consensus should help guide physicians in treating patients with SJS/TEN and thereby improve short-term prognosis and the risk of sequelae.

Bronchiolitis obliterans as a long-term sequela of Stevens-Johnson syndrome and toxic epidermal necrolysis in children.

Toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS) are characterized by widespread skin and mucosal blistering and necrosis. The triggers and long-term sequelae in children may differ from those reported for adults. Bronchiolitis obliterans (BO) is an uncommon complication, with only 15 previously reported cases, but can lead to significant long-term morbidity, requiring lung transplantation in some cases. We report three children with nondrug-related SJS (n = 1) and TEN (n = 2) who developed BO. Two were treated with intravenous immunoglobulin therapy (2-2.4 g/kg) and all three survived. We highlight salient learning points from our cases and potential pitfalls in diagnosis of BO, including delayed onset, and we also review the literature.

STAT4 expression and activation is increased during mitosis in vitro and in vivo in skin- and mucosa-derived cell types: implications in neoplastic and inflammatory skin diseases.

BACKGROUND: The signal transducer and activator of transcription-4 (STAT4/Stat4) is a transcription factor known to convey signals from interleukin-12, interleukin-23, and interferon-alpha/beta to the nucleus, resulting in activation of dendritic cells, T-helper cell differentiation and production of interferon-gamma. OBJECTIVE: To demonstrate a novel role for STAT4 in cell mitosis. RESULTS: Phosphoserine STAT4 (pSerSTAT4) is increased in cells undergoing mitosis and is distributed throughout the cytoplasm during this stage of the cell cycle, whilst phosphotyrosine STAT4 (pTyrSTAT4) is confined to the chromosomal compartment. This distinct pattern of pSerSTAT4 during mitosis is seen in vitro in human keratinocytes and in other cell types. This is also present in vivo in cells undergoing mitosis in normal skin, psoriasis and squamous cell carcinoma. Inhibition of STAT4 phosphorylation by lisofylline and depletion of STAT4 by RNA interference results in a delay in progression of mitosis and leads to a reduction in cells completing cytokinesis. CONCLUSION: Our data demonstrate that STAT4 plays a role in enabling the normal and timely division of cells undergoing mitosis.

Limited exposure to ambient ultraviolet radiation and 25-hydroxyvitamin D levels: a systematic review.

Vitamin D can be synthesized following exposure to ultraviolet radiation (UVR), ingested in the diet or provided through oral supplementation. The medical literature frequently states that humans obtain most of their vitamin D from sunshine and that UVR exposure is essential to maintain vitamin D levels. A systematic review was conducted to determine the requirement for UVR in maintaining adequate (> 50 nmol L(-1) ) serum 25-hydroxyvitamin D [25(OH)D] levels. Studies reporting serum 25(OH)D during situations of negligible UVR exposure were sought. Forty-one studies (from a search yielding 42 698 articles) with a total of 4211 healthy adults met the inclusion criteria, providing 56 datasets from different population groups. Over 50% of subjects had > 50 nmol L(-1) 25(OH)D in 10 of 19 datasets reporting winter levels in areas with limited UVR. In addition, > 50% of subjects had adequate 25(OH)D levels in four of 12 datasets from polar regions during periods of negligible UVR, one of nine datasets documenting clothing-related minimal UVR and two of eight datasets detailing employment-related minimal UVR. The data demonstrate that many adults maintain adequate serum vitamin D levels despite negligible UVR exposure for several months. However, we acknowledge that preceding UVR exposure leading to vitamin D storage and delayed release may account for this maintenance of adequate serum vitamin D levels. There remains a need for further research on whether UVR exposure is required for longer-term maintenance of adequate vitamin D levels.

Presence of the HLA-A*3101 allele in a familial case of drug reaction with eosinophilia and systemic symptoms, secondary to carbamazepine.

Anticonvulsants such as carbamazepine and phenytoin are associated with adverse skin reactions ranging from maculopapular exanthems to more severe reactions, including drug reaction with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome and toxic epidermal necrolysis. In addition to their antiepileptic role, anticonvulsants are also used to treat pain syndromes including trigeminal neuralgia. Until recently, the associated skin reactions were thought to be unpredictable; however, the current literature suggests a genetic predisposition involving the human leucocyte antigen (HLA) in cutaneous reactions associated with carbamazepine usage. We present two familial cases of DRESS secondary to carbamazepine, in which an underlying genetic predisposition and allelic association were identified.

Primary cutaneous nodular amyloidosis associated with psoriasis.

Primary cutaneous nodular amyloidosis (PCNA) presents as solitary or multiple firm, waxy nodules with a predilection for acral areas. Histologically, PCNA can be identical to myeloma-associated systemic amyloidosis with monoclonal immunoglobulin light chain deposits. We describe a patient in whom PCNA developed in a scar in an area affected by chronic plaque psoriasis. PCNA has previously been associated with other autoimmune diseases, but to our knowledge, this is the first association with psoriasis. Interestingly, T helper (Th)17 cells, which are crucial in psoriasis pathogenesis, have recently been implicated in promotion of myeloma and plasma cell dyscrasias. The association of psoriasis and plasma-cell light chain production in the skin, as in this case, suggests a possible role for Th17 cells in PCNA formation. The dermatopathological literature of this rare but important disease is discussed.

In vitro diagnostic assays are effective during the acute phase of delayed-type drug hypersensitivity reactions.

BACKGROUND: Previous reports have suggested that drug-specific lymphocyte proliferation assays (LPA) can be used retrospectively to confirm the culprit drug following delayed-type drug hypersensitivity reactions (DHR). However, only limited evidence supports their use in aiding acute clinical management. The aim of this study was to compare the LPA against combination cytokine assays for potential use in the acute setting. METHODS: A total of 43 patients with DHR (19 during the acute reaction, 20 after recovery, four during acute and after recovery) and 14 control subjects without DHR were investigated using ex vivo analysis of drug-specific proliferation, and interferon (IFN)-γ and interleukin (IL)-4 production. RESULTS: Healthy controls showed negative drug-specific proliferation and cytokine release in contrast to individuals with a known sensitivity (P < 0·0001). The assays demonstrated a test specificity of 95% (LPA), 83% (IFN-γ) and 92% (IL-4). The sensitivity of combined measurement of drug-specific IFN-γ and IL-4 cytokines during acute DHR was better than LPA (82% vs. 50%), but all assays were less sensitive during the recovery phase. The correlation between LPA and IFN-γ assays was strong (r = 0·7, P < 0·0001), whereas the IL-4 assay did not correlate as well with either of these assays. In contrast to LPA, drug enzyme-linked immunosorbent spot assays showed positive responses in patients concurrently taking immunosuppressive medication. CONCLUSIONS: In vitro assays of drug-specific IFN-γ and IL-4 production offer potential for use as rapid diagnostic tests. Cytokine detection offers distinct advantages over the LPA, including a shorter assay time, a greater sensitivity and effectiveness in testing immunosuppressed patients.

Treatment outcomes of patients with Atopic Dermatitis (AD) treated with dupilumab through the Early Access to Medicines Scheme (EAMS) in the UK.

BACKGROUND: Dupilumab, a monoclonal antibody against interleukin (IL)-4 receptor alpha that inhibits IL-4/IL-13 signalling is indicated in dermatology for the treatment of moderate-to-severe atopic dermatitis (AD) in adult and adolescent patients 12 years and older and severe AD in children 6-11 years, who are candidates for systemic therapy. Dupilumab received Early Access to Medicines Scheme (EAMS) approval for adults in March 2017. OBJECTIVES: The purpose of this study was to assess the efficacy outcomes of treatment with dupilumab in EAMS. METHODS: A retrospective analysis of adult patients enrolled in the dupilumab EAMS in the UK. Scores were assessed at baseline and follow up, including the Eczema Area and Severity Index (EASI), Investigator's Global Assessment Score (IGA) and Dermatology Life Quality Index (DLQI). RESULTS: Data were available for 57 adult patients treated with dupilumab for at least 12 weeks; 73.6% of patients had received prior treatment with 3 or 4 immunosuppressants. Baseline scores for the EASI and DLQI were 27.93 (standard deviation, SD 13.09) and 18.26 (SD 6.18) respectively. AD severity scores showed statistically significant improvement at week 16±4 weeks (p <0.001 for all). The mean change in EASI was 14.13 points with 66.7% and 36.7% achieving a 50% (EASI-50) and 75% (EASI-75) improvement in EASI, respectively at 16+/- 4 weeks. IGA scores improved by at least two categories for 75% patients. DLQI scores decreased by a mean of 9.0 points, with 80% patients demonstrating a MCID 4-point improvement. For 85% patients, clinicians rated the treatment response as being either 'better' (19%) or 'much better' (65%). CONCLUSIONS: Dupilumab is associated with a significant and clinically relevant improvements in AD as measured by patient- and physician-reported outcome measures. Importantly, the clinical efficacy, despite the refractory disease of this EAMS cohort, is comparable to that previously reported in clinical trials.

An updated report on the incidence and epidemiological trends of keratinocyte cancers in the United Kingdom 2013-2018.

Introduction: The most common cancers in the UK are keratinocyte cancers (KCs): the combined term for basal cell carcinomas (BCCs) and cutaneous squamous cell carcinomas (cSCCs). Registration of KC is challenging due to high numbers and multiplicity of tumours per person. Methods: We provide an updated report on the descriptive epidemiology of trends in KC incidence for the resident populations of UK countries (England, Northern Ireland, Scotland and Wales) using population-based cancer registry and pathology report data, 2013-18. Results: Substantial increases in cSCC incidence in England, Scotland and Northern Ireland can be detected for the period of 2013-18, and the incidence of cSCC also increased in Wales from 2016 to 2018. In contrast, however, the pattern of annual change in the incidence of BCC across the nations differs. In England, the incidence of BCC declined slightly from 2016 to 2018, however, the overall trend across 2013-18 is not statistically significant. In Scotland, the incidence of BCC shows some variability, declining in 2017 before increasing in 2018, and the overall trend across 2013-18 was also not statistically significant. In Northern Ireland, the incidence of BCC increased significantly over the study period, and in Wales, the incidence of BCC increased from 2016 to 2018. One in five people will develop non-melanoma skin cancers (NMSC) in their lifetime in England. This estimate is much higher than the lifetime risk of melanoma (1 in 36 males and 1 in 47 females born after 1960 in the UK), which further highlights the burden of the disease and importance of early prevention strategies. Conclusions: We highlight how common these tumours are by publishing the first ever lifetime incidence of NMSC. Additionally, the first time reporting of the age standardised incidence of KC in Wales further confirms the scale of the disease burden posed by these cancers in the UK. With approximately one in five people developing NMSC in their lifetime, optimisation of skin cancer prevention, management and research are essential.