How Do Experts Treat Patients with Bullous Pemphigoid around the World? An International Survey.

Many treatments are currently proposed for treating patients with bullous pemphigoid (BP). We assessed treatment modalities of BP depending on the different countries, BP extent, and patients' comorbidities. We surveyed worldwide experts about how they treat patients with BP. A total of 61 experts from 27 countries completed the survey. Severe and moderate BP were treated with oral prednisone (61.4 and 53.7%, respectively) or superpotent topical corticosteroids (CSs) (38.6 and 46.3%, respectively). Conventional immunosuppressants were more frequently combined with oral prednisone (74.5%) than with superpotent topical CS (37.5%) in severe BP. Topical CSs were mainly used in Europe in mild (81.1%), moderate (55.3%), and severe (54.3%) BP. In the United States of America and Asia, systemic CSs were mainly proposed for treating severe (77.8 and 100%, respectively), moderate (70 and 77.8%, respectively), and also mild (47.1 and 33.3%, respectively) BP. Most experts reduced the initial dose of oral CS in patients with diabetes mellitus (48.1%) or cardiac insufficiency (40.2%) but rarely changed BP treatment in patients with neurological disorders or neoplasia. This survey showed major differences in the way patients with BP are treated between AmeriPac countries (United State of America, Latin America, and Australia) and Asia on the one hand and Europe and the Middle East on the other hand.

Interrater Reliability of Clinical Grading Measures for Cutaneous Chronic Graft-vs-Host Disease.

Importance: Cutaneous chronic graft-vs-host disease (cGVHD) is common after allogeneic hematopoietic stem cell transplant and is often associated with poor patient outcomes. A reliable and practical method for assessing disease severity and response to therapy among these patients is urgently needed. Objective: To evaluate the interrater agreement and reliability of skin-specific and range of motion (ROM) variables of the 2014 National Institutes of Health (NIH) response criteria for cGVHD and a skin sclerosis grading scale (SSG). Design, Setting, and Participants: In this observational study performed at a single tertiary academic center, 6 academic blood and marrow transplant specialists and 4 medical dermatologists examined 8 patients with diagnosed cutaneous cGVHD on July 10, 2015. The patient cohort was enriched for patients with sclerotic features. Each patient was evaluated by using the skin-specific and ROM criteria of the 2014 NIH response criteria for cGVHD and an SSG ranging from 0 to 3. Each patient was also asked to complete quality-of-life scoring instruments. Interrater agreement and reliability were estimated by calculating the Krippendorff α and Cohen κ statistics. Data were analyzed from September 29, 2015, through November 22, 2018. Main Outcomes and Measures: Estimation of interrater agreement by interclass coefficient (Krippendorff α and Cohen κ statistics) for the skin-specific and ROM components of the 2014 NIH Response Criteria for Chronic GVHD and for the SSG. Results: The median age of the patients evaluated was 54 years (range, 46-58 years). Patients were predominantly male (6 [75%]). Six of the 8 patients had a predominantly sclerotic cutaneous phenotype. Interrater agreement among our experts was acceptable for NIH skin feature score (0.68; 95% CI, 0.30-0.86) and good for NIH ROM scoring (0.80; 95% CI, 0.68-0.86). Dermatologists had acceptable agreement for NIH skin GVHD score (0.69; 95% CI, 0.25-0.82) and skin feature score (0.78; 95% CI, 0.17-0.98), good agreement in ROM grading (0.85; 95% CI, 0.69-0.90), and near perfect agreement in identifying sclerosis (0.82; 95% CI, 0.27-0.97). Conclusions and Relevance: Although dermatologists had acceptable agreement in NIH skin GVHD score and skin features score, near perfect agreement in identifying cutaneous sclerosis, better agreement in grading severity of cutaneous cGVHD, especially in the intermediate grades, appears to be needed.

Serum Interleukin-8, Osteopontin, and Monocyte Chemoattractant Protein 1 Are Associated With Hepatic Fibrosis in Patients With Nonalcoholic Fatty Liver Disease.

The severity of hepatic fibrosis is the primary predictor of liver-related morbidity and mortality in patients with nonalcoholic fatty liver disease (NAFLD). Unfortunately, noninvasive serum biomarkers for NAFLD-associated fibrosis are limited. We analyzed baseline serum samples for 24 cytokines of 97 patients with biopsy-proven NAFLD. These patients were prospectively enrolled in a clinical study (ClinicalTrials.gov NCT00794716) to identify cytokines associated with liver fibrosis in patients with nonalcoholic steatohepatitis. Patients were stratified according to severity of hepatic fibrosis (mild, stage 0-1, n = 37; moderate, stage 2, n = 40; and advanced, stage 3-4, n = 20) while controlling for age, race, sex, body mass index, and diabetes mellitus. Interleukin-8 (IL-8), osteopontin (OPN), and monocyte chemoattractant protein 1 (MCP1) were associated with liver fibrosis (P < 0.001, P = 0.005, P = 0.016, respectively). After controlling for steatosis, lobular inflammation, hepatocyte ballooning, age, sex, body mass index, diabetes mellitus, hypertension, and metabolic syndrome status, IL-8 remained strongly associated with fibrosis (P = 0.001). Furthermore, IL-8 was also a strong predictor of increased fibrotic liver injury compared to established markers of hepatic fibrosis. Hepatic gene expression from 72 patients with NAFLD (n = 40 mild fibrosis; n = 32 advanced fibrosis) from the Duke University Health System NAFLD Clinical Database and Biorepository revealed IL-8, MCP1, and OPN gene expression to be increased and differentially expressed in patients with advanced hepatic fibrosis. Thus, serum IL-8, MCP1, and OPN may reflect up-regulated gene expression during liver fibrosis in NAFLD. Conclusion: Serum IL-8, MCP1, and OPN may serve as a test for advanced hepatic fibrosis in NAFLD and thus reveal novel targets for antifibrotic therapies. The increased serum IL-8, MCP1, and OPN that correspond with associated hepatic gene expression lend strength to such analytes as ideal surrogate serum biomarkers for severity of hepatic fibrosis.

Noninvasive optical spectroscopy for identification of non-melanoma skin cancer: Pilot study.

OBJECTIVE: Optical spectroscopy offers a noninvasive alternative to biopsy as a first-line screening tool for suspicious skin lesions. This study sought to define several optical parameters across malignant and benign tissue types. STUDY DESIGN: Prospective pilot trial utilizing the Zenalux IM1 optical spectroscopy device from April 2016 to February 2017. For each skin lesion, provider pre-biopsy probability of malignancy was compared to histolopathologic diagnosis. Optical data were characterized across basal cell carcinoma (BCC; n = 9), squamous cell carcinoma (SCC; n = 5), actinic keratosis (AK; n = 4), scar tissue (n = 6), nevus (n = 2), and neurofibroma (NF; n = 1). Across all patients, agreement was determined between control measurements collected adjacent to the lesion and from the upper extremity. METHODS: Prospective single center pilot study. The optical properties of 27 cutaneous lesions were collected from 18 adult patients presenting to Otolaryngology and Dermatology clinics with suspicious skin lesions warranting biopsy. Spectroscopy measurements were recorded for each lesion: two at the lesion site, two at an adjacent site (internal control), and one at the central medial upper extremity (arm control). Variables of interest included absolute oxygenated hemoglobin (Hb), Hb saturation, total Hb concentration, and Eumelanin concentration. For each lesion, internal control averages were subtracted from lesion averages to provide delta parameter values, and lesion averages were divided by internal control averages to provide ratio parameter values. RESULTS: Mean percent difference between pre-biopsy probability of malignancy and histology was 29%, with a difference of 75% or greater seen in 5 of 25 lesions. Mean values for BCC, SCC, AK, and scar tissue varied most between extracted mean reduced scatter estimate (µa'; cm- ) delta values (BCC: -2.2 ± 3.8; SCC: -3.9 ± 2.0; AK: -3.3 ± 4.2, Scar: -1.7 ± 1.2) and total Hb (µM) ratio (BCC: 2.0 ± 3.3; SCC: 3.0 ± 1.3; AK: 1.1 ± 0.6; Scar: 1.4 ± 1.1). Agreement between local and arm controls was poor. CONCLUSION: This pilot trial utilizes optical spectroscopy as a noninvasive method for determining cutaneous lesion histology. Effect sizes observed across optical parameters for benign and malignant tissue types will guide larger prospective studies that may ultimately lead to prediction of lesional histology without need for invasive biopsy. Lasers Surg. Med. 50:246-252, 2018. © 2018 Wiley Periodicals, Inc.

Clinical Implications of Direct Immunofluorescence Findings in Patients With Ocular Mucous Membrane Pemphigoid.

PURPOSE: To examine the clinical implications of positive or negative direct immunofluorescence biopsies (DIF) in patients with clinically typical ocular mucous membrane pemphigoid (MMP). DESIGN: Retrospective cohort study. METHODS: The study population was patients with clinically typical ocular MMP disease with documented DIF results who were followed for at least 1 year at the Duke University multidisciplinary ocular MMP clinic. Data were collected by chart review and included patient demographics, clinical examination findings, and history of autoimmune disease and/or malignancy, as well as topical, systemic, and surgical treatments received. Main outcome measures included MMP Disease Area Index, Foster stages, proportion legally blind, duration of follow-up, and use of systemic immunosuppression and ocular procedures in treatment. RESULTS: In multivariable analysis restricted to 55 patients, patients with negative and positive biopsies were similar in the outcome measures; however, positive-biopsy patients were more likely to be treated with systemic immunosuppression and were followed for longer at our clinic. Patients with isolated ocular disease were also more likely to have negative biopsies compared to those who also had extraocular disease. Patients who had conjunctival biopsies were more likely to have a negative direct immunofluorescence result than patients with biopsies from other sites. CONCLUSIONS: We encourage clinicians and patients to consider treatment with systemic immunosuppression even in the absence of diagnosis confirmation by DIF. Furthermore, this study supports current standard of care to pursue a nonocular biopsy of normal-appearing, perilesional skin or oral mucosa when possible.

TRPV4 Moves toward Center-Fold in Rosacea Pathogenesis.

Mascarenhas et al. report that TRPV4 expression is upregulated in mast cells in response to the proteolytic cathelicidin fragment LL37 in a murine rosacea model and that TRPV4 loss of function attenuates mast cell degranulation. These findings render TRPV4 a translational-medical target in rosacea. However, signaling mechanisms causing increased expression of TRPV4 await elucidation. Moreover, we ask whether TRPV4-mediated Ca++-influx evokes mast cell degranulation.

KIND1 Loss Sensitizes Keratinocytes to UV-Induced Inflammatory Response and DNA Damage.

Loss of function of KIND1, a cytoskeletal protein involved in ß1-integrin function, causes Kindler syndrome, a genetic disease characterized by skin fragility, photosensitivity, and increased risk of squamous cell carcinoma. Dysregulation of ß1-integrin underlies Kindler syndrome skin fragility. However, the mechanisms underlying squamous cell carcinoma susceptibility are unclear. Here, we demonstrate that gene silencing of KIND1 decreased keratinocyte proliferation and increased apoptosis in vitro and in skin grafts regenerated on mice, which was correlated with reduced cyclinB1. In addition, KIND1 loss sensitized keratinocytes to cytokine and UV-induced NF-κB and c-Jun N-terminal kinase activation and upregulation of CXCL10 and tumor necrosis factor-α. Moreover, KIND1 loss impaired DNA repair, as indicated by the increased detection of γH2AX and cyclobutane pyrimidine dimers 24 hours after UVB radiation. Genetic or pharmacological c-Jun N-terminal kinase inhibition and NF-κB inhibition markedly reduced cyclobutane pyrimidine dimers-positive cells. Further, we show that KIND1 was regulated by JunB at the transcriptional level and, like JunB, it was downregulated in human squamous cell carcinoma cells. Together, these results indicate that KIND1 is important not only for keratinocyte proliferation but also for the suppression of UV-induced inflammation and DNA damage. These latter findings support a tumor suppressor function for KIND1, and identify c-Jun N-terminal kinase and NF-κB as potential therapeutic targets for prevention of squamous cell carcinoma in patients with Kindler syndrome.

Redefining the roles of apoptotic factors in carcinogenesis.

In a recent study we reported that mammalian cells exposed to stress such as ionizing radiation can survive with activation of caspase-3 or caspase-7. We found that sublethal activation of the executioner caspases promotes chemical- and radiation-induced genetic instability and carcinogenesis, in contrast to their perceived roles as tumor suppressors.

Transient Receptor Potential Vanilloid 4 Ion Channel Functions as a Pruriceptor in Epidermal Keratinocytes to Evoke Histaminergic Itch.

TRPV4 ion channels function in epidermal keratinocytes and in innervating sensory neurons; however, the contribution of the channel in either cell to neurosensory function remains to be elucidated. We recently reported TRPV4 as a critical component of the keratinocyte machinery that responds to ultraviolet B (UVB) and functions critically to convert the keratinocyte into a pain-generator cell after excess UVB exposure. One key mechanism in keratinocytes was increased expression and secretion of endothelin-1, which is also a known pruritogen. Here we address the question of whether TRPV4 in skin keratinocytes functions in itch, as a particular form of "forefront" signaling in non-neural cells. Our results support this novel concept based on attenuated scratching behavior in response to histaminergic (histamine, compound 48/80, endothelin-1), not non-histaminergic (chloroquine) pruritogens in Trpv4 keratinocyte-specific and inducible knock-out mice. We demonstrate that keratinocytes rely on TRPV4 for calcium influx in response to histaminergic pruritogens. TRPV4 activation in keratinocytes evokes phosphorylation of mitogen-activated protein kinase, ERK, for histaminergic pruritogens. This finding is relevant because we observed robust anti-pruritic effects with topical applications of selective inhibitors for TRPV4 and also for MEK, the kinase upstream of ERK, suggesting that calcium influx via TRPV4 in keratinocytes leads to ERK-phosphorylation, which in turn rapidly converts the keratinocyte into an organismal itch-generator cell. In support of this concept we found that scratching behavior, evoked by direct intradermal activation of TRPV4, was critically dependent on TRPV4 expression in keratinocytes. Thus, TRPV4 functions as a pruriceptor-TRP in skin keratinocytes in histaminergic itch, a novel basic concept with translational-medical relevance.

Use of Drawing Lithography-Fabricated Polyglycolic Acid Microneedles for Transdermal Delivery of Itraconazole to a Human Basal Cell Carcinoma Model Regenerated on Mice.

Itraconazole is a triazole agent that is routinely used for treatment of nail infections and other fungal infections. Recent studies indicate that itraconazole can also inhibit the growth of basal cell carcinoma (BCC) through suppression of the Sonic Hedgehog (SHH) signaling pathway. In this study, polyglycolic acid microneedle arrays and stainless steel microneedle arrays were used for transdermal delivery of itraconazole to a human BCC model which was regenerated on mice. One-by-four arrays of 642-µm-long polyglycolic acid microneedles with sharp tips were prepared using injection molding and drawing lithography. Arrays of 85 stainless steel 800-µm-tall microneedles attached to syringes were obtained for comparison purposes. Skin grafts containing devitalized split-thickness human dermis that had been seeded with human keratinocytes transduced to express human SHH protein were sutured to the skin of immunodeficient mice. Mice with this human BCC model were treated daily for 2 weeks with itraconazole dissolved in 60% dimethylsulfoxane and 40% polyethylene glycol-400 solution; transdermal administration of the itraconazole solution was facilitated by either four 1 × 4 polyglycolic acid microneedle arrays or stainless steel microneedle arrays. The epidermal tissues treated with polyglycolic acid microneedles or stainless steel microneedles were markedly thinner than that of the control (untreated) graft tissue. These preliminary results indicate that microneedles may be used to facilitate transdermal delivery of itraconazole for localized treatment of BCC.

Inflammation Markers and Major Depressive Disorder in Patients With Chronic Heart Failure: Results From the Sertraline Against Depression and Heart Disease in Chronic Heart Failure Study.

BACKGROUND: Major depressive disorder (MDD) and chronic heart failure (CHF) have in common heightening states of inflammation, manifested by elevated inflammation markers such as C-reactive protein. This study compared inflammatory biomarker profiles in patients with CHF and MDD to those without MDD. METHODS: The study recruited patients admitted to inpatient care for acute heart failure exacerbations, after psychiatric diagnostic interview. Patients with Beck Depression Inventory (BDI) scores lower than 10 and with no history of depression served as the nondepressed reference group (n = 25). MDD severity was defined as follows: mild (BDI 10-15; n = 48), moderate (BDI 16-23; n = 51), and severe (BDI ≥ 24; n = 33). A Bio-Plex assay measured 18 inflammation markers. Ordinal logistic models were used to examine the association of MDD severity and biomarker levels. RESULTS: Adjusting for age, sex, statin use, body mass index, left ventricular ejection fraction, tobacco use, and New York Heart Association class, the MDD overall group variable was significantly associated with elevated interleukin (IL)-2 (p = .019), IL-4 (p = .020), IL-6 (p = .026), interferon-γ (p = .010), monocyte chemoattractant protein 1 (p = .002), macrophage inflammatory protein 1ß (p = .003), and tumor necrosis factor α (p = .004). MDD severity subgroups had a greater probability of elevated IL-6, IL-8, interferon-γ, monocyte chemoattractant protein 1, macrophage inflammatory protein 1ß, and tumor necrosis factor α compared with nondepressed group. The nondepressed group had greater probability of elevated IL-17 (p < .001) and IL-1ß (p < .01). CONCLUSIONS: MDD in patients with CHF was associated with altered inflammation marker levels compared with patients with CHF who had no depression. Whether effective depression treatment will normalize the altered inflammation marker levels requires further study. TRIAL REGISTRATION: ClinicalTrials.gov NCT00078286.

Caspase-3 promotes genetic instability and carcinogenesis.

Apoptosis is typically considered an anti-oncogenic process since caspase activation can promote the elimination of genetically unstable or damaged cells. We report that a central effector of apoptosis, caspase-3, facilitates rather than suppresses chemical- and radiation-induced genetic instability and carcinogenesis. We found that a significant fraction of mammalian cells treated with ionizing radiation can survive despite caspase-3 activation. Moreover, this sublethal activation of caspase-3 promoted persistent DNA damage and oncogenic transformation. In addition, chemically induced skin carcinogenesis was significantly reduced in mice genetically deficient in caspase-3. Furthermore, attenuation of EndoG activity significantly reduced radiation-induced DNA damage and oncogenic transformation, identifying EndoG as a downstream effector of caspase-3 in this pathway. Our findings suggest that rather than acting as a broad inhibitor of carcinogenesis, caspase-3 activation may contribute to genome instability and play a pivotal role in tumor formation following damage.

RNA-Seq and ChIP-Seq reveal SQSTM1/p62 as a key mediator of JunB suppression of NF-κB-dependent inflammation.

Mice with epidermal deletion of JunB transcription factor displayed a psoriasis-like inflammation. The relevance of these findings to humans and the mechanisms mediating JunB function are not fully understood. Here we demonstrate that impaired JunB function via gene silencing or overexpression of a dominant negative mutant increased human keratinocyte cell proliferation but decreased cell barrier function. RNA-seq revealed over 500 genes affected by JunB loss of function, which included the upregulation of an array of proinflammatory molecules relevant to psoriasis. Among these were tumor necrosis factor α (TNFα), CCL2, CXCL10, IL6R, and SQSTM1, an adaptor protein involved in nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation. Chromatin immunoprecipitation (ChIP)-Seq and gene reporter analyses showed that JunB directly suppressed SQSTM1 by binding to a consensus AP-1 cis element located around 2 kb upstream of SQSTM1-transcription start site. Similar to JunB loss of function, SQSTM1-overexpression induced TNFα, CCL2, and CXCL10. Conversely, NF-κB inhibition genetically with a mutant IκBα or pharmacologically with pyrrolidine dithiocarbamate (PDTC) prevented cytokine, but not IL6R, induction by JunB deficiency. Taken together, our findings indicate that JunB controls epidermal growth, barrier formation, and proinflammatory responses through direct and indirect mechanisms, pinpointing SQSTM1 as a key mediator of JunB suppression of NF-κB-dependent inflammation.

Keratinocyte growth regulation TRP-ed up over downregulated TRPV4?

This commentary on an exciting new study (Fusi et al., 2014) puts the finding of TRPV4 downregulation in several nonmelanoma skin cancers into context. The original paper point toward possible use of TRPV4 as dermatopathologic marker, also toward the possibility that downregulated TRPV4 can affect biological properties of the cancer, by enhancing, but also regulating tumor growth. As calcium-permeable TRPV4 has recently been identified as UVB-receptor in skin keratinocytes, where it regulates skin tissue injury and pain after UVB overexposure, it is discussed whether TRPV4 downregulation can also be found in other non-UVB-exposed cancers.

CYLD inhibits melanoma growth and progression through suppression of the JNK/AP-1 and ß1-integrin signaling pathways.

The molecular mechanisms mediating cylindromatosis (CYLD) tumor suppressor function appear to be manifold. Here, we demonstrate that, in contrast to the increased levels of phosphorylated c-Jun NH(2)-terminal kinase (pJNK), CYLD was decreased in a majority of the melanoma cell lines and tissues examined. Exogenous expression of CYLD but not its catalytically deficient mutant markedly inhibited melanoma cell proliferation and migration in vitro and subcutaneous tumor growth in vivo. In addition, the melanoma cells expressing exogenous CYLD were unable to form pulmonary tumor nodules following tail-vein injection. At the molecular level, CYLD decreased ß1-integrin and inhibited pJNK induction by tumor necrosis factor-α or cell attachment to collagen IV. Moreover, CYLD induced an array of other molecular changes associated with modulation of the "malignant" phenotype, including a decreased expression of cyclin D1, N-cadherin, and nuclear Bcl3, and an increased expression of p53 and E-cadherin. Most interestingly, coexpression of the constitutively active MKK7 or c-Jun mutants with CYLD prevented the above molecular changes, and fully restored melanoma growth and metastatic potential in vivo. Our findings demonstrate that the JNK/activator protein 1 signaling pathway underlies the melanoma growth and metastasis that are associated with CYLD loss of function. Thus, restoration of CYLD and inhibition of JNK and ß1-integrin function represent potential therapeutic strategies for treatment of malignant melanoma.

Pathophysiology of dermatitis herpetiformis: a model for cutaneous manifestations of gastrointestinal inflammation.

Dermatitis herpetiformis (DH) is an autoimmune blistering skin disease in which antigen presentation in the gastrointestinal mucosa results in cutaneous IgA deposition and distinct, neutrophil-driven cutaneous lesions. Our findings suggest that the qualitatively different immune response to gluten in the intestinal mucosa of patients with DH results in minimal clinical symptoms, allowing the continued ingestion of gluten and the eventual development of DH. Our model may provide a new way to understand the pathogenesis of other skin diseases associated with gastrointestinal inflammation such as pyoderma gangrenosum or erythema nodosum, or explain association of seronegative inflammatory arthritis with inflammatory bowel disease.

Management of dermatitis herpetiformis.

The major treatment strategies for DH are gluten restriction or medical treatment with sulfones. Control of the cutaneous manifestations, but not the gastrointestinal changes, is rapid with dapsone. In addition to control of the cutaneous signs and symptoms of DH, dietary gluten restriction also induces improvement of gastrointestinal morphology and is possibly protective against the development of lymphoma.

Tretinoin and the prevention of keratinocyte carcinoma (Basal and squamous cell carcinoma of the skin): a veterans affairs randomized chemoprevention trial.

Keratinocyte carcinoma (KC) is the most common cancer in the United States, with no proven means for prevention other than systemic retinoids, which have significant toxicity, and sunscreen. Topical tretinoin has been used for KC chemoprevention, although this use is unproven. Hence, we conducted the randomized Veterans Affairs Topical Tretinoin Chemoprevention Trial of high-dose topical tretinoin for KC prevention. We randomized 1,131 patients to topical 0.1% tretinoin or a matching vehicle control for 1.5-5.5 years. The primary outcomes were time to development of new basal cell carcinoma (BCC) and new invasive squamous cell carcinoma (SCC) on the face or ears. The effects were not significant (P=0.3 for BCC and P=0.4 for SCC). The proportions of the tretinoin and control groups who developed a BCC at 5 years were 53 and 54% and an invasive SCC at 5 years were 28 and 31%. These differences (95% confidence intervals) were: for BCC, 1.0% (-6.5, 8.6%); for SCC, 3.6% (-3.1, 10.3%). No differences were observed in any cancer-related end points or in actinic keratosis counts. The only quality of life difference was worse symptoms in the tretinoin group at 12 months after randomization. This trial in high-risk patients demonstrates that high-dose topical tretinoin is ineffective at reducing risk of KCs.