New human in vitro co-culture model of keratinocytes and sensory neurons like cells releasing substance P with an evaluation of the expression of ZIKV entry receptors: A potent opportunity to test Zika virus entry and to study Zika virus' infection in neurons?

During the course of acute ZIKV infection, pruritus is a cardinal symptom widely documented in the literature. Its frequent association with dysesthesia and several dysautonomic manifestations, suggests a pathophysiological mechanism involving the peripheral nervous system. The aim of this study was to develop a functional human model to potentially able to be infected by ZIKV: by demonstrating the functionality on a new human model of co-culture of keratinocyte and sensory neuron derived from induced pluripotent stem cells using a classical method of capsaicin induction and SP release, and verify the presence of ZIKV entry receptor in these cells. Depending of cellular type, receptors of the TAMs family, TIMs (TIM1, TIM3 and TIM4) and DC-SIGN and RIG1 were present/detected. The cells incubations with capsaicin resulted in an increase of the substance P. Hence, this study demonstrated the possibility to obtain co-cultures of human keratinocytes and human sensory neurons that release substance P in the same way than previously published in animal models which can be used as a model of neurogenic skin inflammation. The demonstration of the expression of ZIKV entry receptors in these cells allows to considerate the potent possibility that ZIKV is able to infect cells.

Anti-SAE autoantibody in dermatomyositis: original comparative study and review of the literature.

OBJECTIVE: Among specific autoantibodies in DM, the anti-small ubiquitin-like modifier activating enzyme (SAE) antibody is rare. We aim to describe the clinical characteristics, cancer prevalence, and muscle pathology of anti-SAE-positive DM. METHODS: Patients with a diagnosis of DM and sera positive for the anti-SAE antibody were recruited from 19 centres in this retrospective observational study. The available muscular biopsies were reviewed. We conducted a comparison with anti-SAE-negative DM and a review of the literature. RESULTS: Of the patients in the study (n = 49), 84% were women. Skin involvement was typical in 96% of patients, with 10% having calcinosis, 18% ulceration and 12% necrosis; 35% presented with a widespread skin rash. Muscular disease affected 84% of patients, with mild weakness [Medical Research Council (MRC) scale 4 (3, 5)], although 39% of patients had dysphagia. Muscular biopsies showed typical DM lesions. Interstitial lung disease was found in 21% of patients, mainly with organizing pneumonia pattern, and 26% of patients showed dyspnoea. Cancer-associated myositis was diagnosed in 16% of patients and was responsible for the majority of deaths, its prevalence being five times that of the general population. IVIG therapy was administered to 51% of the patients during the course of the disease. Comparison with anti-SAE-negative DM (n = 85) showed less and milder muscle weakness (P = 0.02 and P = 0.006, respectively), lower creatinine kinase levels (P < 0.0001) and less dyspnoea (P = 0.003). CONCLUSION: Anti-SAE positive DM is a rare subgroup associated with typical skin features but a potentially diffuse rash, a mild myopathy. Interstitial lung disease defines an organizing pneumonia pattern. Cancer associated DM prevalence is five times that of the general population. TRIAL REGISTRATION: ClinicalTrials.gov, http://clinicaltrials.gov, NCT04637672.

Ocular sequelae of epidermal necrolysis: French national audit of practices, literature review and proposed management.

Stevens-Johnson Syndrome (SJS) and toxic epidermal necrolysis (TEN) are serious and rare diseases, most often drug-induced, and their incidence has been estimated at 6 cases/million/year in France. SJS and TEN belong to the same spectrum of disease known as epidermal necrolysis (EN). They are characterized by more or less extensive epidermal detachment, associated with mucous membrane involvement, and may be complicated during the acute phase by fatal multiorgan failure. SJS and TEN can lead to severe ophthalmologic sequelae. There are no recommendations for ocular management during the chronic phase. We conducted a national audit of current practice in the 11 sites of the French reference center for toxic bullous dermatoses and a review of the literature to establish therapeutic consensus guidelines. Ophthalmologists and dermatologists from the French reference center for epidermal necrolysis were asked to complete a questionnaire on management practices in the chronic phase of SJS/TEN. The survey focused on the presence of a referent ophthalmologist at the center, the use of local treatments (artificial tears, corticosteroid eye drops, antibiotic-corticosteroids, antiseptics, vitamin A ointment (VA), cyclosporine, tacrolimus), the management of trichiatic eyelashes, meibomian dysfunction, symblepharons, and corneal neovascularization, as well as the contactologic solutions implemented. Eleven ophthalmologists and 9 dermatologists from 9 of the 11 centers responded to the questionnaire. Based on questionnaire results, 10/11 ophthalmologists systematically prescribed preservative-free artificial tears, and 11/11 administered VA. Antiseptic or antibiotic eye drops or antibiotic-corticosteroid eye drops were recommended as needed by 8/11 and 7/11 ophthalmologists, respectively. In case of chronic inflammation, topical cyclosporine was consistently proposed by 11/11 ophthalmologists. The removal of trichiatic eyelashes was mainly performed by 10/11 ophthalmologists. Patients were referred to a reference center for fitting of scleral lenses (10/10,100%). Based on this practice audit and literature review, we propose an evaluation form to facilitate ophthalmic data collection in the chronic phase of EN and we also propose an algorithm for the ophthalmologic management of ocular sequelae.

Anti-BP180 IgG antibody ELISA values correlate with adverse pregnancy outcomes in pemphigoid gestationis.

BACKGROUND: Adverse pregnancy outcomes (APO) occur in 35% of patients with pemphigoid gestationis (PG). No biological predictor of APO has been established yet. OBJECTIVES: To assess a potential relationship between the occurrence of APO and the serum value of anti-BP180 antibodies at the time of PG diagnosis. METHODS: Multicentre retrospective study conducted from January 2009 to December 2019 in 35 secondary and tertiary care centres. INCLUSION CRITERIA: (i) diagnosis of PG according to clinical, histological and immunological criteria, (ii) ELISA measurement of anti-BP180 IgG antibodies determined at the time of PG diagnosis with the same commercial kit and (iii) obstetrical data available. RESULTS: Of the 95 patients with PG included, 42 had one or more APO, which mainly corresponded to preterm birth (n = 26), intrauterine growth restriction (IUGR) (n = 18) and small weight for gestational age at birth (n = 16). From a ROC curve, we identified a threshold of 150 IU ELISA value as the most discriminating to differentiate between patients with or without IUGR, with 78% sensitivity, 55% specificity, 30% positive and 91% negative predictive value. The threshold >150 IU was confirmed using a cross-validation based on bootstrap resampling, which showed that the median threshold was 159 IU. Upon adjusting for oral corticosteroid intake and main clinical predictors of APO, an ELISA value of >150 IU was associated with the occurrence of IUGR (OR = 5.11; 95% CI: 1.48-22.30; p = 0.016) but not with any other APO. The combination of blisters and ELISA values higher than 150 IU led to a 2.4-fold higher risk of all-cause APO (OR: 10.90; 95% CI: 2.33-82.3) relative to patients with blisters but lower values of anti-BP180 antibodies (OR of 4.54; 95% CI 0.92-34.2). CONCLUSION: These findings suggest that anti-BP180 antibody ELISA value in combination with clinical markers is helpful in managing the risk of APO, in particular IUGR, in patients with PG.

Anti-transcription intermediary factor 1-gamma IgG2 isotype is associated with cancer in adult dermatomyositis: an ENMC multinational study.

OBJECTIVE: To assess the role of the anti-TIF1γ auto-antibody (aAb) IgG2 isotype as a biomarker of cancer in anti-TIF1γ aAb-positive adult DM. METHODS: International multicentre retrospective study with the following inclusion criteria: (i) diagnosis of DM according to ENMC criteria; (ii) presence of anti-TIF1γ IgG aAb determined using an in-house addressable laser bead immunoassay (ALBIA) from cryopreserved serums sampled at time of DM diagnosis and (iii) available baseline characteristics and follow-up data until the occurrence of cancer and/or a minimum follow-up of 1 year for patients without known cancer at diagnosis. Detection and quantification of anti-TIF1γ IgG2 aAb was done using the in-house ALBIA. In addition, a recent ELISA commercial kit was used for anti-TIF1γ IgG aAb quantification. RESULTS: A total of 132 patients (mean age 55±15 years) of whom 72 (54.5%) had an associated cancer were analysed. The association between the presence of cancer and the presence of anti-TIF1γ IgG2 aAb was statistically significant (P = 0.026), with an OR of 2.26 (95% CI: 1.10, 4.76). Patients with cancer displayed significantly higher anti-TIF1γ IgG2 aAb ALBIA values with a median value of 1.15 AU/ml (IQR: 0.14-9.76) compared with 0.50 AU/ml (IQR: 0.14-1.46) for patients without cancer (P = 0.042). In addition, patients with cancer displayed significantly higher anti-TIF1γ IgG aAb ELISA values with a median value of 127.5 AU/ml (IQR: 81.5-139.6) compared with 93.0 AU/ml (IQR: 54.0-132.9) for patients without cancer (P = 0.004). CONCLUSION: These results suggest considering anti-TIF1γ IgG2 ALBIA and IgG ELISA values as biomarkers of cancer in anti-TIF1 γ aAb-positive adult DM.

Real-life impact of immunologic tests to predict relapse after treatment cessation in patients with bullous pemphigoid: A French multicenter retrospective study.

BACKGROUND: A high level of anti-BP180 antibodies on enzyme-linked immunosorbent assay and a persistent positive direct immunofluorescence at the end of treatment (immunologic tests, [ITs]) are predictors of relapse after treatment cessation (TC) in patients with bullous pemphigoid. OBJECTIVE: To evaluate the real-life impact of the immunologic-based decision of TC on the 3- and 6-month relapse rates after TC in bullous pemphigoid. METHODS: Retrospective multicentric study included patients followed almost 6 months after TC. Patients were classified according to whether the TC decision was in accordance with the results of ITs performed during the 3 months before TC, despite the results of ITs or without ITs performed. RESULTS: We included 238 patients. Three months after TC, 36 patients showed relapse: 14 of 95 patients with TC in accordance with IT results (14.7%); 5 of 21 with TC despite ITs (23.8%); and 17 of 122 with TC without ITs (13.9%; P = .5). Six months after TC, the relapse rate was 18.9%, 28.6%, and 18.9% (P = .56), respectively, in the 3 groups. LIMITATIONS: The retrospective design and the limited follow up. CONCLUSION: In real-life practice, in bullous pemphigoid, the 3- and 6-month relapse rates were not significantly reduced with TC decision based on results of ITs as compared with a classic clinical-based decision.

Human host genetics and susceptibility to ZIKV infection.

Managing emerging infectious diseases is a current challenge in the fields of microbiology and epidemiology. Indeed, among other environmental and human-related factors, climate change and global warming favor the emergence of new pathogens. The recent Zika virus (ZIKV) epidemic, of which the large and rapid spread surprised the scientific community, is a reminder of the importance to study viruses currently responsible for sporadic infections. Increasing our knowledge of key factors involved in emerging infections is essential to implement specific monitoring that can be oriented according to the pathogen, targeted population, or at-risk environment. Recent technological developments, such as high-throughput sequencing, genome-wide association studies and CRISPR screenings have allowed the identification of human single nucleotide polymorphisms (SNPs) involved in infectious disease outcome. This review focuses on the human genetic host factors that have been identified and shown to be associated with the pathogenesis of ZIKV infection and candidate SNP targets.

TRIM33 gene somatic mutations identified by next generation sequencing in neoplasms of patients with anti-TIF1γ positive cancer-associated dermatomyositis.

OBJECTIVE: To deep sequence the TRIM33 gene in tumours from patients with cancer-associated anti-TIF1γ autoantibody-positive dermatomyositis (DM) as TRIM33 somatic mutations in tumours may trigger this auto-immune disease. METHODS: Next generation sequencing of tumour DNA samples from patients with cancer-associated anti-TIF1γ autoantibody-positive DM. Fourteen tumours from 13 anti-TIF1γ autoantibody-positive DM individuals were sequenced along with two control tumours from non-DM individuals. RESULTS: Fourteen probable somatic variants from four tumours were identified in the TRIM33 gene. CONCLUSION: These results are in accordance with the previous report of Pinal-Fernandez et al. and support the hypothesis of a role of TRIM33 gene mutations in the pathophysiology of anti-TIF1γ autoantibody-positive DM.

Experimental Assessment of Zika Virus Mechanical Transmission by Aedes Aegypti.

The pandemic emergence of several mosquito-borne viruses highlights the need to understand the different ways in which they can be transmitted by vectors to human hosts. In this study, we evaluated the propensity of Aedes aegypti to transmit mechanically Zika virus (ZIKV) using an experimental design. Mosquitoes were allowed to feed on ZIKV-infected blood and were then rapidly transferred to feed on ZIKV-free blood until they finished their meal. The uninfected blood meals, the mosquito abdomens, as well as the mouthparts dissected from fully and partially engorged mosquitoes were analyzed using RT-qPCR and/or virus titration. All the fully engorged mosquito abdomens were ZIKV-infected, whereas their mouthparts were all ZIKV-negative. Nonetheless, one of the partially engorged mosquitoes carried infectious particles on mouthparts. No infectious virus was found in the receiver blood meals, while viral RNA was detected in 9% of the samples (2/22). Thus, mechanical transmission of ZIKV may sporadically occur via Ae. aegypti bite. However, as the number of virions detected on mouthparts (2 particles) is not sufficient to induce infection in a naïve host, our results indicate that mechanical transmission does not impact ZIKV epidemiology.

The IgG2 Isotype of Anti-Transcription Intermediary Factor 1γ Autoantibodies Is a Biomarker of Cancer and Mortality in Adult Dermatomyositis.

OBJECTIVE: Anti-transcription intermediary factor 1γ (anti-TIF1γ) antibodies are the main predictors of cancer in dermatomyositis (DM). Yet, a substantial proportion of anti-TIF1γ-positive DM patients do not develop cancer. This study was undertaken to identify biomarkers to better evaluate the risk of cancer and mortality in DM. METHODS: This multicenter study was conducted in adult anti-TIF1γ-positive DM patients from August 2013 to August 2017. Anti-TIF1γ autoantibody levels and IgG subclasses were identified using a newly developed quantitative immunoassay. Age, sex, DM signs and activity, malignancy, and creatine kinase (CK) level were recorded. Risk factors were determined by univariate and multivariate analysis according to a Cox proportional hazards regression model. RESULTS: Among the 51 adult patients enrolled (mean ± SD age 61 ± 17 years; ratio of men to women 0.65), 40 (78%) had cancer and 21 (41%) died, with a mean ± SD survival time of 10 ± 6 months. Detection of anti-TIF1γ IgG2 was significantly associated with mortality (P = 0.0011) and occurrence of cancer during follow-up (P < 0.0001), with a 100% positive predictive value for cancer when the mean fluorescence intensity of anti-TIF1γ IgG2 was >385. None of the patients developed cancer after 24 months of follow-up. Univariate survival analyses showed that mortality was also associated with age >60 years (P = 0.0003), active DM (P = 0.0042), cancer (P = 0.0031), male sex (P = 0.011), and CK level >1,084 units/liter (P = 0.005). Multivariate analysis revealed that age >60 years (P = 0.015) and the presence of anti-TIF1γ IgG2 (P = 0.048) were independently associated with mortality. CONCLUSION: Our findings indicate that anti-TIF1γ IgG2 is a potential new biomarker of cancer that should be helpful in identifying the risk of mortality in anti-TIF1γ-positive DM patients.

Use of Anti-transcriptional Intermediary Factor-1 Gamma Autoantibody in Identifying Adult Dermatomyositis Patients with Cancer: A Systematic Review and Meta-analysis.

Anti-transcriptional intermediary factor-1γ (TIF-1γ) autoantibody may be associated with cancer in adult patients with dermatomyositis. The aim of this study was to evaluate the risk of cancer in the presence of anti-TIF-1γ autoantibody in adult dermatomyositis. A comprehensive database search of EMBASE, MEDLINE and the Cochrane Library up to May 2018 was performed using the main key words "dermatomyositis", ""myositis", "inflammatory myopathies" and "anti-TIF-1". Eighteen studies, with a total of 1,962 dermatomyositis, were included in the meta-analysis. The pooled prevalence of cancer-associated dermatomyositis in patients with anti-TIF-1γ autoantibody was 0.41 (95% confidence interval (CI) 0.36-0.45). In the presence of anti-TIF-1γ autoantibody, the overall diagnostic odds ratio of cancer was 9.37 (95% CI 5.37-16.34) with low heterogeneity (Cochran's Q: 14.88 (df = 17, p = 0.604); I2 = 0%). The results of this systematic review confirm that detection of anti-TIF-1γ autoantibody is a valuable tool to identify a subset of adult dermatomyositis patients with higher risk of cancer.

Dermatomyositis and Immune-Mediated Necrotizing Myopathies: A Window on Autoimmunity and Cancer.

Autoimmune myopathies (myositides) are strongly associated with malignancy. The link between myositis and cancer, originally noticed by Bohan and Peter in their classification in 1975 (1), has been evidenced by large population-based cohort studies and a recent meta-analysis. The numerous reports of cases in which the clinical course of myositis reflects that of cancer and the short delay between myositis and cancer onset support the notion that myositis may be an authentic paraneoplastic disorder. Thus, cancer-associated myositis raises the question of cancer as a cause rather than a consequence of autoimmunity. Among myositides, dermatomyositis and more recently, although to a lesser extent, immune-mediated necrotizing myopathies are the most documented forms associated with cancer. Interestingly, the current diagnostic approach for myositis is based on the identification of specific antibodies where each antibody determines specific clinical features and outcomes. Recent findings have shown that the autoantibodies anti-TIF1γ, anti-NXP2 and anti-HMGCR are associated with cancers in the course of myositis. Herein, we highlight the fact that the targets of these three autoantibodies involve cellular pathways that intervene in tumor promotion and we discuss the role of cancer mutations as autoimmunity triggers in adult myositis.