Sun exposure and protection habits: Self-reported attitudes, knowledge and behaviours.

BACKGROUND: As exposure to UV radiation is the primary modifiable environmental risk factor associated with skin cancer, it remains the principal focus of most prevention strategies. Numerous sun protection campaigns have been implemented worldwide; however, their impact on the actual incidence and mortality rates of skin cancer seems to be limited. To create successful skin cancer prevention campaigns, it is important to have a comprehensive understanding of individuals' attitudes and behaviours regarding sun protection. The aim of the current study was to determine and report on the prevalence of self-reported attitudes, knowledge and behaviours regarding two of the major sun protection recommendations-avoidance of sun exposure and use of sunscreens-in an international representative sample across five continents. METHODS: This cross-sectional study was conducted in 20 countries using a web-based online survey. FINDINGS: A total of 50,552 individuals, comprising 25,388 men (50.22%) and 25,164 women (49.78%), participated in the survey. Among them, 83.2% reported having been voluntarily exposed to the sun (for sun-basking reasons) at least once in the last 12 months, and 47.96% acknowledged being exposed to the sun between the hours of 10 AM and 4 PM. The primary reason for non-adherence was that these hours were the most convenient times (32.28%). Only 24.05% reported applying sunscreen every 2 h when outdoors. Forgetfulness was the primary reason as provided by 27.79% of participants. Males and older age groups were less likely to adopt sun-protective behaviours around the world. Forgetfulness and the challenges posed by time constraints seem to be the biggest barriers to proper adherence. INTERPRETATION: These findings should prompt the collaboration with health authorities and the manufacturers to enhance adherence by setting reasonable sunscreen prices and creating formulations that make their application less burdensome.

Whole-Body Positron Emission Tomography with 18F-Fluorodeoxyglucose/Magnetic Resonance Imaging as a Screening Tool for the Detection of Malignant Transformation in Individuals with Neurofibromatosis Type 1.

Malignant peripheral nerve sheath tumors (MPNSTs) are the leading cause of death in patients with neurofibromatosis type 1. They can result from premalignant neurofibromas, including neurofibromas with atypia and atypical neurofibromatous neoplasms of uncertain biologic potential. Some phenotypic characteristics have been described as associated with their development. The aim of this study was to outline our use of whole-body positron emission tomography with 18F-fluorodeoxyglucose/magnetic resonance imaging in adults with neurofibromatosis type 1, especially in the screening of asymptomatic individuals with a higher risk of developing an MPNST, and to study its impact on neurofibroma classification (malignant vs premalignant) and MPNST staging over time. Individuals with neurofibromatosis type 1 who underwent a positron emission tomography with 18F-fluorodeoxyglucose/magnetic resonance imaging between 2017 and 2021 were included, analyzing separately the screened population. Maximum standard uptake value and diffusion-weighted imaging were assessed. Biopsy/surgery confirmed the diagnosis. In all, 345 positron emission tomography with 18F-fluorodeoxyglucose/magnetic resonance imaging were performed in 241 patients, including 149 asymptomatic (62%) but at-risk patients. Eight MPNSTs in 8 screened individuals (5%), 6 neurofibromas with atypia in 4 individuals (3%), and 29 atypical neurofibromatous neoplasms of uncertain biologic potential in 23 individuals (15%) were diagnosed. Over time, the proportion of grade 3 MPNST and the malignant/premalignant ratio in screened individuals significantly decreased (P = .03 and P < .001, respectively). This study emphasizes the diagnostic and screening performances of whole-body positron emission tomography with 18F-fluorodeoxyglucose/magnetic resonance imaging in adults with neurofibromatosis type 1.

A core outcome domain set to assess cutaneous neurofibromas related to neurofibromatosis type 1 in clinical trials.

BACKGROUND: Cutaneous neurofibromas (cNF) are considered one of the highest burdens of neurofibromatosis type 1 (NF1). To date, no medical treatment can cure cNF or prevent their development. In that context, there is an urgent need to prepare and standardize the methodology of future trials targeting cNF. OBJECTIVES: The objective was to develop a core outcome domain set suitable for all clinical trials targeting NF1-associated cNF. METHODS: The validated approach of this work consisted of a three-phase methodology: (i) generating the domains [systematic literature review (SLR) and qualitative studies]; (ii) agreeing (three-round international e-Delphi consensus process and working groups); and (iii) voting. RESULTS: (i) The SLR and the qualitative studies (three types of focus groups and a French e-survey with 234 participants) resulted in a preliminary list of 31 candidate items and their corresponding definitions. (ii) A total of 229 individuals from 29 countries participated in the first round of the e-Delphi process: 71 patients, relatives or representatives (31.0%), 130 healthcare professionals (HCPs, 56.8%) and 28 researchers, representatives of a drug regulatory authority, industry or pharmaceutical company representatives or journal editors (12.2%). The overall participation rate was 74%. After round 2, five candidate items were excluded. Between rounds 2 and 3, international workshops were held to better understand the disagreements among stakeholders. This phase led to the identification of 19 items as outcome subdomains. (iii) The items were fused to create four outcome domains ('clinical assessment', 'daily life impact', 'patient satisfaction' and 'perception of health') and prioritized. The seven items that did not reach consensus were marked for the research agenda. The final core outcome domain set reached 100% of the votes of the steering committee members. CONCLUSIONS: Although numerous outcomes can be explored in studies related to cNF in NF1, the present study offers four outcome domains that should be reported in all trial studies, agreed on by international patients, relatives and representatives of patients; HCPs; researchers, representatives of drug regulatory authorities or pharmaceutical companies and journal editors. The next step will include the development of a set of core outcome measurement instruments to further standardize how these outcomes should be assessed.

Use of multiple correspondence analysis to explore associations between caregivers and sun protective habits during summer vacations.

BACKGROUND: Childhood exposure to ultraviolet radiation (UVR) plays an important role in the development of keratinocyte carcinomas and melanomas. Therefore, sun protective measures ought to be implemented during early childhood. Young children are largely dependent upon adult care providers in order to achieve proper sun protection. OBJECTIVES: To develop effective photoprotection in children, it is necessary to understand caregivers' attitudes and knowledge about UVR exposure. This study aimed to explore the variables associated with sun protective behaviour in parents and grandparents during summer vacations. METHODS: A multinational, cross-sectional study was conducted using a web-based online survey with a representative sample of parents and grandparents of children aged ≤ 12 years, who cared for their children/grandchildren for at least 2 weeks during the summer of 2021, in five countries (France, Germany, Spain, Italy and the USA). Multiple correspondence analysis (MCA) was used to explore in an unbiased way the possible relationships among all the variables and to identify specific profiles. RESULTS: A total of 6190 adult participants responded to the questionnaire: 5104 parents (average age 42.0 years, 54.3% women) and 1086 grandparents (average age 64.2 years, 55.5% women). MCA allowed discrimination of two groups of respondents based on their answers: a profile with 'unprotected sun exposure habits' vs. those with 'protective sun exposure habits'. Parents fell in closer proximity to the 'unprotected sun exposure habits', and 'sunburn reported in youngest child'. Grandparents adopted more cautious behaviours than parents. Nevertheless, grandparents fell in proximity to 'having exposed the grandchild to the sun between 11 h and 17.00 h', 'not using an umbrella' and 'not using sunglasses'. CONCLUSIONS: Although grandparents appear to adopt more cautious behaviours than parents, many gaps in proper sun protection behaviour were observed in both groups of caregivers.

Identification of a new Kir6 potassium channel and comparison of properties of Kir6 subtypes by structural modelling and molecular dynamics.

ATP-sensitive potassium ion channels (KATP) are transmembrane proteins that modulate insulin release and muscle contraction. KATP channels are composed of two types of subunit, Kir6 and SUR, which exist in two and three isoforms respectively with different tissue distribution. In this work, we identify a previously undescribed ancestral vertebrate gene encoding a Kir6-related protein that we have named Kir6.3, which may not have a SUR binding partner, unlike the other two Kir6 proteins. Whereas Kir6.3 was lost in amniotes including mammals, it is still present in several early-diverging vertebrate lineages such as frogs, coelacanth, and rayfinned fishes. Molecular dynamics (MD) simulations using homology models of Kir6.1, Kir6.2, and Kir6.3 from the coelacanth Latimeria chalumnae showed that the three proteins exhibit subtle differences in their dynamics. Steered MD simulations of Kir6-SUR pairs suggest that Kir6.3 has a lower binding affinity for the SUR proteins than either Kir6.1 or Kir6.2. As we found no additional SUR gene in the genomes of the species that have Kir6.3, it most likely forms a lone tetramer. These findings invite studies of the tissue distribution of Kir6.3 in relation to the other Kir6 as well as SUR proteins to determine the functional roles of Kir6.3.

Current and Emerging Imaging Techniques for Neurofibromatosis Type 1-Associated Cutaneous Neurofibromas.

A consistent set of measurement techniques must be applied to reliably and reproducibly evaluate the efficacy of treatments for cutaneous neurofibromas (cNFs) in people with neurofibromatosis type 1 (NF1). cNFs are neurocutaneous tumors that are the most common tumor in people with NF1 and represent an area of unmet clinical need. This review presents the available data regarding approaches in use or development to identify, measure, and track cNFs, including calipers, digital imaging, and high-frequency ultrasound sonography. We also describe emerging technologies such as spatial frequency domain imaging and the application of imaging modalities such as optical coherence tomography that may enable the detection of early cNFs and prevention of tumor-associated morbidity.

Impact of Atopic Dermatitis on Patients and their Partners.

Atopic dermatitis is a chronic, relapsing and inflammatory skin disease. The impact of atopic dermatitis on the partners living with patients has been poorly investigated. The objective of this study was to evaluate the impact of atopic dermatitis in the daily lives of adult patients and to assess the burden of the disease on their partners. A population-based study was conducted on a representative sample of the general population of French adults aged 18 years of age using stratified, proportional sampling with a replacement design. Data were collected on 1,266 atopic dermatitis patient-partner dyads (mean age of patients 41.6 years, 723 (57.1%) women). The mean age of partners was 41.8 years. Patient burden, measured by the Atopic Dermatitis Burden Scale for Adults (ABS-A) score, was closely related to the objective atopic dermatitis severity: the mean score in the mild group (29.5) was significantly lower than in the moderate (43.9) and severe groups (48.6) (p < 0.0001). Partner burden, measured by the EczemaPartner score, was highly related to atopic dermatitis severity (p < 0.0001). Daytime sleepiness, measured by the Epworth Sleepiness Scale, showed a mean score of 9.24 in patients and 9.01 in their partners, indicating impaired sleep. Atopic dermatitis was found to decrease sexual desire in 39% and 26% of partners and patients respectively.

In-Hospital Clinical Features, Morbidity, and Mortality of Patients with Neurofibromatosis 1 in France: A Nationwide, Population-Based Retrospective Cohort Study.

Neurofibromatosis 1 (NF1) is a multisystem disease that can affect nearly every organ system. The aim of our study was to describe the in-hospital population with NF1 in France. We conducted a nationwide retrospective cohort study using the French hospital administrative database. A total of 11,425 patients with NF1 (53.4% female, 19,080 person years) were identified from January 2013 to December 2019. A total of 23% had at least one diagnosis of a comorbidity or NF1-associated complication or disease, and it was highest in the age group of 10-15 years. A total of 2,601 (22.8%) had a diagnosis of cancer. There were 366 (3.2%) in-hospital deaths, and we observed a standardized mortality ratio of 4.14 (95% confidence interval = 3.71-4.56), with a higher standardized mortality ratio in women and in the age group of 10-15 years. The standardized incident ratio (SIR) of cancer was 10.3 (95% confidence interval = 9.6-11.1). We observed high SIR values for cancer in childhood, with a decrease toward that of the general population by age 70 years. We observed high SIRs for NF1-associated cancers: CNS SIR of 195.4 (95% confidence interval = 172.2-220.9) and small intestine SIR of 102.9 (95% confidence interval = 71.7-143.2). The study provides a better understanding of the prognosis in people living with NF1.

cNF-Skindex in Adults Living with Neurofibromatosis 1: Severity Strata in France and Validation in United States Adults.

Cutaneous neurofibromas (cNF) contribute to the impairment of QOL in individuals with neurofibromatosis 1. The cNF-Skindex, validated in a French population, specifically assesses the cNF-related QOL. In this study, we first defined severity strata using an anchoring approach on the basis of patient's burden. In total, 209 patients answered the anchor question and the cNF-Skindex. We tested the agreement among the three strata, generated by all potential couples of cut-off values of the cNF-Skindex and the three strata defined in the anchor question. The cut-off values 12 and 49 provided the highest Kappa value (κ = 0.685, 95% confidence interval = 0.604-0.765). Second, we validated the score and the strata in a United States population using the answers provided by 220 French and 148 United States adults. In the multivariable linear regression analysis, the country of origin was not a factor associated with the score (P = 0.297). The number of cNF along the different severity strata was similar between the French and the United States populations. In conclusion, stratification constitutes a powerful tool to better interpret the cNF-Skindex in daily practice and in clinical trials. This study validates its use in two populations that together constitute a large cohort of patients willing to participate in clinical research.

Has the core outcome (domain) set for vitiligo been implemented? An updated systematic review on outcomes and outcome measures in vitiligo randomized clinical trials.

BACKGROUND: In 2015, a major achievement in vitiligo research was the development of an internationally agreed upon core outcome domain set for randomized clinical trials (RCTs). Three outcomes were identified as being essential: repigmentation, side-effects/harms and maintenance of gained repigmentation. Four items were further recommended for inclusion. The following recommendations then followed: repigmentation should be assessed by measuring the percentage of repigmentation in quartiles (0-25%, 26-50%, 51-79%, 80-100%) and cosmetic acceptability of the results should be assessed using the Vitiligo Noticeability Scale. OBJECTIVES: The primary objective of this study was to assess uptake of the core outcome domain set for RCTs in vitiligo. Secondary objectives were to update the systematic review on outcomes reported in vitiligo RCTs, and to assess whether repigmentation and cosmetic acceptability of the results were measured using the above-mentioned recommended scales. METHODS: We searched PubMed, Cochrane Library (CENTRAL and Systematic Reviews) and ClinicalTrials.gov for vitiligo RCTs between November 2009 and March 2021. Screening and data extraction were independently performed on title and summary by two researchers. All outcomes and outcome measures reported in eligible RCTs were retrieved and collated. RESULTS: In total, 174 RCTs were identified: 62 were published between 2009 and 2015, and 112 were published between 2016 and 2021.Thirty-eight different outcomes were reported. Repigmentation was the primary outcome in 89% of trials (150 of 169). Forty-nine different tools were used to measure repigmentation. Side-effects and harms were reported in 78% of trials (136 of 174). Maintenance of gained repigmentation was reported in only 11% of trials (20 of 174) and duration of follow-up varied greatly from 1 to 14 months. Cosmetic acceptability of the results and cessation of disease activity were assessed in only 2% of trials (four of 174). Quality of life of patients with vitiligo was assessed in 13% of trials (22 of 174). Finally, only 11 of 112 RCTs (10%) published between 2016 and 2021 reported all three essential core outcome domains (repigmentation, side-effects and maintenance of gained repigmentation) and none of the trials reported both essential and recommended core outcome domains. CONCLUSIONS: Efforts are still needed to close the gap between set recommendations and RCT outcome reporting.

Safety and efficacy of high-dose clobetasol propionate 0.05% in cutaneous lichen planus.

Cutaneous lichen planus is a highly pruritic dermatosis with an unmet need in its management. The aim of this study was to evaluate the short-term effect and tolerance of high doses of clobetasol propionate 0.05% in cutaneous lichen planus. We conducted a single-center retrospective cohort study from 2017 to 2021. All adults treated with high-dose (>5 g/day) clobetasol propionate 0.05% for cutaneous lichen planus were included. Patients with less than 10% affected body surface area at initial presentation or who received concomitant systemic therapy were excluded. The primary endpoint was the rate of complete remission by week 16. Secondary endpoints included maximum daily and median cumulative doses, reduction in pruritus and occurrence of adverse events. Fifty-seven patients, 60% female, with a mean age of 48 years (min-max,18-83) were included. Cutaneous lichen planus had been present for a median duration of 2 months at initial presentation (min-max, 1-4) and involved a median body surface area of 27%. Pruritus was reported by 55/57 (96%) patients. At week 16, 41/57 (72%) patients had achieved complete remission without treatment modification, among whom 25/41 (61%) had achieved it at week 6. The median daily and cumulative doses were, respectively, 20 g/day (IQR, 10-20) and 560 g (IQR, 320-925). Three patients experienced mild adverse events. No statistical association was demonstrated between the duration of the disease before treatment initiation and clinical response. In conclusion, high-dose clobetasol propionate 0.05% seems to be an effective, well-tolerated, and easy-to-implement treatment for cutaneous lichen planus.

Tonic Seizures in a Patient With Lennox-Gastaut Syndrome Manifest as "Icicles" Rather Than "Flames" on Quantitative EEG Analysis.

SUMMARY: Quantitative analysis of continuous electroencephalography (QEEG) is increasingly being used to augment seizure detection in critically ill patients. Typically, seizures manifest on QEEG as abrupt increases in power and frequency, a visual pattern often called "flames." Here, we present a case of a 16-year-old patient with intractable Lennox-Gastaut syndrome secondary to a pathogenic variant in the SCN2A gene who had tonic seizures that manifest as abrupt decreases in power on QEEG, a visual pattern we term "icicles." Recognition of QEEG patterns representative of different seizure types is important as QEEG use becomes more widespread including in pediatric populations.

Burden of caregivers and out-of-pocket expenditures related to epidermolysis bullosa in France.

INTRODUCTION AND OBJECTIVES: Inherited epidermolysis bullosa (EB) is a heterogeneous group of genodermatoses characterized by localized or generalized skin and/or mucosal fragility. The objective of this work was to evaluate in France the burden of disease and out-of-pocket (OOP) expenditures for families with a child affected by EB. MATERIAL AND METHODS: A digital questionnaire was built and distributed to parents of children with EB in partnership with the patients' association DEBRA France. The questionnaire collected clinical and socioeconomic characteristics including the estimated amount of money caregivers had to pay out of their own pockets. The burden of caregivers was assessed using the validated Epidermolysis Bullosa Burden of Disease (EB-BoD) tool. Linear univariate regression models were conducted to search for factors associated with higher burden and higher OOP. RESULTS: Between October and December 2021, 77 parents answered the questionnaire. The responder was the child's mother in 77% (n = 59) of cases. Parents represented 40 girls and 37 boys with a mean age of 7.5 years and with different EB types and disease severity. The mean BE-BOD score was 63.9 ± 20.2. The mean score observed in children with severe EB was 69.0 ± 21 versus 59.0 ± 18.6 for moderate/mild. Similarly, the mean BE-BOD scores observed in parents performing daily wound care were 67.9 ± 19.6. All parents (100%) reported OOP expenses. The mean annual OOP cost was 4129€ ± 4321€. Linear regression demonstrated that for each one-point increase in the EB-BoD score, OOP expense increases by 91.1 euros (35.1-147) p = 0.002. CONCLUSION: EB places a considerable burden on families' daily lives. This burden is closely associated with OOP expenditures to manage EB which were on average 20 times higher compared with the French population.

Patient Unique Stigmatization Holistic tool in dermatology (PUSH-D): Development and validation of a dermatology-specific stigmatization assessment tool.

BACKGROUND: The skin plays an important role in establishing interpersonal relationships, and thus visible skin disorders, which have a significant impact on physical appearance, influence other people's behaviours and attitudes. OBJECTIVE: To develop and validate a dermatologic-specific questionnaire to evaluate stigmatization in individuals with visible skin conditions. METHODS: Items were generated by a verbatim report based on qualitative interviews with patients with various dermatologic conditions. Subsequently, a study was implemented for psychometric analysis. A dermatology-specific stigmatization questionnaire (PUSH-D) was refined via item reduction according to inter-question correlations, consensus among experts and exploratory factor analysis. Internal consistency was determined by calculating Cronbach's α. Concurrent validity was determined by calculating the correlation between PUSH-D and the Dermatology Life Quality Index (DLQI) and the Rosenberg Self-Esteem Scale (RSES). RESULTS: From a primary list of 22 items, PUSH-D was reduced to a 17-item questionnaire, covering two pertinent dimensions based on the exploratory factor analysis. Construct validity was demonstrated, and PUSH-D showed good internal consistency (Cronbach's α = 0.9). PUSH-D correlated strongly with the DLQI 0.72 (p < 0.001) and moderately with the RSES 0.49 (p < 0.001). CONCLUSION: PUSH-D allows a comprehensive view of the degree of stigmatization in visible skin disorders, as well as the comparability of stigmatization levels across various skin conditions.

Dynamic evolution of transient receptor potential vanilloid (TRPV) ion channel family with numerous gene duplications and losses.

The transient receptor potential vanilloid (TRPV) ion channel family is involved in multiple sensory and physiological functions including thermosensing and temperature-dependent neuroendocrine regulation. The objective of the present study was to investigate the number, origin and evolution of TRPV genes in metazoans, with special focus on the impact of the vertebrate whole-genome duplications (WGD). Gene searches followed by phylogenetic and synteny analyses revealed multiple previously undescribed TRPV genes. The common ancestor of Cnidaria and Bilateria had three TRPV genes that became four in the deuterostome ancestor. Two of these were lost in the vertebrate ancestor. The remaining two genes gave rise to two TRPV subfamilies in vertebrates, consisting of subtypes 1, 2, 3, 4, 9 and 5, 6, 7, 8, respectively. This gene expansion resulted from the two basal vertebrate WGD events (1R and 2R) and three local duplications before the radiation of gnathostomes. TRPV1, 4 and 5 have been retained in all gnathostomes investigated, presumably reflecting important functions. TRPV7 and 8 have been lost independently in various lineages but are still retained in cyclostomes, actinistians (coelacanth), amphibians, prototherians and basal actinopterygians (Polypteridae). TRPV3 and 9 are present in extant elasmobranchs, while TRPV9 was lost in the osteichthyan ancestor and TRPV3 in the actinopterygian ancestor. The coelacanth has retained the ancestral osteichthyan repertoire of TRPV1, 3, 4, 5, 7 and 8. TRPV2 arose in the tetrapod ancestor. Duplications of TRPV5 occurred independently in various lineages, such as cyclostomes, chondrichthyans, anuran amphibians, sauropsids, mammals (where the duplicate is called TRPV6), and actinopterygians (Polypteridae and Esocidae). After the teleost-specific WGD (3R) only TRPV1 retained its duplicate, whereas TRPV4 and 5 remained as single genes. Both 3R-paralogs of TRPV1 were kept in some teleost species, while one paralog was lost in others. The salmonid-specific WGD (4R) duplicated TRPV1, 4, and 5 leading to six TRPV genes. The largest number was found in Xenopus tropicalis with no less than 15 TRPV genes. This study provides a comprehensive evolutionary scenario for the vertebrate TRPV family, revealing additional TRPV types and proposing a phylogeny-based classification of TRPV across metazoans.

Risk of Inflammatory Bowel Disease in Patients With Psoriasis and Psoriatic Arthritis/Ankylosing Spondylitis Initiating Interleukin-17 Inhibitors: A Nationwide Population-Based Study Using the French National Health Data System.

OBJECTIVE: To investigate whether the initiation of treatment with an interleukin-17 inhibitor (IL-17i) in real life is associated with a higher risk of inflammatory bowel disease (IBD) in patients who had both psoriasis (PsO) and psoriatic arthritis (PsA)/ankylosing spondylitis (AS). METHODS: This nationwide cohort study was conducted using the French National Health Data System database. All adult patients with PsO and PsA/AS who were identified as having newly initiated treatment with an IL-17i during 2016-2019 were included. As controls, patients with PsO and PsA/AS who had newly initiated either 1) apremilast or 2) etanercept (ETN) during this period but had not received IL-17i were included. The follow-up end date was September 30, 2019. The primary end point was the risk of occurrence of IBD associated with exposure to an IL-17i compared to exposure to the other treatments, as determined in a time-to-event analysis with propensity score-weighted Cox and Fine-Gray proportional hazards models. RESULTS: The study included a total of 16,793 new IL-17i users (mean ± SD age 48.4 ± 13 years, 45% men), 20,556 new apremilast users (age 52.6 ± 15 years, 54% men), and 10,294 new ETN users (age 46.3 ± 15 years, 44% men). New IL-17i users and new ETN users had received more biologics for their underlying disease compared to new apremilast users. IBD occurred in 132 patients: 72 new IL-17i users (0.43%), 11 new apremilast users (0.05%), and 49 new ETN users (0.48%). Most IBD cases occurred after 6 months of exposure (82%, 55%, and 76%, respectively). After propensity score weighting, the risk of IBD was significantly greater among patients initiating an IL-17i compared to those initiating apremilast (weighted hazard ratio [HR] 3.8 [95% confidence interval (95% CI) 2.1-6.8]). No difference in the risk of IBD between new IL-17i users and new ETN users was observed (weighted HR 0.8 [95% CI 0.5-1.2]). CONCLUSION: Patients with PsO and PsA/AS who initiate treatment with an IL-17i do not have a higher risk of developing IBD when compared to patients initiating ETN who display the same severity of underlying disease. These results need to be confirmed in other large studies of patients with PsO and PsA/AS.

Lymphoproliferative malignancies in patients with neurofibromatosis 1.

Neurofibromatosis 1 (NF1) is an inherited, autosomal-dominant, tumor predisposition syndrome with a birth incidence as high as 1:2000. A patient with NF1 is four to five times more likely to develop a malignancy as compared to the general population. The number of epidemiologic studies on lymphoproliferative malignancies in patients with NF1 is limited. The aim of this study was to determine the incidence rate of lymphoproliferative malignancies (lymphoma and leukemia) in NF1 patients followed in our referral center for neurofibromatoses. We used the Informatics for Integrated Biology and the Bedside (i2b2) platform to extract information from the hospital's electronic health records. We performed a keyword search on clinical notes generated between Jan/01/2014 and May/11/2020 for patients aged 18 years or older. A total of 1507 patients with confirmed NF1 patients aged 18 years and above were identified (mean age 39.2 years; 57% women). The total number of person-years in follow-up was 57,736 (men, 24,327 years; women, 33,409 years). Mean length of follow-up was 38.3 years (median, 36 years). A total of 13 patients had a medical history of either lymphoma or leukemia, yielding an overall incidence rate of 22.5 per 100,000 (0.000225, 95% confidence interval (CI) 0.000223-0.000227). This incidence is similar to that of the general population in France (standardized incidence ratio 1.07, 95% CI 0.60-1.79). Four patients had a medical history leukemia and 9 patients had a medical history of lymphoma of which 7 had non-Hodgkin lymphoma, and 2 had Hodgkin lymphoma. Our results show that adults with NF1 do not have an increased tendency to develop lymphoproliferative malignancies, in contrast to the general increased risk of malignancy. While our results are consistent with the recent population-based study in Finland, they are in contrast with the larger population-based study in England whereby NF1 individuals were found to be 3 times more likely to develop both non-Hodgkin lymphoma and lymphocytic leukemia. Large-scale epidemiological studies based on nationwide data sets are thus needed to confirm our findings.

MEK inhibitors in RASopathies.

PURPOSE OF REVIEW: An early understanding of the role of the Ras/Raf/MEK/ERK signalling pathway in regulating cell proliferation has set the stage for the development of several potent and selective MEK inhibitors (MEKi). MEKi represent promising therapies for RAS-driven neoplasias and RASopathies associated with increased Ras/MAPK activity. RECENT FINDINGS: Neurofibromatosis 1 (NF1) is a prototypic RASopathy in which early-phase clinical trials with MEKi have been successful in the treatment of plexiform neurofibromas (pNF) and low-grade gliomas (LGGs). The phase 2 trial (SPRINT) of selumetinib in pNF resulted in at least 20% reduction in the size of pNF from baseline in 71% of patients and was associated with clinically meaningful improvements. On the basis of this trial, selumetinib (Koselugo) received FDA approval for children 2 years of age and older with inoperable, symptomatic pNF. The phase 2 trial of selumetinib in LGG resulted in 40% partial response and 96% of patients had 2 years of progression-free survival. SUMMARY: Given the potential of MEK inhibition as an effective and overall well tolerated medical treatment, the use of targeted agents in the NF1 population is likely to increase considerably. Future work on non-NF1 RASopathies should focus on developing preclinical models and defining endpoints for measurement of efficacy in order to conduct clinical trials.

Vitiligo: A focus on pathogenesis and its therapeutic implications.

Vitiligo is the most common depigmenting disorder affecting 0.1%-2% of the population worldwide. The characteristic white patches result from the selective loss of melanocytes. Sustained recent efforts have resulted in a detailed understanding of the genetic architecture of vitiligo. About 80% of vitiligo risk is attributable to genetic factors; and the rest (20%) is attributable to the environment. Over the past decade, substantial progress has been made in our understanding of the pathogenesis of vitiligo which is now clearly classified as an autoimmune disease. Melanocytes from patients with vitiligo are more susceptible to oxidative stress which begets the release of exosomes and inflammatory cytokines that will lead to activation of the innate immune response and subsequently to adaptive immune response through activation of autoreactive cytotoxic CD8+ T cells. These produce interferon-γ (IFN-γ) which promotes disease progression through IFN-γ-induced chemokine secretion from surrounding keratinocytes to further recruit T cells to the skin through a positive feedback loop. CD8 tissue-resident memory T cells are in turn responsible for long-term maintenance and potential relapse of vitiligo in human patients through cytokine-mediated recruitment of T cells from the circulation. This review summarizes the current knowledge on vitiligo and attempt to give an overview of the future in vitiligo treatment.