Beyond the Label: Real-World Side Effects Experienced With FDA-Approved Drugs for Non-Melanoma Skin Cancers.

With immunotherapy historically focused on cutaneous melanoma, there has been a new wave of systemic medications available for treating non-melanoma skin cancers including basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and Merkel cell carcinoma (MCC). The immune checkpoint inhibitors approved by the FDA target programmed cell death protein 1 (PD-1) and the Hedgehog (Hh) signaling pathway. These medications have expanded treatment options; however, side effects are an important consideration. We used the FDA Adverse Events Reporting System (FAERS) to characterize the most prevalent, real-world side effects experienced by patients on these agents. Muscle spasms (23.45%), alopecia (16.06%), ageusia (12.02%), taste disorder (11.91%), and fatigue (11.67%) were the five most common side effects reported with medications used for BCC treatment. Logistic regression analysis showed males on vismodegib for BCC having greater odds of experiencing muscle spasms (aOR 1.33, P<0.001) and ageusia (aOR 1.34,  P<0.001) versus females, who were more likely to exhibit alopecia (aOR 1.82, P<0.001) and nausea (aOR 1.96, P<0.001). With SCC treatment, the 5 most reported adverse events were fatigue (5.58%), rash (3.59%), asthenia (3.59%), pruritus (3.19%), and pyrexia (2.79%). Patients taking cemiplimab-rwlc for BCC compared to SCC were more likely to experience disease progression (aOR 10.98, P=0.02). With medication labels providing an excessively daunting list of side effects, we characterize practical side effects seen in patients receiving systemic treatments for non-melanoma skin cancers.  J Drugs Dermatol. 2024;23(5):301-305. doi:10.36849/JDD.7968.

Efficacy of Botulinum Toxin in the Treatment of Cutaneous Flushing: A Systematic Review and Meta-Analysis.

BACKGROUND: Flushing is a common dermatologic complaint and can be resistant to many treatments. As the utility of botulinum toxin continues to expand, recent data suggest that it may also be a therapeutic option for flushing. OBJECTIVE: To evaluate the efficacy of botulinum toxin for the treatment of cutaneous flushing. MATERIALS AND METHODS: A systematic search of Medline, Embase, Cochrane CENTRAL, CINAHL, Scopus, and Web of Science databases was conducted to identify studies evaluating the effect of botulinum toxin on flushing 1 month after treatment. Prespecified outcome measures included a clinical flushing score, dermatology life quality index (DLQI), and erythema index (EI). Meta-analysis was performed to calculate the mean differences in these outcomes before and after treatment at 1-month follow-up. RESULTS: Nine studies (132 patients) were included in the analysis of this study (2 randomized controlled trials and 7 nonrandomized studies). All studies had a low risk of bias (high quality). The most frequent outcome reported was a clinical flushing score, which significantly decreased by 1.25 points overall (95% confidence interval [CI]: -2.47; -0.04) 1 month after treatment with botulinum toxin. Mean DLQI scores decreased (i.e., improved) by 9.02 points (95% CI: -19.81; 1.77) 1 month after botulinum toxin injections. The EI (measured by Mexameter) before and after botulinum toxin was evaluated in 2 studies; however, not enough statistical information was provided to analyze with meta-analytic techniques. CONCLUSION: Based on this meta-analysis, botulinum toxin significantly improves clinical flushing scores 1 month after treatment.

A cross-sectional analysis of medications used by patients reporting alopecia areata on the FDA adverse events reporting system.

BACKGROUND: Alopecia areata (AA) is an autoimmune condition that leads to patchy, nonscarring hair loss. Its etiology remains unknown; the condition can be debilitating for patients, impacting their psychosocial wellbeing. Various triggers have been reported, ranging from genetic predisposition and infections to environmental factors. Medications have also been thought to be an inciting factor in AA. METHODS: Using the Food and Drug Administration (FDA) Adverse Events Reporting System (FAERS), all cases reporting AA as an adverse event were used to capture associated medications and patient characteristics. RESULTS: There were 1,331 AA cases reported as an adverse event with medication use. Monoclonal antibodies accounted for 6 out of the top 10 drugs associated with the highest number of AA cases. Males were more likely to report AA when taking adalimumab (OR: 1.79, P = 0.04) and dupilumab (OR: 2.56, P = 0.03) compared to females. Individuals between 42 and 64 years old accounted for 46.7% of AA cases. Lastly, females in older age groups showed greater odds of developing AA compared to males (OR: 1.03, P < 0.01). CONCLUSIONS: Based on the FAERS, there has been a steady rise in AA cases, and monoclonal antibodies were the most frequently cited medication class tied to AA. With a dearth of literature on triggers and patient demographics, we sought to describe features of AA cases that could increase awareness and be used to improve future clinical outcomes in patients.

Missed games, financial losses, and characteristics of eye injuries in the National Basketball Association during the 2010-2011 to 2017-2018 seasons.

PURPOSE: The purpose is to report financial loss, demographic metrics, and mechanisms of injury associated with eye injuries in the National Basketball Association (NBA) from the 2010-2011 to 2017-2018 seasons. METHODS: We performed a retrospective review of eye injuries in the NBA from the 2010-2011 to 2017-2018 seasons using publicly available information from Basketball Reference and the Pro Sports Transactions websites. Only injuries of the eye and adnexa that caused players to miss games in the regular season and playoffs were included in the study. Financial loss was calculated based on the regular season salary of the players and normalized for inflation with 2018 as the base year. RESULTS: There were 30 eye injuries causing a total of 106 missed games and $7,486,770 in financial losses across eight seasons. Linear regressions showed a moderately positive increase in eye injuries (Pearson's r = 0.68, P = 0.07, and 0.79 injuries per year/1000 game-days increase) and financial losses (Pearson's r = 0.67, P = 0.07, and $185.75 increase per year/1000 game-days) over time. There were significantly more games missed due to orbital fractures than games missed due to contusions/lacerations (11.5 vs. 2.8 missed games, P = 0.01). CONCLUSION: We demonstrate an increasing trend of eye injuries in the NBA, resulting in increased financial loss. Injuries may be varied in type and affect the number of games missed.

Use of Hydroxychloroquine in Hair Disorders.

Hydroxychloroquine (HCQ) is an antimalarial that is utilized to treat a range of dermatologic and autoimmune disorders. With its ability to alter immunologic mechanisms, it has been used to slow or halt the progression of hair loss in conditions secondary to autoimmune dysfunction. Lichen planopilaris (LPP), frontal fibrosing alopecia (FFA), and alopecia areata (AA) are hair disorders with underlying autoimmune components and no standardized treatment guidelines. We summarized the available literature on the use of HCQ to treat LPP, FFA, and AA. For all three conditions, HCQ showed variable efficacy from halted hair loss to no improvement. While patients did show success with HCQ treatment, there were no clear treatment patterns. Regimens ranged from HCQ monotherapy to combination treatments with other agents like steroids. Overall, HCQ should certainly be considered by clinicians as a treatment option for patient suffering from these hair disorders. While there is no standardized treatment, incorporation of HCQ should take into consideration individual patient characteristics, clinical judgment, and risks of side effects.

Hydroxychloroquine (HCQ) is an antimalarial drug that acts on the immune system. Lichen planopilaris, frontal fibrosing alopecia, and alopecia areata are all disorders that result in hair loss secondary to immune dysfunction. HCQ has been used to treat these conditions, so publications addressing HCQ use for such hair loss disorders were collected, and the findings were summarized. Overall, HCQ showed mixed efficacy but can be a successful treatment option for some patients. Various treatment patterns were seen from using only HCQ to combination therapy plans with HCQ and steroids, for example. Treating these hair loss conditions can be challenging, and while there are no standardized guidelines, HCQ should be considered in the treatment arsenal for patients.

The distribution of industry payments among pediatric dermatologists from 2015 to 2021.

BACKGROUND/OBJECTIVES: To understand the landscape of industry payments to pediatric dermatologists to foster transparency and identify potential disparities in funding. METHODS: Using the Centers for Medicare and Medicaid Services (CMS) Open Payments database, a national cross-sectional study was performed examining payments to pediatric dermatologists from 2015 to 2021. RESULTS: Of the 147 pediatric dermatologists who received industry funding, 35 were male and 112 were female. $9 million in payments was amassed, with 10% of pediatric dermatologists accounting for 94% of total industry payments. Consulting was the most common service, with Pfizer Inc., Amgen Inc., and Regeneron Healthcare Solutions Inc. representing the top three companies. Mean payment was $143,836 for males and $35,943 for females (p < .001). Eight female and seven male pediatric dermatologists received payments in the top 10th percentile, with different average payment in this subgroup (females $447,588 vs. males $698,746, p = .03). 11 states did not have a pediatric dermatologist receiving industry payments, while California (19) and Texas (12) had the most. CONCLUSIONS: There are approximately 400 board-certified pediatric dermatologists in the United States and fewer than 40% are receiving monetary compensation from private industry. A fraction of physicians accounted for a majority of total industry payments and industry payments to male pediatric dermatologists were higher despite nearly triple the number of female pediatric dermatologists. With the rise of valuable partnerships between healthcare and industry in modern medicine, the implications of geographic, gender, and financial disparity of industry payments in pediatric dermatology are worthy of further study.

The top 100 most cited Mohs micrographic surgery articles: an analysis of Altmetrics data from 2010 to 2020.

With skin cancer rates rising, there is a consistent stream of literature published on Mohs micrographic surgery (MMS). However, there are no studies examining MMS article visibility and readership patterns. The Altmetric Attention Score (AAS) is a metric that quantifies article distribution on media platforms. We analyzed the 100 most cited MMS publications from 2010 to 2020 and constructed multivariate regression models using top 25th percentile AASs and mentions on Facebook, Twitter, and new outlets as outcome variables. Articles with an AAS in the top 25th quartile consistently performed better with higher citations, Twitter mentions, Facebook mentions, and journal impact factors compared to articles in the lower three quartiles (53.8 vs 33.9; 4.68 vs 0.44; 0.32 vs 0.08; 53.5 vs 14.6; p < 0.05 for all). There were significantly lower female last authors versus males in the top quartile of AAS articles, with males 142 times more likely to have articles in the top quartile (p < 0.05). Studies comparing MMS to other surgical techniques and funded articles had higher odds of being in the top quartile of AASs (aOR 29.63 p < 0.05; aOR 74.50 p < 0.05). AASs can be useful to understand public interest, readership, and article features that influence the reach of MMS literature.

Interface fluid syndrome after LASIK surgery: retrospective pooled analysis and systematic review.

Interface fluid syndrome (IFS) is a complication associated with laser in situ keratomileusis (LASIK) surgery where a fluid pocket in the corneal stroma decreases visual acuity. A systematic review of IFS cases using PRISMA guidelines was performed yielding a total of 33 patients. 2 outcomes were selected for logistic regression analysis: final corrected distance visual acuity (CDVA) and need for surgical management. Results showed 33.3% of patients required surgery, 51.5% had their IFS resolve within 1 month or sooner, and 51.5% had final CDVA 20/25 or better. Higher presenting intraocular pressure (IOP) and duration of IFS ≤1 month was associated with higher odds of final CDVA 20/25 or better (adjusted odds ratio [aOR] 1.12, P = .04; aOR 7.71, P = .02, respectively). Endothelial cell dysfunction led to 17.55 greater odds for requiring surgical compared to medical management (aOR 0.36, P = .04). Presenting IOP and duration of IFS predicted final CDVA, while prior endothelial cell dysfunction predicted need for surgery.

More than just a stye: identifying seasonal patterns using google trends, and a review of infodemiological literature in ophthalmology.

PURPOSE: We aim to evaluate the utility of internet search query data in ophthalmology by: (1) Evaluating trends in searches for styes in the United States and worldwide, and (2) Performing a review of literature of infodemiological data in ophthalmology. METHODS: Google Trends search data for "stye" was analyzed from January 2004 to January 2020 in the United States and worldwide. Spearman's correlation coefficient and sinusoidal modeling were performed to assess the significance and seasonality of trends. Review of literature included searches for "ophthalmology Google trends," "ophthalmology twitter trends," "ophthalmology infodemiology," "eye google trends," and "social media ophthalmology." RESULTS: Searches for styes were cyclical in the United States and globally with a steady increase from 2004 to 2020 (sum-of-squares F-test for sinusoidal model: p < .0001, r2 = 0.96). Peak search volume index (SVI) months were 7.9 months in the United States and 6.8 months worldwide. U.S. temperature and SVI for stye were correlated in the United States at the state, divisional, and country-wide levels (p < .005; p < .005; p < .01 respectively). Seven articles met our literature review inclusion criteria. CONCLUSIONS: We present a novel finding of seasonality with global and U.S. searches for stye, and association of searches with temperature in the United States. Within ophthalmology, infodemiological literature has been used to track trends and identify seasonal disease patterns, perform disease surveillance, improve resource optimization by identifying regional hotspots, tailor marketing, and monitor institutional reputation. Future research into this domain may help identify further trends, improve prevention efforts, and reduce medical costs.

Utility of diffusion-weighted imaging to differentiate benign and malignant solid orbital tumours.

OBJECTIVE: We assessed the utility of apparent diffusion coefficients (ADCs) derived from diffusion-weighted imaging to differentiate benign and malignant orbital tumours by oculoplastic surgeons in the clinical setting and sought to validate observed ADC cut-off values. DESIGN AND PARTICIPANTS: Retrospective review of patients with benign or malignant biopsy-confirmed orbital tumours. METHODS: Blinded graders including 2 oculoplastic surgeons, 1 neuroradiologist, and 1 medical student located and measured orbital tumour ADCs (10-6 mm2/s) using the Region of Interest tool. OUTCOME MEASURES: Nonradiologist measurements were compared with each other to assess reliability and with an expert neuroradiologist measurement and final pathology to assess accuracy. RESULTS: Twenty-nine orbital tumours met inclusion criteria, consisting of 6 benign tumours and 23 malignant tumours. Mean ADC values for benign orbital tumours were 1430.59 ± 254.81 and 798.68 ± 309.12 mm2/s for malignant tumours. Our calculated optimized ADC cut-off to differentiate benign from malignant orbital tumours was 1120.84 × 10-6 mm2/s (sensitivity 1, specificity 0.9). Inter-rater reliability was excellent (intraclass correlation coefficient = 0.92; 95% CI, 0.86-0.96). Our 3 graders had a combined accuracy of 84.5% (92.3%, 92.3%, and 65.4%). CONCLUSIONS: Our ADC cut-off of 1120.84 × 10-6 mm2/s for benign and malignant orbital tumours agrees with previously established values in literature. Without priming with instructions, training, or access to patient characteristics, most tumours were correctly classified using rapid ADC measurements. Surgeons without radiologic expertise can use the ADC tool to quickly risk stratify orbital tumours during clinic visits to guide patient expectations and further work-up.

IL-6R/Signal Transducer and Activator of Transcription 3 Signaling in Keratinocytes rather than in T Cells Induces Psoriasis-Like Dermatitis in Mice.

Signal transducer and activator of transcription 3 (STAT3) is important for psoriasis pathogenesis because STAT3 signaling downstream of IL-6, IL-21, IL-22, and IL-23 contributes to T helper type 17 cell development and because transgenic mice with keratinocyte (KC) STAT3 expression (K14-Stat3C mice) develop psoriasis-like dermatitis. In this study, the relative contribution of STAT3 signaling in KCs versus in T cells was evaluated in the imiquimod model of psoriasis-like dermatitis. Mice with STAT3-inducible deletion in KCs (K5-Stat3-/- mice) had decreased psoriasis-like dermatitis and epidermal STAT3 phosphorylation compared with wild-type mice, whereas mice with constitutive deletion of STAT3 in all T cells were similar to wild-type mice. Interestingly, mice with KC-inducible deletion of IL-6Rα had similar findings to those of K5-Stat3-/- mice, identifying IL-6/IL-6R as a predominant upstream signal for KC STAT3-induced psoriasis-like dermatitis. Moreover, psoriasis-like dermatitis inversely associated with type 1 immune gene products, especially CXCL10, whereas CXCL10 limited psoriasis-like dermatitis, suggesting that KC STAT3 signaling promoted psoriasis-like dermatitis by restricting downstream CXCL10 expression. Finally, treatment of mice with the pan-Jak inhibitor, tofacitinib, reduced psoriasis-like dermatitis and epidermal STAT3 phosphorylation. Taken together, STAT3 signaling in KCs rather than in T cells was a more important determinant for psoriasis-like dermatitis in a mechanism that involved upstream KC IL-6R signaling and downstream inhibition of type 1 immunity‒associated CXCL10 responses.

Pan-caspase inhibition as a potential host-directed immunotherapy against MRSA and other bacterial skin infections.

Staphylococcus aureus causes most skin infections in humans, and the emergence of methicillin-resistant S. aureus (MRSA) strains is a serious public health threat. There is an urgent clinical need for nonantibiotic immunotherapies to treat MRSA infections and prevent the spread of antibiotic resistance. Here, we investigated the pan-caspase inhibitor quinoline-valine-aspartic acid-difluorophenoxymethyl ketone (Q-VD-OPH) for efficacy against MRSA skin infection in mice. A single systemic dose of Q-VD-OPH decreased skin lesion sizes and reduced bacterial burden compared with vehicle-treated or untreated mice. Although Q-VD-OPH inhibited inflammasome-dependent apoptosis-associated speck-like protein containing caspase activation and recruitment domain (ASC) speck formation and caspase-1-mediated interleukin-1ß (IL-1ß) production, Q-VD-OPH maintained efficacy in mice deficient in IL-1ß, ASC, caspase-1, caspase-11, or gasdermin D. Thus, Q-VD-OPH efficacy was independent of inflammasome-mediated pyroptosis. Rather, Q-VD-OPH reduced apoptosis of monocytes and neutrophils. Moreover, Q-VD-OPH enhanced necroptosis of macrophages with concomitant increases in serum TNF and TNF-producing neutrophils, monocytes/macrophages, and neutrophils in the infected skin. Consistent with this, Q-VD-OPH lacked efficacy in mice deficient in TNF (with associated reduced neutrophil influx and necroptosis), in mice deficient in TNF/IL-1R and anti-TNF antibody-treated WT mice. In vitro studies revealed that combined caspase-3, caspase-8, and caspase-9 inhibition reduced apoptosis, and combined caspase-1, caspase-8, and caspase-11 inhibition increased TNF, suggesting a mechanism for Q-VD-OPH efficacy in vivo. Last, Q-VD-OPH also had a therapeutic effect against Streptococcus pyogenes and Pseudomonas aeruginosa skin infections in mice. Collectively, pan-caspase inhibition represents a potential host-directed immunotherapy against MRSA and other bacterial skin infections.

Trends in Anti-VEGF Injection Medicare Part B Claims among Male and Female Ophthalmologists from 2012-2016.

Background: Compared to male ophthalmologists, female ophthalmologists have significantly reduced salaries, fewer faculty roles and authored publications, garnered less federal research funding, and achieved less editorial advancement. We aimed to use the most recently available Centers for Medicare and Medicaid Services data to characterize trends and differences in anti-VEGF reimbursements coded for by male and female ophthalmologists.Methods: We used Medicare Fee-For Service Provider Utilization and Payment Data: Part B Provider public use files for 2012-2016 to quantify service and reimbursement patterns for anti-VEGF injections between male and female ophthalmologists. Five outcome variables were studied: number of providers, average Medicare payment amount, total payment, number of services, and number of Medicare beneficiaries.Results: Number of services performed per female provider was 71.2% that of a male ophthalmologist in 2012, and this percentage did not change from 2012 to 2016 (95%CI [0.63, 0.804], [0.984, 1.04], respectively). Female providers had 76.1% of beneficiaries as males in 2012, and this percentage stayed constant throughout the years (95%CI [0.69, 0.84] and [0.99, 1.03], respectively). The total payment difference between female and males was $102,175 per provider in 2012, and this gap widened by $18,292 yearly (95% CI [-162599.17, -41760.47], [-33060.35, -3524.38], respectively).Conclusion: While male and female providers saw considerable increases in aflibercept services and payments in the 5-year period, the gap between male and female reimbursements widened significantly. Moving forward, analysis of large-scale Medicare datasets provides a tangible report card on how effective our attitudes and policies are in cultivating equal opportunity.

Epicutaneous Staphylococcus aureus induces IL-36 to enhance IgE production and ensuing allergic disease.

IgE induced by type 2 immune responses in atopic dermatitis is implicated in the progression of atopic dermatitis to other allergic diseases, including food allergies, allergic rhinitis, and asthma. However, the keratinocyte-derived signals that promote IgE and ensuing allergic diseases remain unclear. Herein, in a mouse model of atopic dermatitis-like skin inflammation induced by epicutaneous Staphylococcus aureus exposure, keratinocyte release of IL­36α along with IL-4 triggered B cell IgE class-switching, plasma cell differentiation, and increased serum IgE levels-all of which were abrogated in IL-36R-deficient mice or anti-IL­36R-blocking antibody-treated mice. Moreover, skin allergen sensitization during S. aureus epicutaneous exposure-induced IL-36 responses was required for the development of allergen-specific lung inflammation. In translating these findings, elevated IL­36 cytokines in human atopic dermatitis skin and in IL­36 receptor antagonist-deficiency patients coincided with increased serum IgE levels. Collectively, keratinocyte-initiated IL­36 responses represent a key mechanism and potential therapeutic target against allergic diseases.

Eye injuries in the National Hockey League from 2010 to 2018: an analysis of injury rates, mechanisms, and the National Hockey League visor policy.

OBJECTIVE: We aim to assess the efficacy of widespread visor adoption by assessing eye injury rates during the 2010-2018 seasons. We also compare injury rates, missed games, and financial losses to previously reported data in order to track progress over time. Lastly, we characterize the mechanism and type of eye injuries sustained by National Hockey League (NHL) players to examine risk areas within NHL games. DESIGN: We performed a retrospective review of NHL player injuries using official NHL team reports, ProSportsTransactions, and TSN Sports. PARTICIPANTS: All NHL players who suffered an eye injury from 2010 to 2018 were included; 31 injuries matched this criterion. METHODS: Trends in injuries, missed games, and financial losses over time were analyzed using Pearson's correlation coefficients. Wilcoxon-Mann-Whitney tests were performed to compare our data with eye injury data. Fisher's exact test was performed to assess significance between mechanism and type of eye injury and outcome. RESULTS: There were 31 total eye injuries causing 233 missed games and a total of US$8 951 000 in financial losses across the 2010-2018 seasons. There was a strong decrease in the number of eye injuries (r = -0.83, p = 0.01) and a moderate decrease in number of missed games (r = -0.62, p = 0.09). Injuries due to direct puck strikes contributed to over US$6.5 million in financial losses and led to significantly more missed games compared with stick injuries (14.6 vs 4.3). CONCLUSION: We tangibly demonstrate the financial and physical effects of recent safety interventions and indicate areas for improved safety in the NHL.

Seasonal variability in public searches of keratosis pilaris: How the internet can illuminate a pattern in public interest.

In this study, we examine keratosis pilaris search patterns using Google Trends to determine any seasonality. Monthly searches were collected from January 2004 to January 2020 using "keratosis pilaris" as the search term in the Google Trends database. The US search data were compared to monthly temperatures and tested for correlation. Worldwide search interest was also acquired and, along with the US data, a two-model analysis was performed to determine any seasonal patterns. Peaks in search interest closely overlapped with higher temperatures in the United States and showed correlation (.44; P < .0001). The US and worldwide search interest also exhibited seasonality, which was confirmed with a sinusoidal regression being the best-fit model (R2 = .867 and .895). These results show higher search volume during warmer months in the United States and a clear cyclical pattern in searches worldwide and in the United States. Examination of these trends could elucidate peaks that health care providers may not have been aware of yielding improved resource allocation and preparedness for larger volume periods. This information in conjunction with clinical data could also shed more light in the future on potential peak seasons of incidence and prevalence.

Clonal Vγ6+Vδ4+ T cells promote IL-17-mediated immunity against Staphylococcus aureus skin infection.

T cell cytokines contribute to immunity against Staphylococcus aureus, but the predominant T cell subsets involved are unclear. In an S. aureus skin infection mouse model, we found that the IL-17 response was mediated by γδ T cells, which trafficked from lymph nodes to the infected skin to induce neutrophil recruitment, proinflammatory cytokines IL-1α, IL-1ß, and TNF, and host defense peptides. RNA-seq for TRG and TRD sequences in lymph nodes and skin revealed a single clonotypic expansion of the encoded complementarity-determining region 3 amino acid sequence, which could be generated by canonical nucleotide sequences of TRGV5 or TRGV6 and TRDV4 However, only TRGV6 and TRDV4 but not TRGV5 sequences expanded. Finally, Vγ6+ T cells were a predominant γδ T cell subset that produced IL-17A as well as IL-22, TNF, and IFNγ, indicating a broad and substantial role for clonal Vγ6+Vδ4+ T cells in immunity against S. aureus skin infections.

Injury, dysbiosis, and filaggrin deficiency drive skin inflammation through keratinocyte IL-1α release.

BACKGROUND: Atopic dermatitis (AD) is associated with epidermal barrier defects, dysbiosis, and skin injury caused by scratching. In particular, the barrier-defective epidermis in patients with AD with loss-of-function filaggrin mutations has increased IL-1α and IL-1ß levels, but the mechanisms by which IL-1α, IL-1ß, or both are induced and whether they contribute to the aberrant skin inflammation in patients with AD is unknown. OBJECTIVE: We sought to determine the mechanisms through which skin injury, dysbiosis, and increased epidermal IL-1α and IL-1ß levels contribute to development of skin inflammation in a mouse model of injury-induced skin inflammation in filaggrin-deficient mice without the matted mutation (ft/ft mice). METHODS: Skin injury of wild-type, ft/ft, and myeloid differentiation primary response gene-88-deficient ft/ft mice was performed, and ensuing skin inflammation was evaluated by using digital photography, histologic analysis, and flow cytometry. IL-1α and IL-1ß protein expression was measured by means of ELISA and visualized by using immunofluorescence and immunoelectron microscopy. Composition of the skin microbiome was determined by using 16S rDNA sequencing. RESULTS: Skin injury of ft/ft mice induced chronic skin inflammation involving dysbiosis-driven intracellular IL-1α release from keratinocytes. IL-1α was necessary and sufficient for skin inflammation in vivo and secreted from keratinocytes by various stimuli in vitro. Topical antibiotics or cohousing of ft/ft mice with unaffected wild-type mice to alter or intermix skin microbiota, respectively, resolved the skin inflammation and restored keratinocyte intracellular IL-1α localization. CONCLUSIONS: Taken together, skin injury, dysbiosis, and filaggrin deficiency triggered keratinocyte intracellular IL-1α release that was sufficient to drive chronic skin inflammation, which has implications for AD pathogenesis and potential therapeutic targets.