Paradoxical Psoriasiform Eruptions in Children Receiving Tumor Necrosis Factor α Inhibitors.

Importance: Tumor necrosis factor α (TNF) inhibitor-induced psoriasiform eruption is well recognized in adults, but few reports document this paradoxical effect in children. Objective: To characterize the clinical features and the clinical time course of TNF inhibitor-induced psoriasiform eruptions in children. Design, Setting, and Participants: A multicenter retrospective case series of children younger than 18 years seen between January 1, 2000, and December 31, 2016, who developed a new-onset psoriasiform eruption while taking a TNF inhibitor for a nondermatologic disorder. Participating sites were members of the Pediatric Dermatology Research Alliance. Data were entered into a Research Electronic Data Capture database at the Mayo Clinic (ie, the coordinating center). Results: Psoriasiform eruptions were identified in 103 TNF inhibitor-treated patients (median age, 13.8 years [IQR, 11.7-16.4 years]; 52 female patients [50%]; 57 White patients [55%]), with 67 patients (65%) treated with infliximab, 35 (34%) with adalimumab, and 1 (1%) with certolizumab pegol. Most patients had no personal history (101 [98%]) or family history of psoriasis (60 patients [58%]). Inflammatory bowel disease was the most common indication for treatment with TNF inhibitor (94 patients [91%]). The primary extracutaneous disease was under control in 95 patients (92%) who developed the eruption. Most patients (n = 85 [83%]) developed psoriasiform eruptions at multiple anatomic sites, with scalp involvement being most common (65 patients [63%]). Skin disease developed at a median of 14.5 months (IQR, 9-24 months) after TNF inhibitor initiation. To treat the psoriasiform eruption, topical steroidal and nonsteroidal medication was prescribed for all patients. Systemic therapy was added for 30 patients (29%): methotrexate for 24 patients (23%), oral corticosteroids for 8 patients (8%), and azathioprine for 1 patient (1%). For 26 patients (25%), suboptimal effectiveness with topical medications alone prompted discontinuation of the initial TNF inhibitor and a change to a second-line TNF inhibitor with cutaneous improvement in 23 patients (88%) by a median of 3 months (IQR, 2-4 months). Eight patients (31%) who started a second-line TNF inhibitor developed a subsequent TNF inhibitor-induced psoriasiform eruption at a median of 6 months (IQR, 4-8 months). Persistent skin disease in 18 patients (17%) prompted discontinuation of all TNF inhibitors; 11 patients changed to a non-TNF inhibitor systemic therapy, and 7 discontinued all systemic therapy. Conclusions and Relevance: In this case series, paradoxical TNF inhibitor-induced psoriasiform eruptions were seen in children treated with TNF inhibitors for any indication, and there appears to be a class effect among the varying TNF inhibitors. The majority of these children were able to continue TNF inhibitor therapy with adequate skin-directed and other adjuvant therapies.

Secukinumab responses vary across the spectrum of congenital ichthyosis in adults.

IMPORTANCE: Treatment of congenital ichthyoses primarily focuses on reversing skin scaling and is not pathogenesis based. Recent studies showed Th17 immune skewing, as in psoriasis, across the spectrum of ichthyosis, suggesting that targeting this pathway might broadly reduce disease severity. OBJECTIVE: To determine whether secukinumab, an IL-17A inhibitor, can improve ichthyosis across several congenital ichthyosis subtypes. DESIGN: Exploratory 16-week double-blind, randomized, placebo-controlled trial comparing secukinumab 300 mg every 4wks to placebo (1:1 randomization) in adults with the four major congenital ichthyosis subtypes (NCT03041038), followed by a 16-week open-label phase to evaluate response of the placebo-first group and a 20-week extension for safety. Significant differences in secukinumab- vs. placebo-treated subjects at Wk16 in the Ichthyosis Area Severity Index (IASI) score and lack of increased mucocutaneous bacterial and/or fungal infections were the co-primary efficacy and safety endpoints, respectively. SETTING: Two tertiary referral centers: Northwestern University Feinberg School of Medicine, Chicago, and Mount Sinai Icahn School of Medicine, New York. PARTICIPANTS: Twenty subjects ≥ 18 yo with genotype-confirmed epidermolytic ichthyosis, Netherton syndrome, lamellar ichthyosis, or congenital ichthyosiform erythroderma with at least moderate erythroderma. RESULTS: IL-17A inhibition did not significantly reduce severity or increase mucocutaneous infections among the 18 who completed the 16-week double-blind phase. Five patients with 29-50% clinical improvement at Wk32 requested drug continuation. Th17-related biomarkers were not significantly reduced vs. baseline or placebo-treated levels. LIMITATIONS: Small sample size; heterogeneous ichthyosis subsets. CONCLUSION: IL-17 inhibition with secukinumab is safe, but not efficacious across the spectrum of adult ichthyoses. GOV REGISTRATION NUMBER: NCT03041038; first posted on 02/02/2017.

A phase 2a randomized vehicle-controlled multi-center study of the safety and efficacy of delgocitinib in subjects with moderate-to-severe alopecia areata.

Alopecia areata/AA is an autoimmune cause of nonscarring hair loss. The pathogenesis of AA involves many immune axes, including Th1/Th2 pathways. Delgocitinib is a pan-Janus kinase/JAK inhibitor that broadly blocks pro-inflammatory cytokines and has been effective in other inflammatory skin conditions. Recent human studies/reports have shown that use of some systemic JAK inhibitors led to hair regrowth, suggesting this medication class as a potential therapy for AA. However, topical treatment is desirable due to potential systemic side effects. To assess the efficacy and safety of topical delgocitinib in AA, we conducted a double-blind, randomized, vehicle-controlled clinical trial in 31 moderate-to-severe AA patients that were randomized 2:1 to receive delgocitinib ointment 30 mg/g (n = 20) or ointment vehicle (n = 11) for 12 weeks. The primary endpoint was change in severity of Alopecia Tool/SALT score from baseline to week 12. The secondary endpoint included safety profile by reported adverse events. Twenty-three subjects completed the trial, with eight discontinuing mostly due to voluntary withdrawal. Ten patients receiving delgocitinib ointment and three patients receiving vehicle showed SALT score improvements after 12 weeks, but the mean percent SALT improvement at week 12 compared to baseline between the two arms was not significant (p = 0.92). Our study suggests that delgocitinib ointment is not effective in moderate-to-severe AA, likely due to its inability to penetrate sufficiently deeply into the dermis of the scalp, but larger studies are necessary to assess whether a different formulation of topical JAK inhibitors may be suitable to treat mild or more localized forms of AA.

Distinct skin microbiome community structures in congenital ichthyosis.

BACKGROUND: The ichthyoses are rare genetic keratinizing disorders that share the characteristics of an impaired epidermal barrier and increased risk of microbial infections. Although ichthyotic diseases share a T helper (Th) 17 cell immune signature, including increased expression of antimicrobial peptides, the skin microbiota of ichthyoses is virtually unexplored. OBJECTIVES: To analyse the metagenome profile of skin microbiome for major congenital ichthyosis subtypes. METHODS: Body site-matched skin surface samples were collected from the scalp, upper arm and upper buttocks of 16 healthy control participants and 22 adult patients with congenital forms of ichthyosis for whole metagenomics sequencing analysis. RESULTS: Taxonomic profiling showed significant shifts in bacteria and fungi abundance and sporadic viral increases across ichthyosis subtypes. Cutibacterium acnes and Malassezia were significantly reduced across body sites, consistent with skin barrier disruption and depletion of lipids. Microbial richness was reduced, with specific increases in Staphylococcus and Corynebacterium genera, as well as shifts in fungal species, including Malassezia. Malassezia globosa was reduced at all body sites, whereas M. sympodialis was reduced in the ichthyotic upper arm and upper buttocks. Malassezia slooffiae, by contrast, was strikingly increased at all body sites in participants with congenital ichthyosiform erythroderma (CIE) and lamellar ichthyosis (LI). A previously undescribed Trichophyton species was also detected as sporadically colonizing the skin of patients with CIE, LI and epidermolytic ichthyosis subtypes. CONCLUSIONS: The ichthyosis skin microbiome is significantly altered from healthy skin with specific changes predominating among ichthyosis subtypes. Skewing towards the Th17 pathway may represent a response to the altered microbial colonization in ichthyosis. What is already known about this topic? The skin microbiome of congenital ichthyoses is largely unexplored. Microbes play an important role in pathogenesis, as infections are common. The relative abundances of staphylococci and corynebacteria is increased in the cutaneous microbiome of patients with Netherton syndrome, but extension of these abundances to all congenital ichthyoses is unexplored. What does this study add? A common skin microbiome signature was observed across congenital ichthyoses. Distinct microbiome features were associated with ichthyosis subtypes. Changes in microbiome may contribute to T helper 17 cell immune polarization. What is the translational message? These data provide the basis for comparison of the microbiome with lipidomic and transcriptomic alterations in these forms of ichthyosis and consideration of correcting the dysbiosis as a therapeutic intervention.

Transcriptomic Analysis of the Major Orphan Ichthyosis Subtypes Reveals Shared Immune and Barrier Signatures.

Preliminary work suggested upregulation of inflammatory pathways in patients with common forms of ichthyosis. However, a comprehensive characterization of skin from various ichthyosis subtypes is unavailable, precluding the development of targeted treatments. Thus, we sought to characterize the immune and barrier profiles of common and subtype-specific skin transcriptomes in a large group of patients with ichthyosis. We performed a global RNA-sequencing analysis in 54 patients with ichthyosis (7 with Netherton syndrome, 13 with epidermolytic ichthyosis, 16 with lamellar ichthyosis, and 18 with congenital ichthyosiform erythroderma) and 40 healthy controls. Differentially expressed genes were defined on the basis of fold changes > 2 and false discovery rate < 0.05 criteria. We found robust and significant T helper (Th) 22/Th17 skewing in all subtypes (e.g., IL-17A/C/F, S100A7/8/9/12; P < 0.001) with modest changes in Th2 pathway, primarily in Netherton syndrome, and Th1 skewing in congenital ichthyosiform erythroderma. Across all subtypes (less evident in epidermolytic ichthyosis), lipid metabolism and barrier junction markers were downregulated (e.g., FA2H, CDH10/11/12/2; P < 0.05), whereas epidermal cornification and proliferation measures were upregulated (e.g., SPRR1A/1B/2C/2G, EREG; P < 0.05). Our findings suggest that the common ichthyosis variants share aberrations in Th17/Th22 and barrier function, with minimal Th2 modulation. This may help to elucidate the pathogeneses of these subtypes and inform the development of subtype-specific treatments.

Transepidermal water loss in the orphan forms of ichthyosis.

As a surrogate measure of skin barrier dysfunction, we sought to determine differences in transepidermal water loss (TEWL) among ichthyosis subtypes and correlate TEWL with clinical severity. Subjects with Netherton syndrome had the highest TEWL values (increased water loss), while TEWL values were lowest in subjects with epidermolytic ichthyosis. TEWL correlated with severity only in lamellar ichthyosis and age was inversely correlated with TEWL (rs  = -.213, P = .02). TEWL is an objective measure that complements disease severity in ichthyosis and may be used as an adjuvant to monitor treatment response.

A Brief Dermatology Curriculum in Skin Cancer Detection and Prevention to Improve Medical Student Knowledge and Confidence.

Introduction: While the incidence of skin cancers continues to rise, there remains a disproportionate lack of introductory training on skin cancer screening and identification of modifiable behaviors in medical curricula. Trainees and students have cited low confidence in their ability to counsel patients and lack of instruction as barriers. Methods: To address this need, we created a 1-hour didactic lecture based on a cognitive teaching framework for third-year medical students during their core primary care clerkship. The session highlighted visual identification of different skin cancers, factors increasing individual risk, and photoprotective behaviors. Session content was based on American Academy of Dermatology recommendations for skin cancer prevention. An assessment of knowledge, behaviors, and attitudes given before, immediately following, and at 6 months after the session was used to determine efficacy. Results: One hundred eight students before and immediately after the session demonstrated significantly improved knowledge (mean correct: 71% presession vs. 99% postintervention, p < .0001). Based on 39 participants completing 6-month follow-up, knowledge remained improved (mean answered correctly: 80%, p < .0001). Confidence in patient counseling on preventive behaviors, risk assessment, and reported likelihood of counseling significantly increased across the three time points (p < .0001 for all attitude questions). Specific topics included appropriate referral to a dermatologist, sunscreen application, and dangers of indoor tanning bed usage. Discussion: Our session on skin cancer screening and prevention demonstrated improvements in medical student knowledge, confidence, and patient counseling likelihood. This introductory curriculum could be adapted for multiple core clerkships or specialties.

Epidemiology of alopecia areata, ophiasis, totalis, and universalis: A systematic review and meta-analysis.

BACKGROUND: Alopecia areata (AA) is a common autoimmune alopecia with heterogeneous severity and distribution. Previous studies found conflicting results about AA epidemiology. OBJECTIVE: To determine the prevalence, incidence, and predictors of AA, alopecia totalis, alopecia ophiasis, and alopecia universalis. METHODS: A systematic review of all published cohort and cross-sectional studies that analyzed AA and its subtypes. MEDLINE, Embase, LILACS, Scopus, Cochrane Library, and GREAT were searched. At least 2 reviewers performed study title/abstract review and data extraction. Random-effects meta-analysis was used because of significant heterogeneity (I2 = 99.97%). RESULTS: Ninety-four studies met the inclusion criteria. The pooled prevalence (95% confidence interval, N) of AA overall was 2.11% (1.82-2.42, N = 302,157,365), with differences of population-based (0.75% [0.49-1.06%], N = 301,173,403) and clinic-based (3.47% [3.01-3.96], N = 983,962) studies. The prevalences of alopecia totalis, ophiasis, and universalis were 0.08% (0.04-0.13, N = 1,088,149), 0.02% (0.00-0.06, N = 1,075,203), and 0.03% (0.01-0.06, N = 1,085,444), respectively. AA prevalence (95% confidence interval) increased over time (<2000: 1.02% [0.85-1.22]; 2000-2009: 1.76% [1.51-2.03]; >2009: 3.22% [2.59-3.92]; P < .0001) and differed by region. AA prevalence was significantly lower in adults (1.47% [1.18-1.80]) than children (1.92% [1.31-2.65]; P < .0001). CONCLUSIONS: AA affects 2% of the global population. AA prevalence is lower in adults than children, is increasing over time, and significantly differs by region.

Binodal, wireless epidermal electronic systems with in-sensor analytics for neonatal intensive care.

Existing vital sign monitoring systems in the neonatal intensive care unit (NICU) require multiple wires connected to rigid sensors with strongly adherent interfaces to the skin. We introduce a pair of ultrathin, soft, skin-like electronic devices whose coordinated, wireless operation reproduces the functionality of these traditional technologies but bypasses their intrinsic limitations. The enabling advances in engineering science include designs that support wireless, battery-free operation; real-time, in-sensor data analytics; time-synchronized, continuous data streaming; soft mechanics and gentle adhesive interfaces to the skin; and compatibility with visual inspection and with medical imaging techniques used in the NICU. Preliminary studies on neonates admitted to operating NICUs demonstrate performance comparable to the most advanced clinical-standard monitoring systems.

The Medical and Psychosocial Associations of Alopecia: Recognizing Hair Loss as More Than a Cosmetic Concern.

Alopecia encompasses a broad range of hair loss disorders, generally categorized into scarring and non-scarring forms. Depending on the specific pathogenesis of hair loss and geographic location, a number of psychiatric and medical comorbidities, including but not limited to thyroid disease, lupus erythematosus, diabetes mellitus, atopic dermatitis, sinusitis, coronary artery disease, anxiety, depression, and suicidality, have been identified in association with alopecia. In addition to the numerous associated comorbid conditions, patients with alopecia report decreased quality-of-life measures across symptomatic, functional, and global domains. While alopecia can affect patients of all ages, genders, and ethnicities, hair loss may more significantly impact women as hair represents an essential element of femininity, fertility, and female attractiveness in society. Individuals of lower socioeconomic status may also face health disparities in the context of alopecia as a majority of hair loss treatments are considered cosmetic in nature and accordingly are not covered by third-party insurance providers. Although traditionally thought of as a merely aesthetic concern, alopecia encompasses a significant burden of disease with well-defined comorbid associations and genuine psychosocial implications, and thus should be assessed and managed within a proper medical paradigm.

IL-23 inhibitors for moderate-to-severe psoriasis.

Since the identification of high levels of interleukin 23 (IL- 23) in psoriasis lesional skin, as well as finding that IL-23 was the most important source of the p40 subunit shared by IL-12 and IL-23, significant effort has been made in identifying potential new drugs that specifically block the unique IL-23 p19 subunit. At this time, 2 inhibitors of IL-23 p19 have been approved by the United States Food and Drug Administration, guselkumab and tildrakizumab. Two other agents, risankizumab and mirikizumab, have completed phase 3 and phase 2 of development, respectively. Pivotal trials in the development of these agents and clinical use of the approved agents are discussed. Thus far, this class of medications seems to provide a high level of efficacy, along with infrequent dosing and very favorable safety results.

Rate of serious infection in patients who are prescribed systemic biologic or nonbiologic agents for psoriasis: A large, single center, retrospective, observational cohort study.

BACKGROUND: Systemic biologic and nonbiologic agents used to treat psoriasis may or may not contribute to serious infection (SI) risk. Safety data, particularly for biologic agents, and associated risk for SI, are scarce. The study's aim was to explore the risk for SI in psoriasis patients exposed to systemic biologic or nonbiologic agents. METHODS: A large, single-center electronic medical record repository was searched between January 2010 and December 2014. Records for patients prescribed a systemic agent for psoriasis (SAP) with psoriasis or psoriatic arthritis diagnoses were included (ICD-9 codes 696.1 and 696.0, respectively). SIs were those who required hospitalization, and/or injectable antibacterial, antiviral or antifungal therapy. SIs occurring within 120 days after exposure to a SAP, were included for study. RESULTS: A total of 1,346 patients were exposed to a SAP between January 2010 and December 2014; 27 (2%) had a SI. Comparing biologic and nonbiologic agent exposure, no statistically significant difference for risk of SI was detectable (p = .83). CONCLUSION: In this population, the SI rate for biologic and nonbiologic systemic agents was clinically indistinguishable, thereby supporting consideration of the entire spectrum of available systemic therapeutic agents, both biologic and nonbiologic agents, for management of moderate to severe psoriasis.

Racial differences in opiate administration for pain relief at an academic emergency department.

INTRODUCTION: The decision to treat pain in the emergency department (ED) is a complex, idiosyncratic process. Prior studies have shown that EDs undertreat pain. Several studies demonstrate an association between analgesia administration and race. This is the first Midwest single institution study to address the question of race and analgesia, in addition to examining the effects of both patient and physician characteristics on race-based disparities in analgesia administration. METHODS: This was a retrospective chart review of patients presenting to an urban academic ED with an isolated diagnosis of back pain, migraine, or long bone fracture (LBF) from January 1, 2007 to December 31, 2011. Demographic and medication administration information was collected from patient charts by trained data collectors blinded to the hypothesis of the study. The primary outcome was the proportion of African-Americans who received analgesia and opiates, as compared to Caucasians, using Pearson's chi-squared test. We developed a multiple logistic regression model to identify which physician and patient characteristics correlated with increased opiate administration. RESULTS: Of the 2,461 patients meeting inclusion criteria, 57% were African-American and 30% Caucasian (n=2136). There was no statistically significant racial difference in the administration of any analgesia (back pain: 86% vs. 86%, p=0.81; migraine: 83% vs. 73%, p=0.09; LBF: 94% vs. 90%, p=0.17), or in opiate administration for migraine or LBF. African-Americans who presented with back pain were less likely to receive an opiate than Caucasians (50% vs. 72%, p<0.001). Secondary outcomes showed that higher acuity, older age, physician training in emergency medicine, and male physicians were positively associated with opiate administration. Neither race nor gender patient-physician congruency correlated with opiate administration. CONCLUSION: No race-based disparity in overall analgesia administration was noted for all three conditions: LBF, migraine, and back pain at this institution. A race-based disparity in the likelihood of receiving opiate analgesia for back pain was observed in this ED. The etiology of this is likely multifactorial, but understanding physician and patient characteristics of institutions may help to decrease the disparity by raising awareness of practice patterns and can provide the basis for quality improvement projects.