Intrapatient comparison of atopic dermatitis skin transcriptome shows differences between tape-strips and biopsies.

BACKGROUND: Our knowledge of etiopathogenesis of atopic dermatitis (AD) is largely derived from skin biopsies, which are associated with pain, scarring and infection. In contrast, tape-stripping is a minimally invasive, nonscarring technique to collect skin samples. METHODS: To construct a global AD skin transcriptomic profile comparing tape-strips to whole-skin biopsies, we performed RNA-seq on tape-strips and biopsies taken from the lesional skin of 20 moderate-to-severe AD patients and the skin of 20 controls. Differentially expressed genes (DEGs) were defined by fold-change (FCH) ≥2.0 and false discovery rate <0.05. RESULTS: We detected 4104 (2513 Up; 1591 Down) and 1273 (546 Up; 727 Down) DEGs in AD versus controls, in tape-strips and biopsies, respectively. Although both techniques captured dysregulation of key immune genes, tape-strips showed higher FCHs for innate immunity (IL-1B, IL-8), dendritic cell (ITGAX/CD11C, FCER1A), Th2 (IL-13, CCL17, TNFRSF4/OX40), and Th17 (CCL20, CXCL1) products, while biopsies showed higher upregulation of Th22 associated genes (IL-22, S100As) and dermal cytokines (IFN-γ, CCL26). Itch-related genes (IL-31, TRPV3) were preferentially captured by tape-strips. Epidermal barrier abnormalities were detected in both techniques, with terminal differentiation defects (FLG2, PSORS1C2) better represented by tape-strips and epidermal hyperplasia changes (KRT16, MKI67) better detected by biopsies. CONCLUSIONS: Tape-strips and biopsies capture overlapping but distinct features of the AD molecular signature, suggesting their respective utility for monitoring specific AD-related immune, itch, and barrier abnormalities in clinical trials and longitudinal studies.

Clinical and molecular effects of oral CCR4 antagonist RPT193 in atopic dermatitis: A Phase 1 study.

BACKGROUND: RPT193 is an orally administered small molecule antagonist of the human C-C motif chemokine receptor 4 (CCR4) that inhibits the migration and downstream activation of T-helper Type 2 (Th2) cells. We investigated single- and multiple-ascending doses of RPT193 in healthy subjects, and multiple doses of RPT193 in subjects with moderate-to-severe atopic dermatitis (AD). METHODS: This was a first-in-human randomized, placebo-controlled Phase 1a/1b monotherapy study (NCT04271514) to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and CCR4 surface receptor occupancy in eligible healthy subjects and subjects with moderate-to-severe AD. Clinical efficacy and skin biomarker effects of RPT193 monotherapy were assessed as exploratory endpoints in AD subjects. RESULTS: In healthy (n = 72) and AD subjects (n = 31), once-daily RPT193 treatment was generally well tolerated, with no serious adverse events reported and all treatment-emergent adverse events reported as mild/moderate. In AD subjects, numerically greater improvements in clinical efficacy endpoints were observed with RPT193 monotherapy versus placebo up to the end of the treatment period (Day 29), with statistically significant improvement, compared to Day 29 and placebo, observed 2 weeks after the end of treatment (Day 43) on several endpoints (p < .05). Moreover, significant changes in the transcriptional profile were seen in skin biopsies of RPT193-treated versus placebo-treated subjects at Day 29, which were also significantly correlated with improvements in clinical efficacy measures. CONCLUSIONS: To our knowledge, this is the first clinical study with an oral CCR4 antagonist that showed clinical improvement coupled with modulation of the cutaneous transcriptomic profile in an inflammatory skin disease.

Age of onset defines two distinct profiles of atopic dermatitis in adults.

BACKGROUND: The incidence of adult-onset atopic dermatitis (AOAD) is increasing. However, the unique characteristics of AOAD compared to pediatric-onset AD persisting into adulthood (POAD) are underexplored, hampering the development of targeted-therapeutics for this growing population. We thus assessed the profile of AOAD in skin and blood compared to that of POAD. METHODS: We collected skin biopsies and blood from adults with AOAD, POAD, and healthy controls (n = 15 in each group). Skin samples were analyzed by RNA sequencing, qRT-PCR, and immunohistochemistry, and Olink Proseek multiplex assay was used to identify the serum proteomic profile. RESULTS: Compared to healthy controls, both AOAD and POAD showed cutaneous immune and barrier dysregulations with a shared Th2/Th22 hyperactivation. Overall, POAD showed greater inflammation in lesional skin, with more prominent expression of Th2/Th17/Th22 markers (CCL17/22, S100A8/9, IL-36A, PI3/Elafin, DEFB4) in POAD compared to AOAD (p-value < .05). In contrast, higher Th1-(IFN-γ, IL-2, IL-15, CCL5) upregulation and Th1-skewing were seen in AOAD. The epidermal barrier was also more compromised in POAD, with greater epidermal hyperplasia and lower expression of markers related to terminal differentiation, lipids, and cell adhesion. In parallel with increased rates of cardiovascular comorbidities, AOAD demonstrated many more significantly dysregulated proteins in serum (n = 148) compared to POAD (n = 86), including pro-inflammatory and cardiovascular-risk markers. Th1-related products showed significant correlations between their skin and blood expressions only in AOAD subjects. CONCLUSION: Age-of-onset delineates two distinct endophenotypes in adult AD potentially suggesting the need for broader (beyond Th2) therapeutic targeting in AOAD.

Scalp biomarkers during dupilumab treatment support Th2 pathway pathogenicity in alopecia areata.

BACKGROUND: The mechanisms driving alopecia areata (AA) are still unclear, hindering development of targeted therapeutics. Specific Th2 targeting with dupilumab in AA provides a unique opportunity to dissect its pathogenesis and explore the role of Th2 pathway. METHODS: We evaluated changes in scalp biomarkers in AA patients (with and without concomitant atopy) randomized to weekly dupilumab or placebo for 24 weeks, followed by open-label dupilumab for 24 weeks. Changes in biomarker levels were measured at weeks 12, 24, and 48 and were also correlated with clinical hair regrowth. RESULTS: At week 24, preceding clinical hair regrowth outcomes, only dupilumab-treated patients presented significant suppression of cellular infiltrates, and multiple Th2-related, markers (CCL13/MCP-4, CCL18/PARC, CCL26/eotaxin-3, CCL24/Eotaxin-2), coupled with significant upregulation in the hair keratins. Th1-related suppression was evident later (week 48) when all patients received open-label dupilumab. Results were more pronounced in atopic AA patients, that showed 48% and 97% improvements in the lesional AA scalp profile at weeks 24 and 48, respectively, while 2% worsening was seen in the placebo arm at week 24. Moreover, placebo-treated patients presented 54% worsening in hair keratins when compared with baseline at week 24. At week 24, increases in hair keratins showed significant correlations only with decreases in Th2-related markers. CONCLUSIONS: Scalp biomarkers provide evidence of dupilumab efficacy in AA, detected even prior to clinical response, with exclusive correlations between early suppression of Th2 markers and increased hair keratins. These findings strengthen previous reports suggesting a possible role for Th2 cytokines as AA drivers.

Cross-Sectional Study of Psoriasis, Atopic Dermatitis, Rosacea, and Alopecia Areata Suggests Association With Cardiovascular Diseases.

BACKGROUND: A growing body of evidence suggests that several inflammatory skin diseases (ISDs) are associated with systemic inflammation and cardiovascular disease (CVDs). METHODS: We used the TriNetX analytics platform to conduct a retrospective, cross-sectional, single-center study in the Mount Sinai Health System network. Cases (all patients ≥18 years of age with a diagnosis of 1 of the 4 ISDs studied) were compared with matched controls (no history of any of these ISDs) to evaluate odds ratios for being diagnosed with CVD. RESULTS: We identified a total of 70,090 patients with ISDs, including 35,160 patients with atopic dermatitis, 19,490 with psoriasis, 12,470 with rosacea, and 2,970 with alopecia areata, and 70,090 propensity score-matched controls without any of these ISDs. Patients with atopic dermatitis and psoriasis had significantly increased odds of all CVD diagnoses analyzed compared to controls (P<0.001 for all comparisons). Patients with rosacea had significantly increased odds of being diagnosed with all diseases of the circulatory system (P<0.001), hypertensive diseases (P<0.001), cerebrovascular diseases (P=0.037), and arterial disease (P<0.001) compared to controls. Patients with alopecia areata had increased odds for all diseases of the circulatory system (P<0.001), hypertensive diseases (P<0.001), and arterial disease (P<0.001). The prevalence of patients with elevated C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) levels was significantly greater in all ISD groups compared to controls. CONCLUSION: This study identified significant associations between ISDs and several CVD diagnoses. Furthermore, CRP and ESR were elevated in all ISD groups compared to controls. Pagan AD, Jung S, Caldas S, et al. Cross-sectional study of psoriasis, atopic dermatitis, rosacea, and alopecia areata suggests association with cardiovascular diseases. J Drugs Dermatol. 2023;22(6):576-581. doi:10.36849/JDD.7424.

Seasonal Patterns in Tetracycline-Associated Hyperpigmentation Among Patients With Acne Vulgaris.

BACKGROUND: Oral tetracyclines (TCNs) are commonly prescribed for acne, but they have been shown to increase the risk of hyperpigmentation, particularly in the setting of sun exposure. OBJECTIVE: We evaluated seasonal trends in TCN-associated hyperpigmentation incidence in addition to Google search trends for hyperpigmentation-related terms. METHODS: We performed a retrospective review of acne patients seen at Massachusetts General Brigham and Women’s Hospital between 1992 and 2022. We calculated the incidence of new hyperpigmentation diagnoses for each drug cohort. We also analyzed search volume of hyperpigmentation-related terms extracted from Google Trends. RESULTS: Seasonal differences in new hyperpigmentation diagnoses were identified among acne patients prescribed doxycycline (P=0.016), with peak incidence in April. In the control group of patients who had never received a TCN, diagnoses peaked in May. There were no significant seasonal differences among patients prescribed minocycline (P=0.885). There was greater search volume for hyperpigmentation-related terms in spring and summer compared to fall and winter (P<0.001). Limitations of this study include its retrospective nature and reliance on prescription and diagnosis coding data. CONCLUSIONS: Our findings support the seasonal periodicity of acne-related hyperpigmentation, underscoring the importance of photoprotection counseling for patients with acne. Additionally, doxycycline may be associated with an earlier onset of hyperpigmentation, suggesting a potential benefit of considering minocycline or other alternatives to doxycycline. J Drugs Dermatol. 2023;22(11):e9-e11    doi:10.36849/JDD.7409e.

Cartilage Grafting Outcomes in Intermediate and Definitive Cleft Rhinoplasty.

OBJECTIVE: To compare cartilage grafting outcomes in intermediate versus definitive cleft rhinoplasty. DESIGN: A retrospective chart review was conducted. The χ2 and Fisher exact tests were used for statistical analyses. Results were considered statistically significant at P < .05. PARTICIPANTS: All subjects who underwent revision cleft rhinoplasties between July 2011 and June 2019 were included. Subjects with syndromic conditions were excluded. RESULTS: A total of 46 subjects with a cleft nose deformity underwent 65 rhinoplasty procedures. The ages averaged 17 years (range 5-50) with 34 (73.9%) males and 12 (26.1%) females. In the intermediate group, 6 (28.6%) subjects required cartilage grafting as part of 6 cleft rhinoplasties, whereas 15 (71.4%) subjects underwent a total of 26 cleft rhinoplasties that did not require grafting. In the definitive group, 18 (76%) subjects required cartilage grafting over 21 cleft rhinoplasties, whereas 7 (24%) subjects underwent a total of 9 cleft rhinoplasties where cartilage grafting was not required. The difference between the number of subjects requiring cartilage grafting in the intermediate versus the definitive group was statistically significant (P = .007). Ear concha and nose were the most frequently used cartilage donor sites, with no observed complications. CONCLUSIONS: Cartilage grafting was significantly more common in the definitive rhinoplasty group. Intermediate cleft rhinoplasty during the 5- to 13-year age period was effective, with a low-risk profile. In our experience, ear concha and nose were the preferred cartilage donor sites, with effective results and an excellent safety profile.

Laser-Assisted Prostaglandin Analogs in the Treatment of Hypopigmented Scars: A Systematic Review.

Background: Hypopigmented scars are challenging to treat due to a lack of effective treatments and often transient results. Recent reports suggest that prostaglandin analog-induced hyperpigmentation may have favorable dermatological applications. Objective: Analyze previous studies involving the use of prostaglandin analogs in the treatment of hypopigmented scars. Methods: PubMed/Medline was queried through 10/01/2022 with the following search terms: (bimatoprost AND scar), (latanoprost AND scar), (travoprost AND scar), (prostaglandin analogs AND hypopigmented scars), (PGF2alpha AND hyperpigmentation), (prostaglandin analogs AND hyperpigmentation). Results: In total, 88 unique studies were reviewed for eligibility. Five studies met inclusion criteria including two prospective, double-blinded, randomized (only one was placebo-controlled), one prospective case series, one retrospective chart review, and one case report; comprising a total of 87 patients. All five studies utilized topical prostaglandin analogs as an adjunctive treatment via laser-assisted delivery. While both, the placebo-controlled and non-placebo-controlled, trials reported more than 75 percent of patients experienced at least 50 percent or more (Grade 3 or higher) improvement, the retrospective study reported 100 percent of patients experienced at least 75 percent or more (Grade 4 or higher) improvement, measured as scar repigmentation. The prospective case series and the reported single case showed overall qualitative improvement in all patients measured as repigmentation of hypopigmented and depigmented scars. Limitations: Different laser devices, parameters, treatment frequency, and follow-up timepoints. Conclusion: All studies evaluated demonstrated favorable treatment outcomes with no reported adverse events. Additional, large randomized controlled trials are needed to fully assess the effectiveness and long-term safety of PGF2α agonists for hypopigmented scars.

Applications of Laser Speckle Contrast Imaging Technology in Dermatology.

Laser speckle contrast imaging or laser speckle imaging (LSI) is a noninvasive imaging technology that can detect areas of dynamic perfusion or vascular flow. Thus, LSI has shown increasing diagnostic utility in various pathologies and has been employed for intraoperative, postoperative, and long-term monitoring in many medical specialties. Recently, LSI has gained traction in clinical dermatology because it can be effective in the assessment of pathologies that are associated with increased perfusion and hypervascularity compared with that of normal tissue. To date, LSI has been found to be highly accurate in monitoring skin graft reperfusion, determining the severity of burns, evaluating neurosurgical revascularization, assessing persistent perfusion in capillary malformations after laser therapy, and differentiating malignant and benign skin lesions. LSI affords the advantage of noninvasively assessing lesions before more invasive methods of diagnosis, such as tissue biopsy, while remaining inexpensive and exhibiting no adverse events to date. However, potential obstacles to its clinical use include tissue movement artifact, primarily qualitative data, and unclear impact on clinical practice given the lack of superiority data compared with the current standard-of-care diagnostic methods. In this review, we discuss the clinical applications of LSI in dermatology for use in the diagnosis and monitoring of vascular, neoplastic, and inflammatory skin conditions.

Dupilumab Improves Clinical Scores in Children and Adolescents With Moderate to Severe Atopic Dermatitis: A Real-World, Single-Center Study.

BACKGROUND: Dupilumab has proven safe and effective in children and adolescents with atopic dermatitis (AD) in clinical trials. However, comprehensive real-world studies in the pediatric AD population are still needed. OBJECTIVE: To characterize the long-term treatment responses and adverse events of dupilumab-treated children and adolescents with AD during dermatology follow-up assessments. METHODS: We reviewed electronic medical records from March 2017 to September 2021 of moderate to severe AD patients starting dupilumab at less than age 18 years. Demographics, AD scores (body surface area [BSA], Eczema Area and Severity Index [EASI], and Investigator's Global Assessment [IGA]) as well as safety data were collected. RESULTS: A total of 89 patients, 50 females (56.2%) and 39 males (43.8%), were included. Mean ± SD treatment duration was 1.3 ± 0.9 years. Of these, 73 had score assessments at baseline and weeks 12 to 24. Mean ± SD improvements in BSA, EASI, and IGA were 63.1% ± 29.2%, 39.6% ± 29.9%, and 59.6% ± 30.7%, respectively. All patients (n = 23) who received dupilumab for 1 year or more achieved 75% improvement in EASI and IGA 0/1, and 60.8% achieved 90% improvement in EASI. Positive history of atopy was associated with greater percent improvement in BSA at weeks 12 to 24 (P < .05). Twelve patients had adverse events (13.5%), of which conjunctivitis (5.6%) and joint pain (2.2%) were most common. There were no serious adverse events. CONCLUSIONS: Dupilumab was well-tolerated and effective in treating pediatric and adolescent AD regardless of age, sex, race, or ethnicity.

An Unusual Case of Deep Localized Scleroderma in a Patient with Chronic Kidney Disease.

Localized scleroderma (LS) is a rare fibrosing disorder of skin and underlying tissues. Although it can affect all races, it has a higher prevalence in whites. Deep LS is the least common among seven LS variants, representing less than 5% of cases, and typically affects areas of pressure such as the hips and waist. We report a unique clinical case of bilateral lower extremity deep LS in a 51-year-old Puerto Rican woman with chronic kidney disease (CKD). In patients with CKD, it is important to distinguish LS from nephrogenic systemic fibrosis (NSF). Both can present with skin fibrosis and contractures over joints yet have significantly differing treatment approaches and prognosis. Our case report is unique due to the patient's Puerto Rican ethnicity, CKD history, and isolated anterior lower extremity involvement. In this report, we highlight key clinical and histopathological findings of LS, and how they differ from that of NSF.

The role of MiT/TFE family members in autophagy regulation.

The MiT/TFE family of proteins are important regulators of a number of metabolic processes. One of their most important roles is activating the autophagy pathway in the setting of nutrient deprivation or buildup of toxic metabolites. Their proper and improper functioning in this role has been linked to several types of disease, including cancer and multiple forms of neurodegeneration. In this review we will briefly outline what is known about individual family members' roles in regulating autophagy across a variety of contexts.