Methotrexate for inflammatory skin disease in pediatric patients: Consensus treatment guidelines.

Methotrexate (MTX) is a readily accessible drug, first used in 1948 and employed for a wide variety of indications since then. However, despite widespread off-label use, FDA labeling does not include approved indications for the use of MTX for many inflammatory skin diseases in pediatric patients, including morphea, psoriasis, atopic dermatitis, and alopecia areata, among others. Without published treatment guidelines, some clinicians may be hesitant to use MTX off-label, or uncomfortable prescribing MTX in this population. To address this unmet need, an expert consensus committee was convened to develop evidence- and consensus-based guidelines for use of MTX to treat pediatric inflammatory skin disease. Clinicians with experience and expertise in clinical research, drug development, and treating inflammatory skin disease in pediatric patients with MTX were recruited. Five committees were created based on major topic areas: (1) indications and contraindications, (2) dosing, (3) interactions with immunizations and medications, (4) adverse effects (potential for and management of), and (5) monitoring needs. Pertinent questions were generated and addressed by the relevant committee. The entire group participated in a modified Delphi process to establish agreement on recommendations for each question. The committee developed 46 evidence- and consensus-based recommendations, each with >70% agreement among members, across all five topics. These are presented in tables and text, along with a discussion of supporting literature, and level of evidence. These evidence- and consensus-based recommendations will support safe and effective use of MTX for the underserved population of pediatric patients who may benefit from this valuable, time-honored medication.

Association between nailfold capillaroscopy abnormalities and autoimmune disease in pediatric populations.

OBJECTIVE: Time to diagnosis of autoimmune disease in pediatric populations can take years but nailfold capillaroscopy (NFC) may identify early signs of autoimmune disease. The aim of this study is to assess the association between nailfold capillary abnormalities and autoimmune disease in children. METHODS: A systematic search of PubMed, EMBASE, and Scopus was performed to identify all studies published before March 17, 2021. Observational studies reporting NFC outcomes in children with autoimmune disease and healthy controls (HC) were eligible for inclusion. Odds ratios (OR) and 95% confidence intervals (CI) were pooled using a random-effects meta-analytical model. RESULTS: Nine of 3665 studies reporting on 641 patients (398 subjects, 243 controls) were included. Pediatric patients with autoimmune disease were 9.88 (95% CI 3.16-30.87, I2  = 80.1%) times more likely to have abnormal nailfold capillaries than HC. Of the capillaroscopic features, dilated capillaries (OR 27.90, 95% CI 2.17-349.05, I2  = 59.9%) were the most likely abnormality observed on NFC. This was followed by the likelihood of reduced capillary density (<7 capillaries/mm) (OR 19.91, 95% CI 3.79-105.52, I2  = 0%), giant capillaries (OR 12.87, 95% CI 2.38-69.45, I2  = 0%), hemorrhages (OR 13.89, 95% CI 5.34-36.16, I2  = 0%), and avascularity (OR 10.38, 95% CI 2.20-49.04, I2  = 0%). CONCLUSIONS: Children with autoimmune disease are significantly more likely to have nailfold capillary abnormalities. NFC may be useful in identifying early signs of underlying rheumatic disease and potentially decrease the time to diagnosis for this patient population.

Off-label use of dupilumab for pediatric patients with atopic dermatitis: A multicenter retrospective review.

BACKGROUND: Atopic dermatitis (AD) is a common, chronic type 2 inflammatory skin disease, typically starting in infancy, with increased risk for subsequent extracutaneous atopic morbidities. Dupilumab is the first biologic agent targeting type 2 inflammation approved by the U.S. Food and Drug Administration (USFDA); it was licensed in 2017 for adults with moderate to severe AD and 2 years later for adolescents. Systemic treatment for pediatric AD remains a significant unmet medical need. OBJECTIVE: To analyze off-label use of dupilumab in children with AD. METHODS: Multicenter retrospective review that evaluated children who were prescribed dupilumab for moderate to severe AD. RESULTS: One hundred eleven of 124 patients (89.5%) gained access to dupilumab after a mean of 9 weeks. The dosing range was 4 to 15.5 mg/kg for the loading dose and 2.0 to 15.3 mg/kg every other week for maintenance. The range was widest for 6- to 11-year-olds and was related to use of either full or half of adult dosing. Associated morbidities, treatment response, and adverse events were comparable to those in previous adolescent and adult trials. LIMITATIONS: The retrospective design of the study limited uniform data collection. CONCLUSION: Access to dupilumab was achievable for the majority of children after a mean 9-week delay because of insurance payment denial. This review supports dupilumab response and tolerability in children. Optimal dosing for patients younger than 12 years has not been defined. Availability of the drug in 2 different concentrations is an important safety issue.

Real-World Effectiveness of Dupilumab in Adult and Adolescent Patients with Atopic Dermatitis: 2-Year Interim Data from the PROSE Registry.

INTRODUCTION: There is a scarcity of data beyond 1 year for the use of dupilumab to treat atopic dermatitis (AD) in a real-world setting. This study aimed to evaluate the 2-year effectiveness of dupilumab among adult and pediatric patients with moderate-to-severe AD included in a real-world, longitudinal database study. METHODS: PROSE is an ongoing, prospective, observational, multi-center registry in the USA and Canada, designed to collect real-world data from patients aged ≥ 12 years with moderate-to-severe AD who initiate dupilumab in accordance with country-specific prescribing information. Assessments include body surface area affected by AD (BSA), Eczema Area and Severity Index (EASI), Dermatology Life Quality Index (DLQI), Pruritus Numerical Rating Scale (P-NRS), Patient-Oriented Eczema Measure (POEM), Patient Global Assessment of Disease (PGAD) questionnaire score, and occurrence of adverse events (AEs). RESULTS: Of 764 patients who enrolled in PROSE, 632 (83%) remained in the study at the time of this interim analysis. Improvements were observed at the first post-baseline clinic visit (approximately 3 months) in the clinician-assessed measures (mean BSA and EASI scores); improvements were sustained throughout the 2-year period covered in the present study. Consistent and sustained improvements were also observed over the 2-year period in the patient-reported measures of P-NRS, POEM, and DLQI, and in the proportion of patients reporting "very good/excellent" in answer to the question in the PGAD questionnaire: "Considering all the ways in which your eczema affects you, indicate how well you are doing". Dupilumab treatment was well tolerated, with safety findings consistent with those previously reported in studies of dupilumab for the treatment of AD. CONCLUSIONS: In the real-world PROSE registry, patients with moderate-to-severe AD experienced sustained improvement in disease control, symptoms, and quality of life up to 2 years after initiating dupilumab treatment. Safety data were consistent with the known safety profile of dupilumab. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03428646. Video abstract (MP4 20,717 kb).

Atopic dermatitis (AD) is a long-term disease that affects the skin of patients, causing rash, inflammation, and intense itching, all leading to profound negative effects on their quality of life. In short-term studies, dupilumab has been shown to improve the signs and symptoms of AD, and to improve patients' quality of life. However, there is currently little information about the effectiveness of dupilumab when patients use it over the long term in the real world. This study used data from the ongoing PROSE registry, which is collecting information on 764 adults and adolescents (aged ≥ 12 years) with moderate-to-severe AD who are using dupilumab in the real world; patients were allowed to use other AD treatments and could even stop using dupilumab. Most patients (83%) were evaluated after 2 years of treatment. The study looked at how physicians judged changes over time in the severity of patients' AD. Importantly, it also used measures to allow patients themselves to report how they felt treatment affected their AD, the amount of itch they experienced, and their quality of life. Improvements in the severity of AD were already seen at 3 months, and they were maintained over the 2-year period. Patients also reported consistent and sustained improvements in their AD symptoms and quality of life during the 2 years of treatment. This analysis shows that patients with AD who began dupilumab treatment can have sustained long-term improvements.

Cutaneous Manifestations in Hereditary Alpha Tryptasemia.

Hereditary alpha tryptasemia (HaT) is a recently identified disorder that is associated with dermatologic manifestations such as urticaria, flushing, pruritus, and atopic dermatitis (AD), as well as a broad range of other symptoms affecting multiple systems. Given the potential cutaneous manifestations and the fact that dermato-logic symptoms may be the initial presentation of HaT, awareness and recognition of this condition by dermatologists are essential for diagnosis and treatment. This review aims to summarize cutaneous presentations consistent with HaT and various conditions that share overlapping dermatologic symptoms with HaT.

Congenital Cutaneous Candidiasis in Preterm Infants.

Congenital cutaneous candidiasis (CCC) is a rare condition, which typically affects premature and very low birthweight neonates. Affected infants present with a diffuse rash of variable morphology, which can appear as peeling, sloughing desquamation; maculopapular lesions; or, less commonly, pustules, vesicles, or bullae. Due to the varied nature of the clinical presentation, the diagnosis of CCC can be quite difficult but critically important because early treatment with intravenous fluconazole can prevent disease progression. In this review, we summarize the epidemiology, pathogenesis, clinical presentation, evaluation, and management of CCC.

Identifying risk factors for cutaneous disease among solid organ transplant recipients: A retrospective review.

Background: As solid organ transplant recipient (SOTR) life expectancy lengthens, the risk of developing other chronic diseases also increases. Objective: To determine the cutaneous pathologies for which SOTRs are at an increased risk. Methods: We performed a retrospective review of SOTRs seen by dermatology from January 1, 2012 and June 1, 2022. Data were analyzed using multivariate logistic regression. Benjamini Hochberg-adjusted P values were examined for multiplicity. Results: Five hundred and thirty SOTRs were identified. Patients had cutaneous malignancy (38.3%), precancerous lesions (32.5%), inflammatory (35.5%), and infectious diseases (33.1%). Odds of precancerous lesions were higher with increased age at transplant (odds ratio [OR], 1.04; adjusted P =.006), and lower with female sex (OR, 0.505; adjusted P =.006) and African American race (OR, 0.027; adjusted P =.006). Odds of inflammatory lesions were lower with increased age at transplant (OR, 0.979; adjusted P =.023). Odds of infectious diseases were higher with prednisone use (OR, 2.615; adjusted P value =.023). Limitations: This study is retrospective and was not able to capture patients seen by dermatology outside of our institution. Conclusions: SOTRs at risk of cutaneous lesions should be referred to dermatology because these conditions may place a significant burden on the quality of life.

Characterizing Skin Cancer in Transplant Recipients by Fitzpatrick Skin Phototype.

INTRODUCTION: Nearly half of organ transplants occur annually in patients with Fitzpatrick skin phototypes (Fitz type) III-VI. Organ transplant recipients (OTRs) are at risk for sequelae of chronic immunosuppression, of which skin cancer is common. As literature regarding skin cancer risk is largely conducted in OTRs with Fitz types I and II, we aimed to further characterize the incidence and risk factors for skin cancer in OTRs with higher Fitz types. METHODS: We conducted a retrospective review of OTRs with Fitz types III-VI evaluated by dermatology between 1 January 2012 and 1 June 2022. The primary outcome of this study was development of skin cancer post-transplant. Secondary outcomes included risk factors for skin cancer development. Data were analyzed using two-sample t-tests and Pearson's chi-squared. RESULTS: Of 530 OTRs, 193 had Fitz type III or higher. Ten patients (5.18%) developed 87 skin cancers and one recurrence at a mean of 5.17 years posttransplant. Patients with skin cancer self-identified as Black (70%, p-value ≤ 0.001), male (70%, p-value ≤ 0.001), and kidney transplant recipients (70%, p-value ≤ 0.001), with a mean age of 58.20 years at transplant (p-value ≤ 0.001). Subjects with skin cancer were more likely to be former smokers (60%) and prescribed tacrolimus (p-value ≤ 0.001 each). Development of cutaneous squamous cell carcinoma (66, 75.86%) was most common, followed by basal cell carcinoma (17, 19.54%), and malignant melanoma (3, 3.45%). Skin cancer most often occurred on the face or scalp (60%, p-value = 0.027), though also developed in sun-protected sites (30%, p-value = 0.002). Verruca vulgaris was present in 10% of patients (p-value = 0.028). CONCLUSIONS: Risk factors for skin cancer post-transplant differ in OTRs with higher Fitz types. Our results suggest that among OTRs who self-identified as Black, kidney recipients are at increased risk for skin cancer in non-sun-exposed regions. These cancers may be associated with human papillomavirus (HPV). Education is key for preventing morbidity and mortality secondary to skin cancer.

Kappa opioid agonists in the treatment of itch: just scratching the surface?

Chronic pruritus is a debilitating condition affecting 23-44 million Americans. Recently, kappa opioid agonists (KOAs) have emerged as a novel class of potent antipruritic agents. In 2021, the Food and Drug Administration approved difelikefalin (Korsuva) for the treatment of moderate-to-severe pruritus associated with chronic kidney disease in adults undergoing hemodialysis. Difelikefalin is a potent, peripherally restricted KOA that is intravenously available. Although promising, difelikefalin is currently available as an intravenous composition only, limiting the scope of use. Oral formulations of difelikefalin did not meet the primary endpoint criteria in recent phase 2 clinical trials; however, additional clinical studies are ongoing. The future for KOAs in the treatment of pruritus is encouraging. Orally active pathway-biased KOAs, such as triazole 1.1, may serve as viable alternatives with broader applications. Extended-release compositions, such as the TP-2021 ProNeura subdermal implant, may circumvent the pharmacokinetic issues associated with peptide-based KOAs. Lastly, dual-acting kappa opioid receptor agonist/mu opioid receptor antagonists are orally bioavailable and may be useful in the treatment of various forms of chronic itch. In this review, we summarize the results of KOAs in clinical and preclinical trials and discuss future directions of drug development.

Vascular Anomalies: Nomenclature and Diagnosis.

Before the development of the International Society for the Study of Vascular Anomalies (ISSVA) classification system in 1996, nomenclature used to describe vascular lesions was inconsistent and imprecise. This since widely adopted system stratifies vascular anomalies into vascular malformations and tumors. Vascular tumors involve abnormal proliferation of vascular cells and are further classified as benign, locally aggressive/borderline, or malignant. Vascular malformations are lesions of defective vascular morphogenesis with quiescent endothelium and are named according to their vessel composition, and subdivided into simple; combined, of major named vessels; and syndrome-associated malformations. The updated 2018 ISSVA criteria are referenced in this review.

Neonatal Skin Emergencies.

Although the majority of neonatal skin rashes can be safely monitored without intervention, there are a significant few that are dermatologic emergencies. When called to assess a neonate, it is important to distinguish what requires immediate diagnosis and treatment from those that represent benign etiologies. The skin may be the first clue to certain infections such as herpes simplex virus, syphilis, varicella, cytomegalovirus, fungal infections, and staphylococcal scalded skin syndrome, all of which require immediate testing and some of which may lead to severe sequelae. Cutaneous findings in neonates may also indicate the need for further evaluation. Purpura fulminans, sclerema neonatorum, neonatal lupus, and blueberry muffin rash can be indications of other underlying disorders and are reviewed as well. This article outlines these potential neonatal dermatologic emergencies and highlights the important clinical clues to each. [Pediatr Ann. 2019;48(1):e36-e42.].