Clinical Presentation and Diagnosis of Drug Reaction with Eosinophilia and Systemic Symptoms (DReSS) in Children: A Scoping Review.

Effective treatment of drug reactions with eosinophilia and systemic symptoms (DReSS) requires early diagnosis and close monitoring. Diagnosing DReSS is especially challenging in children due to a low incidence rate, heterogeneous clinical presentation, and a lack of (pediatric) diagnostic criteria and clinical practice guidelines. We performed a scoping review, according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, to summarize the clinical presentation and diagnostic process of DReSS in children (aged 0-18 years). Data from 644 individuals showed that DReSS manifests differently in children compared to adults. Children have a higher number of organs involved, including higher rates of cardiac and respiratory involvement compared to adults. Children < 6 years of age appear more prone to develop neurologic symptoms. Conversely, eosinophilia, edema, and kidney involvement are less frequently observed in children. Anti-seizure medications are by far the most common causative drug class, but the range of implicated drugs increases as children get older. This study highlights that children with DReSS not only differ from adults but also that differences exist between children of different ages. As such, there is a need to establish pediatric-specific diagnostic criteria. These efforts will promote earlier diagnosis of DReSS and likely lead to improved clinical care offered to children and their families.

Characteristics and onset of presentation of pediatric stiff skin syndrome: A retrospective cohort study of 11 patients in a tertiary care center.

BACKGROUND/OBJECTIVE: Stiff skin syndrome (SSS) is a rare disorder characterized by "rock hard" indurated skin affecting different body parts. The localized variant poses a diagnostic challenge, as it is frequently mistaken for other inflammatory connective tissue disorders. The aim of this study is to provide insightful clinical, radiologic and diagnostic data that might prove useful for the evaluation, management and treatment of pediatric patients with segmental SS. METHODS: This single-center cohort study included patients ≤18 years diagnosed with localized SSS from 1988 to 2021 in a quaternary pediatric healthcare center in Toronto, Canada. Data included demographics, clinical, histopathologic and radiologic features, treatments, and clinical course. Data were summarized with descriptive statistics (mean, standard deviation, medians, interquartile ranges [IQRs]) and frequencies. RESULTS: A total of 11 patients were included. The sclerotic changes were measured clinically and radiologically, by a total of 16 imaging studies: 13 magnetic resonance imaging (MRI) and 3 ultrasound. MRI readings showed abnormal high signal intensity of the affected tissue correlating with the anatomical site of involvement in all cases, specifically, in the shoulder/pelvic girdle with limb extension. Shear wave ultrasound elastography (SWE) demonstrated higher values within the dermis compared to the control site. CONCLUSION: The presence of segmental sclerotic changes that affects the pelvic/shoulder girdle with extension to the extremities, in the absence of inflammation on biopsy and abnormal signaling intensity on imaging is suggestive of SSS. Skin SWE is a feasible, noninvasive, and objective instrument to evaluate and monitor sclerotic changes overtime, it could be potentially extrapolated to other pediatric skin sclerotic conditions.

Multicenter Canadian case series of pediatric patients less than 12 years of age with moderate-to-severe atopic dermatitis treated with dupilumab.

BACKGROUND: Dupilumab is approved for moderate-severe atopic dermatitis (AD) in patients aged ≥6 months by the US Food and Drug Administration and Health Canada; however, there are little real-world data because providers have limited practical experience with this recently approved therapy. OBJECTIVES: To describe the real-world effectiveness and safety in patients aged <12 years with moderate-severe AD currently receiving or previously having received dupilumab. METHODS: A multicenter retrospective study was conducted at six Canadian sites. Cases were divided into Group 1 ≤2 years old, Group 2 >2 to <6 years old, and Group 3 ≥6 to <12 years old. Medical history and details of dupilumab treatment were collected. The primary outcome was to measure the improvement in eczema area and severity index. Secondary outcomes examined included the children's dermatology life quality index/infant's dermatitis quality of life, peak pruritus numerical rating scale, and delay to dupilumab access for patients who were considered off-label for dupilumab due to their age. RESULTS: Sixty three pediatric patients (37 males) with moderate-to-severe AD were included; the mean age was 6.4 years old (range: 2-11) when dupilumab treatment was started. Overall, 75% (36/48) achieved EASI-75% and 71% (34/48) achieved EASI-90. EASI-75 and EASI-90 were achieved in 90% (17/19) and 73% (12/19) in patients <6 years old, and 76% (22/29) and 59% (17/29) in patients >6 years old, respectively. No serious adverse events were reported. CONCLUSIONS: Dupilumab is safe and effective for patients under the age of 12. However, even for experienced providers, access to the medication was challenging.

Systematic Review of Health-Related Quality of Life Impact in Juvenile Localized Scleroderma.

OBJECTIVE: The prevalence and types of psychosocial complications of juvenile localized scleroderma (JLS), also known as morphea, an inflammatory and sclerosing disease involving the skin, fascia, muscle, and bone, are poorly understood. METHODS: We performed a systematic review of literature published between 2000 and 2020 in PubMed, EMBASE, the Cochrane Skin Group Specialized Register, the Cochrane Central Register of Controlled Trials, and the Cumulative Index to Nursing and Allied Health Literature using the search terms "scleroderma, localized," "Morphea," "anxiety," "depression," "resilience," "social stigma," "quality of life," "mood," or "stress" and limited the search to pediatric patients and English language. Patient demographics, characteristics of JLS, and comorbidities were extracted. The outcomes included measures of health-related quality of life (HRQoL), psychosocial functioning, evaluation of self-perception, and the treatment burden of the study population. The protocol was registered with PROSPERO (CRD42021257124). Thematic synthesis generated descriptive analysis. RESULTS: Thirteen studies fulfilled the inclusion criteria: three retrospective cohort studies, two prospective cohort studies, and eight cross-sectional studies. A total of 690 pediatric patients with JLS were included (n = 484 with linear scleroderma). Six studies used the Children's Dermatology Life Quality Index, reporting little to no effect on HRQoL. One study used the Health-Related Quality of Life in Children and Adolescents Questionnaire and did not find differences between children with JLS or atopic dermatitis and healthy controls. One study used a self-perception questionnaire that showed normal self-worth of patients with JLS. Two studies used focus groups, both reporting elevated levels of stress, decreased self-worth, "feeling different," and bullying/teasing in patients with JLS. These emotions were associated with skin symptoms (pain, itch, and tightness), physical limitations, and treatment burden. CONCLUSION: Overall, quantitative studies did not report a statistically significant impairment in HRQoL in JLS. However, qualitative studies (focus groups) reported significant psychosocial impacts related to JLS. There is a need to develop a JLS-specific tool for the HRQoL evaluation of this population.

Characterizing the cutaneous late effects of allogeneic hematopoietic stem cell transplantation: A systematic review.

BACKGROUND: There is a well-documented risk of secondary cutaneous malignancies following allogeneic hematopoietic stem cell transplant (HSCT), but data on risk in pediatric populations are limited. The objective of this study is to perform a systematic review of reported features and outcomes of skin cancers in pediatric allogeneic HSCT recipients. METHODS: MEDLINE, EMBASE, CINAHL, Cochrane, and Web of Science were systematically searched (Prospero CRD42022342139). Studies reporting cutaneous cancer outcomes were included if the age at transplant was ≤19 years. Titles, abstracts, and full-text articles were screened in duplicate. RESULTS: Out of 824 citations that were screened, 12 articles were selected for analysis. The final sample included 67 pediatric HSCT recipients, comprising 65 allogeneic transplant recipients and 2 cases of HSCT with an unknown donor type. The median age at transplant and skin cancer diagnosis were 7.4 and 13 years, respectively. Out of the 67 pediatric HSCT recipients, some patients developed more than one lesion, resulting in 71 lesions. The most common skin cancer type was cutaneous squamous cell carcinoma (32 lesions), followed by basal cell carcinoma (25 lesions). The median latency period between HSCT and skin cancer diagnosis ranged from 0 to 29 years. Identified risk factors for skin cancers included younger age at the time of transplant, exposure to total body irradiation, prolonged post-transplant immunosuppression, graft versus host disease, and sunburn. CONCLUSION: Skin cancers are reported in pediatric allogeneic HSCT recipients, and the risk appears to be increased. More data are needed to better characterize this risk.

Evaluation of Methotrexate Intolerance in Children With Morphea.

OBJECTIVE: Methotrexate is an immunosuppressant commonly used in dermatology. The prevalence of intolerance using the Methotrexate Intolerance Severity Score (MISS) in pediatric juvenile idiopathic arthritis (JIA) ranges from 25% to 75%, but studies in morphea patients are lacking. We sought to determine the prevalence and predictors of methotrexate intolerance in children with morphea compared with children with inflammatory skin diseases and JIA/uveitis. METHODS: Eligible patients were ages 2 to 18 years and were taking methotrexate for at least 3 months to treat morphea, inflammatory skin disease, or uveitis/JIA. Methotrexate intolerance was calculated using the MISS. A 1-way analysis of variance compared absolute intolerance scores. Multivariate regression analysis was used to compare MISS across diseases and covariates. RESULTS: Of 48 participants (mean ± SD age, 11.3 ± 4.1 years, 70.8% female), 15 had morphea, 16 had JIA/uveitis, and 17 had inflammatory skin diseases. The overall prevalence of intolerance was 20.8%. Age, sex, duration, and dose did not correlate with overall MISS. The MISS mean ± SD total for oral dosing was 2.5 ± 3.4, compared with 6.78 ± 6.8 for subcutaneous dosing. Patients with JIA/uveitis had the highest prevalence of intolerance (37.5%, n = 6), followed by morphea patients (20%, n = 3) and inflammatory skin disease patients (5.9%, n = 1). The OR of intolerance according to route of administration was 11.2 (95% CI, 2.03-61.89). CONCLUSIONS: Methotrexate intolerance was highest among patients with JIA/uveitis. The only predictor for risk of intolerance was subcutaneous route of administration. Future work could examine disease activity correlations and interventions designed to minimize intolerance.

Eligibility Criteria for Active Ulcerative Pyoderma Gangrenosum in Clinical Trials: A Delphi Consensus on Behalf of the UPGRADE (Understanding Pyoderma Gangrenosum: Review and Assessment of Disease Effects) Group.

At present, there are no standardized guidelines for determining patient eligibility for pyoderma gangrenosum (PG) clinical trials. Thus, we aim to determine which clinical features, histopathological features, or laboratory features should be included in active ulcerative PG clinical trial eligibility criteria for treatment-naïve patients and patients already treated with immunomodulating medications (treatment-exposed patients). This study employed 4 rounds of the Delphi technique. Electronic surveys were administered to 21 international board-certified dermatologists and plastic surgeon PG experts (June 2022-December 2022). Our results demonstrated that for a patient to be eligible for a PG trial, they must meet the following criteria: (i) presence of ulcer(s) with erythematous/violaceous undermining wound borders, (ii) presence of a painful or tender ulcer, (iii) history/presence of rapidly progressing disease, (iv) exclusion of infection and other causes of cutaneous ulceration, (v) biopsy for H&E staining, and (vi) a presence/history of pathergy. These criteria vary in importance for treatment-naïve versus treatment-exposed patients. Given the international cohort, we were unable to facilitate live discussions between rounds. This Delphi consensus study provides a set of specific, standardized eligibility criteria for PG clinical trials, thus addressing one of the main issues hampering progress toward Food and Drug Administration approval of medications for PG.

Hidradenitis Suppurativa in Children and Adolescents: An Update on Pharmacologic Treatment Options.

Hidradenitis suppurativa (HS) is a chronic, recurrent, inflammatory skin condition that manifests as painful, deep-seated, inflamed nodules and abscesses in the axillary, groin, perianal, perineal, and inframammary regions. The associated pain, malodour, and disfigurement contribute to its profound negative impact on psychosocial spheres and overall quality of life in affected individuals. Although the symptoms of HS classically begin in the second or third decade of life, HS affects children and adolescents as well. Despite this, there are limited pediatric data on treatment, which are largely based on expert opinion, extrapolation of efficacy data in adults with HS, and safety information from medication use in other pediatric diseases. On this basis, there exist several pharmacological modalities in the treatment of children and adolescents with HS including topical therapies, systemic therapies, and biologics. The goals of this review article are to: (1) review the efficacy of different pharmacological treatment modalities in children and adolescents with HS, and (2) review the safety and monitoring considerations of the different treatment options in children and adolescents with HS.

Pediatric Dermatology in Canada: A Broad Review of Population Needs, Workforce and Training With Proposed Solutions.

INTRODUCTION: The need for pediatric dermatology services is increasing across Canada. In parallel, the complexity of treatment with novel targeted therapeutics has increased. Currently, there is no accredited and limited non-accredited fellowship training access to pediatric dermatology in Canada. HYPOTHESIS: Understanding the current state of pediatric dermatology training in Canada will provide insight into opportunities for strategic improvement. METHODS: A survey was distributed to 44 pediatric dermatology providers. In addition, a review of the burden of pediatric skin disease and education/training in Canada was performed. RESULTS: Thirty-four specialists responded to the survey (77% response rate). One third of current pediatric dermatology providers are over 50 years old and half of these (15%) plan to retire within the next 5 years. Half of respondents were dermatologists, 35% were pediatricians, and 11% were double boarded. Almost all respondents practiced in an academic setting (94%). Most had further fellowship training in pediatric dermatology (82.4%) but only 57% achieved this training in Canada, due to lack of accredited or non-accredited funded fellowship positions. CONCLUSION: There is a high and growing need for pediatric dermatology specialty care in a diverse range of settings. The current provider population and training programs are insufficient to meet current and future demands. We highlighted solutions to close this gap between supply and demand including increased double board certification in Pediatrics and Dermatology, a protected pediatric stream within existing Dermatology residency training programs and accredited fellowships in Pediatric Dermatology for both dermatologists and pediatricians.

Characteristics and complications of anogenital infantile hemangiomas: A multicenter retrospective analysis.

BACKGROUND: Infantile hemangiomas (IHs) of the anogenital region remain poorly characterized. OBJECTIVE: To examine the distribution, ulceration rate, and associated congenital anomalies of anogenital IHs. METHODS: Retrospective study at 8 tertiary referral centers. RESULTS: A total of 435 infants with an IH of the anogenital region were enrolled (of which, 319 [73%] were girls). Congenital anomalies were present in 6.4% (n = 28) of infants with an anogenital IH. Segmental or partial segmental anogenital IHs ulcerated in 72% (n = 99 of 138) of infants, whereas 45% (n = 133 of 297) of focal anogenital IHs experienced ulceration (P < .001). In a multivariable logistic regression analysis, segmental or partial segmental morphology (adjusted odds ratio [aOR], 2.70; 95% CI, 1.60-4.64), mixed type (aOR, 3.44; 95% CI, 2.01-6.07), and perianal (aOR, 3.01; 95% CI, 1.53-6.12) and buttocks location (aOR, 2.08; 95% CI, 1.17-3.76) had increased odds of ulceration. Segmental or partial segmental IHs of the genitalia were confined to distinct anatomic territories and were predominantly distributed unilaterally, with a linear demarcation at the perineal raphe. LIMITATIONS: Possible selection bias, given recruitment at tertiary referral centers. CONCLUSION: This study improves our understanding of high-risk features of anogenital IHs and demonstrates that genital segmental or partial segmental IHs develop within distinct anatomic territories.

Biomarkers in alopecia Areata: A systematic review and meta-analysis.

BACKGROUND: Alopecia areata (AA) is an autoimmune non-scarring alopecia that affects the scalp or any hair-bearing areas in the body. The pathophysiology of AA is complex, but Th1, Th2, and Th17 cytokines dysregulation, as well as chemokines, immunoglobulins and other biomarkers have been shown to play a role in the pathogenesis of the disease. OBJECTIVE: To conduct a systematic review and Meta-analysis to identify biomarkers that reflect AA activity and severity that could be used to better assess disease activity and response in both trials and clinical practice. METHODS: A literature search was conducted using the PUBMED, EMBASE and the Cumulative Index to Nursing and Allied Health Literature (CINAHL) from inception to December 2021. Articles reporting on associations between AA and serum clinical biomarkers (cytokines, chemokines, antibodies, immunoglobulins, and others) were included. Serum biomarkers were identified in patients with AA and were correlated with disease severity and patient characteristics (ex. age, sex, comorbidities). The quality of the studies was assessed using the National Heart, Lung, and Blood Institute's Quality Assessment Tool for Case-Control Studies. Meta-analysis pooling of the standardized mean differences (SMD) by the method of Cohen using the common-effect inverse-variance model was performed. For the Meta-analysis, data was pulled for all the markers with a minimum of 4 studies with means and standard deviations. Analysis of data reported as Median with range or inter-quartile range (IQR) revealed that the data was too skewed to recommend calculation and use of mean with standard deviation (SD). If the data were not skewed, mean and SD were calculated. RESULTS: One thousand seven hundred fourteen studies were screened, with 91 included, reporting on a total of 52 biomarkers. Meta-analyses revealed pooled SMD that were significant for interleukin 6 (IL6), C-reactive protein (CRP) and vitamin D. CONCLUSIONS: Serum IL6 and CRP levels are significantly increased in patients with AA compared to healthy age and sex matched controls. Conversely, serum vitamn D levels are significantly decreased in patients with AA compared to healthy age and sex matched controls. This data has the potential to influence the clinical guidelines for the diagnostic workup of AA to include testing the serum levels of CRP and vitamin D.

Upadacitinib for the treatment of alopecia areata and severe atopic dermatitis in a paediatric patient: A case report.

This case report describes the first successful treatment of alopecia areata and atopic dermatitis with the Janus kinase 1 inhibitor upadacitinib in a paediatric patient. After minimal response to topical corticosteroids and spironolactone, improvements in hair growth on the scalp and body were noted after only 6 weeks of upadacitinib treatment.