Pharmacokinetics, Safety, Tolerability, and Exploratory Efficacy of Upadacitinib in Children with Severe Atopic Dermatitis.

PURPOSE: This study aims to characterize the pharmacokinetics, safety, tolerability, and exploratory efficacy of upadacitinib, an oral Janus kinase inhibitor approved for treating moderate to severe atopic dermatitis (AD) in adults and adolescents, in children with severe AD. METHODS: In an open-label, multiple-dose, Phase 1 study, pediatric patients with severe AD from two age groups (2 to <6 years and 6 to <12 years) received bodyweight-based dosing regimens of upadacitinib using either twice-daily immediate-release (IR) oral solution or once-daily extended-release (ER) tablets. A pharmacokinetic assessment was conducted on Day 7 of the study, which was followed by a long-term safety and exploratory efficacy evaluation for up to 108 weeks. The results reported here are based on an interim analysis when the study had completed enrollment and pharmacokinetic assessment. FINDINGS: A total of 35 patients were enrolled and received upadacitinib. The maximum upadacitinib plasma concentration was attained within a median time of 0.5 to 2 hours and 2 to 2.5 hours for the IR oral solution and ER tablet formulations, respectively. Upadacitinib functional half-life was generally shorter with IR oral solution relative to ER tablets. Upadacitinib apparent oral clearance decreased with decreasing body weight in the pediatric patients enrolled in this study. Upadacitinib was generally safe and well tolerated. The most common (≥3 patients) adverse events were upper respiratory tract infection, COVID-19 infection, headache, abdominal discomfort, vomiting, asthma, and cough. No new safety risks were identified compared to the known safety profile for upadacitinib in adults and adolescents. In the 30 patients with available exploratory efficacy data at Week 12, 36.7% achieved validated Investigator's Global Assessment scale for AD score of 0 or 1 (Validated Investigator Global Assessment for AD 0/1), and 70.0% had Eczema Area and Severity Index (EASI) improvement of at least 75% (EASI 75). IMPLICATIONS: The characterized pharmacokinetic profiles in this study, together with the observed safety and exploratory efficacy results, support further investigation of the current upadacitinib dosing regimen in future confirmatory Phase 3 clinical trials in children with AD. CLINICAL TRIAL NUMBER: NCT03646604, registered 2018-08-23.

Dupilumab therapy for atopic dermatitis is associated with increased risk of cutaneous T cell lymphoma: A retrospective cohort study.

BACKGROUND: Dupilumab, a human monoclonal antibody targeting the interleukin 4 alpha receptor, is used for treatment of moderate to severe atopic dermatitis (AD). Previous studies have reported diagnoses of cutaneous T cell lymphoma (CTCL) after dupilumab use. OBJECTIVE: Investigate the risk of CTCL after dupilumab use in patients with AD. METHODS: Using the TrinetX database, incidence of cutaneous and lymphoid malignancies including CTCL was compared between a cohort of patients with AD who used dupilumab and a cohort of patients with AD who never used dupilumab. A second analysis excluding prior disease-modifying antirheumatic drug use was performed. Propensity score matching was performed to control for covariates. RESULTS: An increased risk of CTCL was found in the cohort of AD patients who used dupilumab (odds ratio 4.1003, 95% confidence interval 2.055-8.192). The increased risk persisted after exclusion of prior disease-modifying antirheumatic drug use. Risk was not increased for other cutaneous or lymphoid malignancies. Most (27/41) cases of CTCL were diagnosed more than 1 year after dupilumab use. LIMITATIONS: There is potential for misclassification in the database. Severity of AD could not be assessed. Association between dupilumab and CTCL does not prove causality. CONCLUSION: Dupilumab use is associated with an increased risk of CTCL in patients with AD in this cohort.

The Safety of Isotretinoin Treatment in Patients with Peanut Allergies.

Background: Isotretinoin, the gold standard treatment for nodulocystic acne vulgaris, is contraindicated in patients with a soy allergy. Due to potential cross-reactivity, a history of peanut allergy is listed as a contraindication to isotretinoin use in some countries. Objective: We sought to further evaluate the safety of isotretinoin use in patients with peanut allergy. Methods: Using Epic's SlicerDicer, patients were identified with both an allergy to peanuts and history of isotretinoin use for treatment of acne vulgaris. Clinical manifestation to peanut exposure, peanut-specific skin prick and/or IgE testing, and adverse reactions to isotretinoin use were recorded via chart review and phone interviews. Results: Ten patients were identified having both a peanut allergy and treatment for acne vulgaris with isotretinoin. All patients tolerated isotretinoin without evidence of allergy. Conclusion: Isotretinoin use did not result in allergic eruptions in patients with a known peanut allergy, however, more robust clinical studies are needed to confirm the extent of its use in this patient population.

Propranolol therapy for hemangiomas in infants with neonatal abstinence syndrome may produce intolerable side effects.

We report three infants with infantile hemangioma who experienced severe agitation and diarrhea following propranolol administration. Propranolol, a non-selective ß-adrenergic receptor blocker, is the first-line treatment for infantile hemangiomas. All three infants were exposed to opioids in utero and experienced neonatal abstinence syndrome at birth. We hypothesize that chronic opioid exposure in utero may cause protracted upregulation of ß2-adrenergic receptors in the central nervous system, resulting in increased susceptibility to adverse reactions to propranolol.

BASCULE syndrome in a child with prior asymptomatic COVID-19 infection.

BASCULE syndrome, characterized by Bier anemic spots, cyanosis, and an urticaria-like eruption, has been described as a benign vasomotor dermatosis that occurs in the setting of transient tissue hypoxia. It has been postulated that dermal ischemia triggers an exaggerated vasoconstrictive arteriolar reaction, which then causes a paradoxical urticarial rash by an unknown mechanism. In patients with COVID-19, there is evidence of angiocentric inflammation leading to vasoconstriction, endothelial damage, and thrombosis. We present a case of acute-onset BASCULE syndrome appearing after asymptomatic infection with COVID-19. BASCULE syndrome should be considered in the expanding spectrum of dermatologic manifestations associated with COVID-19.

A case of capillary malformation-arteriovenous malformation and Ebstein's anomaly in a child with EphB4 mutation.

Capillary malformation-arteriovenous malformation (CM-AVM) is a rare condition characterized by multiple cutaneous capillary malformations with potential associated arteriovenous malformations. RAS p21 protein activator 1 (RASA1) and ephrin type-B receptor 4 (EPHB4) genes are implicated. We present a child with CM-AVM, due to EPHB4 mutation, and Ebstein's anomaly. Although EPHB4 is a known effector of vascular remodeling, its contribution to cardiogenesis is still being explored. Further research is needed to determine causality of Ebstein's anomaly in the setting of CM-AVM due to EPHB4 mutation.

Management of cutaneous side effects of inflammatory bowel disease therapy: A dermatologic viewpoint.

Medications used in the treatment of inflammatory bowel disease cause a wide range of dermatologic side effects, and minimal guidance exists on how to manage them. The intention of this review article is to summarize common dermatologic adverse reactions related to inflammatory bowel disease therapy and to provide evidence-based guidance on management. We conducted a scoping review using PubMed and Google Scholar to identify studies reporting clinical information on dermatologic side effects of medications used in the treatment of inflammatory bowel disease. The most commonly reported dermatological adverse effects from inflammatory bowel disease therapy were cutaneous malignancy and cutaneous infections. Thiopurines, methotrexate, tumor necrosis factor (TNF) inhibitors, interleukin (IL)-12/23 inhibitors, and integrin inhibitors can be continued if nonmelanoma skin cancer arises during therapy and the malignancy should be surgically excised. TNF inhibitors and IL-12/23 inhibitors can be continued in the setting of stage I surgically resectable melanoma but should be discontinued in advanced melanoma. For complicated cutaneous bacterial infections, methotrexate and TNF inhibitors should be halted, and IV antibiotics should be administered. Complicated herpes zoster infection warrants discontinuation of TNF inhibitors, whereas IL-12/23 and JAK inhibitors can be continued. Inflammatory bowel disease therapies are associated with several dermatological adverse effects, and management options vary by agent. Certain agents may require discontinuation in the setting of nonmelanoma skin cancer, melanoma, and cutaneous infections. Many other dermatological adverse effects from inflammatory bowel disease therapy require specialized management or referral to dermatology.

The positive environmental impact of virtual isotretinoin management.

BACKGROUND/OBJECTIVES: Other medical specialties have studied how their practices influence the environment, but environmental impact studies in the field of dermatology remain limited. With respect to dermatology, vehicle emissions by patients traveling to and from appointments are an important factor influencing climate change. This study was undertaken to determine the greenhouse gas emissions avoided by managing isotretinoin virtually at West Virginia University Hospital. METHODS: A retrospective cross-sectional study was conducted during the COVID-19 outbreak from March 25 to December 1, 2020, where travel data were acquired and converted to emission data. RESULTS: 5,137 kg of GHG emissions in CO2 equivalents were prevented by managing isotretinoin virtually during the study period. 49 400 kg of GHG emissions in CO2 equivalents would be prevented annually. This is the emission load released when 24 690 kg of coal are burned. CONCLUSIONS: Environmental impact studies in the field of dermatology remain limited. GHG emissions were significantly reduced by virtually managing isotretinoin at a single institution. The practice of dermatology could reduce its carbon footprint by managing isotretinoin virtually, even in non-pandemic periods. Given that isotretinoin management represents a small percentage of the overall carbon footprint associated with dermatology, dermatologists should identify other conditions amenable to virtual medicine to produce greater environmental impact.

Clinical outcomes of COVID-19 in patients taking tumor necrosis factor inhibitors or methotrexate: A multicenter research network study.

BACKGROUND: Data on the impact of biologics and immunomodulators on coronavirus disease 2019 (COVID-19)-related outcomes remain scarce. OBJECTIVE: We sought to determine whether patients taking tumor necrosis factor inhibitors (TNFis) or methotrexate are at increased risk of COVID-19-related outcomes. METHODS: In this large comparative cohort study, real-time searches and analyses were performed on adult patients who were diagnosed with COVID-19 and were treated with TNFis or methotrexate compared with those who were not treated. The likelihood of hospitalization and mortality were compared between groups with and without propensity score matching for confounding factors. RESULTS: More than 53 million (53,511,836) unique patient records were analyzed, of which 32,076 (0.06%) had a COVID-19-related diagnosis documented starting after January 20, 2020. Two hundred fourteen patients with COVID-19 were identified with recent TNFi or methotrexate exposure compared with 31,862 patients with COVID-19 without TNFi or methotrexate exposure. After propensity matching, the likelihood of hospitalization and mortality were not significantly different between the treatment and nontreatment groups (risk ratio = 0.91 [95% confidence interval, 0.68-1.22], P = .5260 and risk ratio = 0.87 [95% confidence interval, 0.42-1.78], P = .6958, respectively). LIMITATIONS: All TNFis may not behave similarly. CONCLUSION: Our study suggests that patients with recent TNFi or methotrexate exposure do not have increased hospitalization or mortality compared with patients with COVID-19 without recent TNFi or methotrexate exposure.

Association between psoriasis, psoriatic arthritis and gastrointestinal disease : An exploratory nationwide inpatient sample analysis.

BACKGROUND: Psoriasis is associated with cardiovascular disease, inflammatory bowel disease (IBD), metabolic syndrome, and psychiatric disease. Furthermore, psoriasis is associated with immune dysregulation and systemic inflammation. OBJECTIVE: To determine the association of psoriasis and psoriatic arthritis with IBD and the association of the combination of psoriasis or psoriatic arthritis with IBD and other gastrointestinal illnesses. METHODS: Discharge data from the 2000-2014 Nationwide Inpatient Sample, Healthcare Cost and Utilization Project (HCUP), which approximates a 20% stratified sample of all US hospitalizations, were analyzed. Multivariable logistic regression was used to examine the association between psoriasis and psoriatic arthritis with IBD and 23 gastrointestinal illnesses adjusting for sociodemographic characteristics. RESULTS: Psoriasis was associated with IBD (Crohn's disease adjusted odds ratio (aOR) = 2.13, 95% confidence interval (CI) [2.0-2.3], p < 0.001). When adjusting for sociodemographics and IBD, psoriasis was associated with 21 of 23 gastrointestinal diseases examined, most notably celiac disease, autoimmune hepatitis, and non-alcoholic fatty liver disease. Psoriatic arthritis was also associated with IBD (Crohn's disease, aOR = 1.95, 95% CI [1.7-2.2], and ulcerative colitis, aOR = 2.66, 95% CI [2.4-2.9]). CONCLUSION: Psoriasis and psoriatic arthritis inpatients have an associated increase in IBD and numerous other gastrointestinal illnesses.

The effect of a low-nickel diet and nickel sensitization on gastroesophageal reflux disease: A pilot study.

BACKGROUND/AIMS: Gastroesophageal reflux disease (GERD) is a common medical condition, frequently refractory to medical therapy. Nickel is a leading cause of allergic contact dermatitis. Although nickel is widely found in foods, the effect of nickel on GERD is unknown. This pilot study sought to evaluate the effect of a low-nickel diet on GERD and determine if epicutaneous patch testing to nickel could predict responsiveness to a low-nickel diet. METHODS: This prospective, single-site pilot study recruited 20 refractory GERD patients as determined by GERD Health-Related Quality of Life (GERD-HRQL) scores. All patients had epicutaneous patch testing for nickel and were then instructed to follow a low-nickel diet for 8 weeks regardless of patch test results. GERD-HRQL was recorded at baseline and following 8 weeks of a low-nickel diet. Demographic and clinical data associated with GERD and nickel allergy were recorded. A Wilcoxon signed-rank test and nonparametric analysis of longitudinal data were run to determine statistical significance in pre- and post- GERD-HRQL scores in nickel patch test-positive and negative groups. RESULTS: Nearly all (19/20 [95%]) participants reported reduced GERD symptoms after 8 weeks on a low-nickel diet. Mean total GERD-HRQL, regurgitation, and heartburn scores declined (27.05 ± 16.04, 11.45 ± 6.46, 10.85 ± 8.29). Participants with positive vs. negative patch testing to nickel responded equivalently to a low-nickel diet. CONCLUSIONS: A low-nickel diet improves GERD symptoms, but responsiveness to a low-nickel diet does not correlate with epicutaneous patch testing to nickel. TRIAL REGISTRATION: ClinicalTrials.gov number: NCT03720756.

Erythema Ab Igne in a 12-Year-Old Boy Diagnosed via Telemedicine.

In March of 2020, an otherwise healthy 12-year-old boy developed a unilateral patch of reticulated erythema limited to his left lower extremity. The child could not be examined in the clinic due to limited in-person appointments during the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, so he was examined via a telemedicine visit. The diagnosis of erythema ab igne was made as his mother verified that the child was spending approximately two hours per day playing video games in the cold basement of his house, with a space heater positioned close to his left leg. Our case of erythema ab igne is unique due to the relatively young age of the affected child, and it provides an example of how this diagnosis can be made via a telemedicine visit. Being able to recognize the classic appearance of erythema ab igne through the scrutiny of photographs and obtaining pertinent history can preclude the need for an in-person visit during times when home sequestration may be a necessity.

Ileostomy adenocarcinoma in Crohn's disease.

PURPOSE: Adenocarcinoma of an ileostomy is rare with less than 50 reported cases in the literature. Ileostomy adenocarcinoma in Crohn's disease is even more rare, with only 4 reported cases. We present a case of ileostomy adenocarcinoma with lymph node metastasis occurring 51 years after proctocolectomy and Brooke ileostomy in a female with Crohn's disease. This case represents the longest documented interval between Brooke ileostomy and ileostomy adenocarcinoma diagnosis and summarizes clinical signs that warrant biopsy of a peristomal plaque to differentiate adenocarcinoma from clinical mimics such as pyoderma gangrenosum (PG). METHODS: Clinical, histological, and surgical patient data were reviewed. A literature review of adenocarcinoma arising from ileostomy sites was performed. RESULTS: We report a case of a 67-year-old woman that presented with a peristomal skin lesion developing over 10 years. After multidisciplinary discussion between gastroenterology, colorectal surgery, and dermatology, ileoscopy revealed moderately differentiated, invasive adenocarcinoma arising from the ileostomy site. Wide surgical excision and en bloc resection of the peristomal lesions were performed, and the final pathology revealed lymph node metastasis. The patient is currently undergoing adjuvant chemotherapy. CONCLUSIONS: Clinicians should maintain a high level of suspicion when ileostomy patients develop a peristomal lesion.