Topical Steroid Withdrawal is a Targetable Excess of Mitochondrial NAD.

Background: Topical corticosteroids (TCS) are first-line therapies for numerous skin conditions. Topical Steroid Withdrawal (TSW) is a controversial diagnosis advocated by patients with prolonged TCS exposure who report severe systemic reactions upon treatment cessation. However, to date there have been no systematic clinical or mechanistic studies to distinguish TSW from other eczematous disorders. Methods: A re-analysis of a previous survey with eczematous skin disease was performed to evaluate potential TSW distinguishing symptoms. We subsequently conducted a pilot study of 16 patients fitting the proposed diagnostic criteria. We then performed: tissue metabolomics, transcriptomics, and immunostaining on skin biopsies; serum metabolomics and cytokine assessments; shotgun metagenomics on microbiome skin swabs; genome sequencing; followed by functional, mechanistic studies using human skin cell lines and mice. Results: Clinically distinct TSW symptoms included burning, flushing, and thermodysregulation. Metabolomics and transcriptomics both implicated elevated NAD+ oxidation stemming from increased expression of mitochondrial complex I and conversion of tryptophan into kynurenine metabolites. These abnormalities were induced by glucocorticoid exposure both in vitro and in a cohort of healthy controls (N=19) exposed to TCS. Targeting complex I via either metformin or the herbal compound berberine improved outcomes in both cell culture and in an open-label case series for patients with TSW. Conclusion: Taken together, our results suggest that TSW has a distinct dermatopathology. While future studies are needed to validate these results in larger cohorts, this work provides the first mechanistic evaluation into TSW pathology, and offers insights into clinical identification, pharmacogenomic candidates, and directed therapeutic strategies.

Survey of topical exposure concerns for patients and caregivers dealing with atopic dermatitis.

Background: Despite the recent expansion of treatment options in atopic dermatitis (AD), most management responsibilities fall on the patient and/or caregivers. Disease control often requires vigilance about and avoidance of common exposures, however the concerns for patients and caregivers living with AD have not been well enumerated. Methods: An IRB approved survey was distributed to the public to evaluate the patient and caregiver concerns for topical exposures and potential triggers. Results: 323 people accessed the link to the survey with 259 providing response to at least one section of questions (response rate 80.2%). Results indicated that temperature and other weather related changes were the most common trigger. Nearly all respondents avoided at least one topical ingredient, with fragrances being the most common. Steroid exposure was common, however respondents expressed concerns about overall steroid exposure. Conclusions: Our results attempt to enumerate the daily topical exposure concerns for patients and caregivers living with AD. While our online survey is both limited and without mechanistic insights, our results provide insight to providers by highlighting the role of temperature in AD symptoms; identifying commonly perceived triggers; indicating the value of provider insight for topical product selection; and indicating that no specific aspect of topical corticosteroid exposure may alleviate the general steroid concerns for patients or caregivers.

Corticosteroid exposure and cumulative effects in patients with eczema: Results from a patient survey.

BACKGROUND: Individuals with eczema may have substantial lifetime corticosteroid exposure, increasing the risk of corticosteroid-related side effects. OBJECTIVE: To conduct a patient survey evaluating corticosteroid exposure and its cumulative effects in individuals with eczema. METHODS: The multinational online survey was conducted between November 5, 2020, and January 11, 2021. Participants were aged 18 years or older and a patient (n = 1889) or a caregiver of a child (n = 271) diagnosed with having eczema by a medical professional. RESULTS: All participants reported using corticosteroids. Average duration of topical corticosteroid (TCS) use was 15.3 years in adults and 3.6 years in children; 75% used TCS 1 to 2 times a day and 50% applied TCS 15 to 30 days/mo. Frequency and duration could not be determined by varying prescription TCS potencies. Oral corticosteroid use was reported by 36% of the participants (23% for eczema), with a lifetime average of 8.4 courses in adults and 8.1 courses in children. Corticosteroids for non-eczema atopic conditions were reported by 49% of the participants. In participants using TCS, 83% of adults and 64% of children experienced worsening symptoms over time. Development of new symptoms and conditions increased with a greater number of corticosteroid treatments and longer duration of TCS use but may have been owing to eczema progression. Symptoms consistent with topical steroid withdrawal syndrome after TCS discontinuation were reported by many participants. CONCLUSION: Reported substantial corticosteroid exposure throughout their lifetime eczema experience placed participants at risk of negative outcomes. Corticosteroids are a critical component of eczema treatment for many patients. However, careful corticosteroid prescribing practices and monitoring are needed to avoid side effects. When possible, corticosteroid-sparing strategies should be explored.

The Multidimensional Burden of Atopic Dermatitis Among Adults: Results From a Large National Survey.

Importance: Atopic dermatitis (AD) is long term and burdensome. Studies investigating disease burden in adults are limited in scope with gaps in understanding of the adult patient lived experience. Objective: To describe the multidimensional burden of AD among mainly US adults. Design, Setting, and Participants: This survey study for an externally led patient-focused drug development meeting with the US Food and Drug Administration on adult patients with AD was conducted between August 1, 2019, and October 11, 2019. Data were analyzed betwean March 26, 2021, and June 29, 2021. Main Outcomes and Measures: We used multivariable ordinal regression to assess associations between demographic and clinical variables and patient-reported overall AD impact scores (ordinal scale from 1 [no impact] to 5 [significant impact]). Results: Among 1065 survey respondents, 114 (11%) were aged 18 to 24 years, 235 (22%) were 25 to 34 years, 242 (23%) were 35 to 50 years, 288 (27%) were 51 to 64 years, and 186 (17%) were aged 65 years or older; 881 (83%) were women. Four hundred eighty-nine (46%) participants reported low-moderate AD impact scores (2-3), 544 (51%) reported high-significant impact scores (4-5), whereas 32 (3%) reported no association of AD with disease burden (impact score, 1). Variables strongly associated with overall impact scores were current AD severity (moderate: OR, 4.13; 95% CI, 2.94-5.79; severe: OR, 13.63; 95% CI, 8.65-21.50 vs mild), and time spent managing AD (11-20 hours: OR, 2.67; 95% CI, 1.77-4.03, ≥21 hours: OR, 5.34; 95% CI, 3.22-8.85, vs <5 hours). Conclusions and Relevance: In this survey study, AD severity and time spent managing symptoms showed the strongest associations with disease burden. This analysis highlights the multidimensional burden of AD in adults and emphasizes the need for more effective treatment strategies that reduce the time patients spend managing their AD.