Topical Steroid Withdrawal Is a Targetable Excess of Mitochondrial NAD

Area of Science:

• Dermatology
• Biochemistry
• Neuroimmunology

Background:

• Topical steroid withdrawal (TSW) is a patient-reported condition often misdiagnosed as atopic dermatitis.
• Objective criteria are needed to differentiate TSW from other dermatological conditions.

Purpose of the Study:

• To establish objective diagnostic criteria for TSW.
• To investigate the underlying mechanisms of TSW, focusing on neuroinflammation and cellular metabolism.
• To explore potential therapeutic interventions for TSW.

Main Methods:

• Multimodal pilot study comparing TSW patients, atopic dermatitis patients, and healthy controls.
• Clinical evaluations for diagnostic criteria.
• Skin biopsy analysis using metabolomics and transcriptomics.
• Cellular and mouse models to study NAD+ metabolism.
• Functional assays to assess glucocorticoid effects and Complex I blockade.
• Open-label trial of Complex I-inhibiting interventions.

Main Results:

• Objective clinical criteria were developed to distinguish TSW from atopic dermatitis.
• Neuroinflammatory pathways associated with Complex I-mediated NAD+ oxidation were identified in TSW.
• NAD+ metabolism was found to be proinflammatory and responsive to glucocorticoids.
• Complex I blockade mitigated glucocorticoid effects in relevant cell types.
• An open-label trial using metformin and berberine was successful.

Conclusions:

• This study provides novel mechanistic insights into Topical Steroid Withdrawal.
• Neuroinflammation and altered NAD+ metabolism are implicated in TSW pathogenesis.
• Targeting Complex I offers a potential therapeutic strategy for TSW.