Topical Steroid Withdrawal: Study Identifies Mitochondrial Dysfunction as a Potential Target for Treatment
NIH researchers also proposed new diagnostic criteria that include a combination of major and minor symptoms, offering improved sensitivity for identifying TSW cases.
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A new study published in the Journal of Investigative Dermatology provides evidence that topical steroid withdrawal (TSW) is a distinct dermatologic condition with unique metabolic and inflammatory signatures. The findings suggest that mitochondrial dysfunction—specifically, excess nicotinamide adenine dinucleotide (NAD+) production—plays a central role in TSW pathology, offering potential avenues for targeted treatment.
Researchers at the National Institutes of Health (NIH) analyzed 16 patients with TSW, 10 with AD, and 11 healthy controls, identified a metabolic imbalance in TSW patients marked by increased NAD+ oxidation linked to overexpression of mitochondrial complex I. Transcriptomic and metabolomic analyses of skin biopsies revealed that NAD+ metabolism is both proinflammatory and glucocorticoid-responsive, contributing to the persistent and severe symptoms observed in TSW, including redness, burning, and temperature dysregulation.
Clinically, the study confirmed that TSW symptoms differ from AD, with features such as full-body erythema, hair loss, and delayed recovery extending beyond corticosteroid application sites. The researchers proposed new diagnostic criteria that include a combination of major and minor symptoms, offering improved sensitivity for identifying TSW cases.
An open-label trial conducted as part of the study demonstrated that treatment with complex I inhibitors—metformin and berberine—led to notable symptom improvements. Patients reported a reduction in inflammation, decreased itching, and improved skin texture within three to five months of treatment. While further controlled trials are necessary, these findings introduce a promising new avenue for TSW management.
"Although this work represents a pilot study, to our knowledge, this work offers previously unreported mechanistic insights into TSW," investigators wrote.
The study underscores the importance of distinguishing TSW from AD, particularly in patients reporting worsening skin symptoms despite prolonged topical corticosteroid use. Given the study’s findings, physicians may consider metabolic interventions targeting mitochondrial dysfunction in TSW management. The study authors advocate for further clinical trials to assess the long-term safety and efficacy of these interventions.
"Importantly, although our case series suggests that expanded clinical assessments are warranted, no patient reported complete resolution of symptoms," researchers concluded. "Although prolonged treatment may yield continued improvement, pre-emptive caution may be warranted for exposures longer than 4 consecutive months, and identifying preventive strategies and predictive factors should remain paramount."
Reference: Shobnam N, Ratley G, Saksena S, et al. Topical steroid withdrawal is a targetable excess of mitochondrial NAD. J Invest Dermatol. Published online March 13, 2025. doi:10.1016/j.jid.2024.11.026
