Topical steroid withdrawal dermatitis linked to excess NAD+

Graphical abstract, Shobnam N, et al. Journal of Investigative Dermatology (March 14, 2025, online ahead of print)

Researchers at the U.S. National Institutes of Health (NIH) have determined that dermatitis resulting from topical steroid withdrawal (TSW) is distinct from eczema and is caused by an excess of nicotinamide adenine dinucleotide (NAD+), a form of vitamin B3. Scientists from NIH’s National Institute of Allergy and Infectious Diseases (NIAID) identified treatments that could be studied in clinical trials for the condition based on their potential to lower levels of NAD+.

The findings were published in the Journal of Investigative Dermatology.

In a press release from the NIH, the agency notes that physicians have long used glucocorticoids or topical corticosteroids as a first-line treatment for dermatitis caused by eczema as the medications are safe, effective, easy to apply, and considered well-tolerated.

However, some people experience dermatitis after using topical steroids for prolonged periods and then stopping—a condition called TSW. Diagnosing and treating this condition is difficult because TSW is not well understood. Symptoms include skin redness, burning sensations, skin heat (thermal dysregulation), itching and peeling, which can even occur on parts of the body where topical steroids were not applied. As TSW and eczema have similar symptoms, it has been difficult to distinguish the two disorders.

To better understand TSW, a team led by scientists in NIAID’s Laboratory of Clinical Immunology and Microbiology evaluated a previous survey that included 1,889 adults with symptoms similar to eczema. By dividing the participants into those with self-reported TSW and those without, the researchers identified characteristics unique to TSW. The researchers then conducted a pilot study that included 16 people with symptoms consistent with TSW, 10 with eczema but no symptoms of TSW, and 11 people without skin disease. They found that people with TSW symptoms had elevated levels of NAD+ in their blood serum and skin, while NAD+ levels were within a typical range in people without TSW symptoms.

The researchers then used cultured skin cells and a mouse model to mimic TSW conditions. They found that NAD+ was produced in response to topical steroids and caused inflammation. The models suggested that administering a medication that blocked the formation of NAD+—called a mitochondrial complex I blockade—would improve TSW symptoms. In a pilot study to further assess this treatment strategy, the researchers evaluated subjective responses among participants who used the mitochondrial complex I-blocking drugs metformin, berberine, or both. After three to five months of use, most participants reported improvement in TSW symptoms.

The scientists provisionally established criteria that healthcare providers can use to identify TSW in people. Practitioners may diagnose people who have stopped topical steroid treatment and meet the criteria as having TSW. The researchers suggest that patients identified as having TSW could be treated using the proposed mitochondrial complex I-blocking drugs.

Results from this study may help practitioners identify TSW in patients and work toward developing safe and effective treatments. According to the researchers, more research is needed to determine whether all patients with TSW have an excess of NAD+, or if there are other features that define TSW. Additionally, the diagnostic criteria will help healthcare providers and researchers better understand the prevalence of TSW and evaluate the effects of topical steroids.