Scientists discover the cause of hidden mysterious skin condition

For thousands of people who struggle to debilitate skin symptoms after stopping topical steroid treatment, a new National Institutes of Health (NIH) study offers both validation and hope. The researchers not only identified a unique biological mechanism behind “local steroid withdrawal” (TSW), but also discovered two drugs that might help with the treatment.

The findings, published this week in the Journal of Investigative Dermatology, represent the first major scientific study, a situation that has been controversial in the dermatology circle despite affecting thousands of patients.

“Some people label patients’ concerns as ‘steroid phobia’. However, this new study provides compelling evidence that TSW is indeed a “unique iatrogenic skin disease worth further investigation.”

Topical steroids (more accurately called glucocorticoids or topical corticosteroids) have long been the first-line treatment for eczema and other inflammatory skin conditions. While effective for most people, some patients can react severely after discontinuing these medications, especially after prolonged use.

The groundbreaking study is how to connect these symptoms to a specific biological mechanism: excessive nicotinamide adenine dinucleotide (NAD+), a form of vitamin B3 that naturally exists in the body. This excessive number of people seems to trigger severe inflammation, burning sensation and other symptoms of TSW.

The study was led by researchers (NIAID) from the National Institute of Allergy and Infectious Diseases of NIH, which combines patient surveys, biological samples and laboratory experiments to establish diagnostic criteria that distinguish TSW from common eczema. The team evaluated 16 people who were consistent with TSW and treated them with 10 people with eczema but no TSW symptoms, and 11 people with no skin disease.

Their analysis showed that NAD+ levels in serum and skin were significantly elevated in TSW patients, whereas those without TSW symptoms had typical levels. This excess appears to be produced against topical steroids and causes inflammation.

For many patients, TSW symptoms may last for several years after discontinuation of steroid use – almost 25% of respondents reported symptoms lasting for more than three years. This long-term pain leads to online communities where patients share experiences and seek solutions.

The NIH team found that the key difference between TSW and common eczema is that TSW symptoms usually occur in parts of the body where topical steroids have never been applied. Patients usually experience redness throughout their body, burning sensations, temperature disorders and a lot of skin loss.

Based on their findings that overdose of NAD+ drives these symptoms, the researchers tested a drug that blocks mitochondrial complex I, which produces NAD+. Two drugs (usually used for diabetes) and sapphire (a plant compound used in traditional Chinese medicine) show a special promise.

In a small pilot study, most participants reported improvements in TSW symptoms after three to five months of using the two drugs. While not a cure, this represents the first evidence-based treatment to be managed by avoiding steroids and time.

“These results suggest the need to expand clinical evaluation,” the researchers noted, although they warned, “no patient reports fully addressing the symptoms.”

The study also provides temporary diagnostic criteria that healthcare providers can use to identify patients with TSW. People who are now diagnosed with topical steroid treatment with TSW and meet specific symptom criteria instead of simply being told that they are experiencing an outbreak of their original skin condition.

Dr. Ian Myles, principal investigator at the NIAID Clinical Immunology and Microbiology Laboratory, led the research team. These findings represent collaborations between NIAID scientists and patient advocacy groups, such as the International Local Steroid Awareness Network, whose members participated in the study.

For co-authors of the study that advocates for TSW recognition, Kelly Barta and Kathryn Tullos, the study confirmed what patients have been reporting for years. Their participation highlights the growing trend of patient investigator partnerships in addressing poor medical conditions.

The team recommends caution may be needed for four consecutive months of topical steroid exposure. They stressed that, given the potential life-changing nature of TSW, identification of prevention strategies and predictors should be kept at their highest.

Like many preliminary studies, the researchers acknowledged limitations, including smaller sample sizes and the need for a specific expected severity index of TSW. Further research is needed to understand why some people develop this, while others use topical steroids without any incidents.

These findings also raise questions about current prescription practices for topical steroids, one of the most commonly used drugs in dermatology. While the study does not recommend avoiding these effective treatments altogether, it does highlight the need for monitoring long-term use.

For patients currently suffering from TSW symptoms, the study not only provides hope for treatment, but also provides validation that many people seek from the medical community. As one participant said, the most important relief was that their experience was scientifically validated because years of symptoms were the return of psychological or primitive conditions.

The study was collaborated by the Air Force Office of Scientific Research, the Biology and Biophysics of RNP Particles, and the Biophysics of the National Institutes of Health.