Researchers report successfully treating the rare condition with a JAK inhibitor.
An oral Janus kinase inhibitor has successfully helped reduce Netherton syndrome symptoms in a young woman whose skin involvement dropped from 84% to 5% within three weeks of starting treatment.
Describing the case history of a 29-year-old woman, Chinese researchers said they treated a patient with the condition with 200mg oral abrocitinib after she had not responded to treatment with secukinumab and dupilumab.
“After taking abrocitinib, her skin condition improved within a few days and continued improving during the following three months without an increase in infections, such as pneumonia, herpetic eczema or herpes zoster,” the researchers wrote in a letter in JAMA Dermatology.
“Netherton syndrome is a rare, life-threatening autosomal recessive skin disease with ichthyosis, characteristic hair shaft defects and atopic manifestations. Treatment for Netherton syndrome has been challenging.”
The patient had been given diagnoses of eczema and psoriasis for 20 years. She had been treated with topical emollients, corticosteroids, oral methotrexate and cyclosporine “with little success”, the researchers wrote.
The researchers reported that 76% of the patient’s skin was affected by Netherton syndrome at her initial presentation, but that improved after taking secukinumab for eight weeks.
The patient discontinued secukinumab when she became pregnant. After giving birth prematurely at eight months, she resumed secukinumab for three months, but it was ineffective, the researchers said.
“She was then switched to taking dupilumab, which decreased her pruritus,” the researchers wrote.
“However, her skin lesions and symptoms recurred after one week. Her skin involvement increased to 84% body surface area one month after discontinuing treatment with dupilumab.”
The patient then tried abrocitinib at 200mg daily, the researchers said. Her pruritis score and dermatological quality of life score both improved within a week after she started the new treatment.
“Her skin lesions exhibited visible improvement and decreased to 30% body surface area involvement,” the researchers wrote.
However, the patient felt lightheaded and nauseous, so the dosage was decreased to 100mg daily.
“The patient claimed that the skin lesions were nearly gone (5% body surface area involvement) after three weeks of treatment, and the numerical rating scale and dermatological life quality index scores fell to two. After three months of treatment, the patient continued to improve,” the researchers wrote.
“Interleukin-17 and IL-4/IL-13 antagonists could be potential Netherton syndrome therapies. Although most individuals with Netherton syndrome respond well to these treatments, a few do not, necessitating different therapies for these refractory cases.”
In the US, abrocitinib is approved for adults with moderate to severe atopic dermatitis. In Australia, however, the drug is not yet approved and the PBAC reported in November 2021 that the drug would be considered at a future PBAC meeting.
The researchers said a phase III randomised clinical trial showed that abrocitinib was effective and well tolerated in people with moderate to severe atopic dermatitis.
“In contrast to secukinumab and dupilumab, solely suppressing the Th2 or Th17 pathway, the putative action of abrocitinib on refractory Netherton syndrome, may involve blocking the Th2 and Th17 pathways, suggesting that abrocitinib may be another option for patients who are not responding to more conventional therapies, such as corticosteroids and biologics,” the researchers wrote.
Commenting on the study, consultant dermatologist Associate Professor David Orchard said Netherton syndrome was a rare genetic condition that usually manifested at birth.
“As babies they run into trouble with fluid balance and electrolytes, and they’ve got a high propensity for allergies,” said Professor Orchard, from Royal Children’s Hospital and University of Melbourne. He sees several young patients with the syndrome.
Patients are born with red, extremely sensitive skin with a defective skin barrier and typically also have “fragile” hair that doesn’t grow to any decent length, he said.
“It’s like having a chronic severe eczema. Some patients are red all over, and others have phases of being red all over,” he said.
“At other times they’ll get more patterned, scaly raw eruptions that break out over their skin.”
Professor Orchard said Netherton syndrome had a huge impact on quality of life both due to the discomfort of the condition and the cosmetic impact.
“It fluctuates. At times their skin can be relatively good, and then they have breakouts,” he said.
“Some of them are just persistently red all the time and others vary a little bit and every time they get hot or cold their skin flares.
“At other times – we can’t explain why – they have patterned breakouts. And at other times they become red all over.”
Treatment was similar to the care of eczema, including moisturising inflamed areas and using topical steroids, he said, although there had been a recent move to biologic medicines used in psoriasis and eczema.
Professor Orchard said the JAMA Dermatology case study showed that the adult patient had used other medications before trying a JAK inhibitor.
The standard of care would be to try biologic medications such as interleukin 17 and interleukin 13 inhibitors before trying immunosuppressants such as JAK inhibitors, he said.
“There are novel ways of trying to suppress the process without immunosuppressing the individual. I think they should always be used before JAK inhibitors because JAK inhibitors are technically immunosuppressive,” he said.
“As a rule, topical medications will only help so much in these individuals because they’re usually quite severely affected.”
Using a JAK inhibitor in a patient with severe Netherton syndrome was a new approach, he said.
“There may be the potential that JAK inhibitors might come out in a topical preparation at some stage in the future as well, which will be an interesting approach,” he said.
“There’s a variety of systemic approaches. We can’t fix the gene, but the mechanism of why their skin ends up red and inflamed is through these inflammatory pathways, and there is the potential of trying to do something to suppress these inflammatory pathways.”
Professor Orchard said for a child to inherit Netherton syndrome, both parents had to be carriers of the gene, but the parents themselves didn’t usually have the condition.
