Early, aggressive treatment best in eczema

New advances in disease modifying drugs suggest chronic disease could be averted if action is taken sooner in life.

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Early and intense appears to be the best way to treat eczema in children, according to new developments in disease modifying medications.

But treatment cost remains a major barrier, delegates of the Australasian College of Dermatologists annual scientific meeting heard in Brisbane earlier this month.

Associate Professor Li-Chuen Wong, a Sydney-based paediatric and adult dermatologist, called on the audience to promote new disease modifying treatments for even the really young eczema patients.

“It’s a paradigm shift, really, because we have been used to just putting out fires and treating symptoms. We now have advanced therapies that will enduringly impact the natural course of the disease, leading to sustained remission after cessation of treatment,” Professor Wong said.

But these interventions to modify the disease must happen in childhood.

“It has to happen when the immune response is more receptive to intervention. So this window of opportunity actually occurs in infancy, and if you treat then, you might actually prevent the progression to chronic disease and reduce comorbidities,” Professor Wong said.

“However, to treat and to disease modify, you have to go upstream. You’ve got to do it before the inflammatory cascade develops and before we generate a whole lot of resident memory T cells.”

Research was currently underway to define cellular and molecular biomarkers in skin biopsies and blood in kids with eczema, and then correlate it with disease severity using common eczema assessment tools, such as Eczema Area and Severity Index (EASI) and Scoring Atopic Dermatitis (SCORAD) scores, to better target treatments those patients, Professor Wong said.

Professor Wong outlined the major advances in paediatric eczema research in the last few years that have overturned our understanding of the disease.

Primary prevention

The February PEBBLES trial from Melbourne showed the importance of ceramides in skin barrier function in infants from families of high allergic disease. Lower levels of protein-bound ceramides on the skin at six weeks predicted the development of eczema at one year of age, suggesting early life lipid restoration could prevent later atopic dermatitis.

Calcineurin inhibitors

A 2023 systematic review on calcineurin inhibitors, which included over three million mostly paediatric patients, found no link to cancer. It concluded the treatments were safe, even for young children, regardless of disease severity.

“There was a black box warning put out on calcineurin inhibitors, which arguably would have led to sub-optimal treatment for our patients with eczema for many years,” Professor Wong said.

“Hopefully this comprehensive review will allay the fears of families, our patients and us.”

Topical nonsteroidal agents

Professor Wong then highlighted four new topical nonsteroidal agents she was “very excited about”.

“Unfortunately, they are not available in Australia at the moment, [but] hopefully they will come on the PBS,” she said. “I think that they will be important for our paediatric population, particularly in the mild-to-moderate cohort, because they’re creams and they don’t sting.”

The first was ruxolitinib, a JAK1/2 inhibitor, which showed significant improvement in eczema severity and quality of life in adolescents and children who used the cream twice daily, with no serious adverse events or systemic absorption.

Pooled data from two randomised controlled trials in teens found that itch resolved or substantially diminished by day two, there was a good clinical response by week two and 60% had achieved an EASI of 75 by month two, she said.

The treatment is now approved in the US and Europe for patients over age 12. However, the cost to import 100g into Australia was nearly $2000, she said.

Professor Wong also shared some preliminary and unpublished data from a trial into delgocitinib, a pan-JAK inhibitor currently approved for adults with chronic, moderately severe hand eczema. The results suggest the cream is safe and effective compared with placebo in adolescents, but 60g would also cost almost $2000 to import, she said.

Tapinarof, a first-in-class nonsteroidal receptor agonist, was another exciting cream that had been well received so far in North America in the moderate-to-severe subgroup, Professor Wong said. 

“As it’s a cream, it potentially might be good for a young population that hates needles and can’t swallow tablets,” she said. “It seems to have benefit, not only in reducing symptoms and decreasing IgA, but maintains remission in terms of treatment.”

“It up-regulates the skin barrier proteins. It also increases production of ceramides, and it down-regulates proinflammatory cytokines.”

Data from two phase 3 trials published last year show that at least half of patients over age two achieved an EASI score of 75 by two months.

“It’s well tolerated. It doesn’t sting. It’s daily in application, so therefore great for compliance,” said Professor Wong, before noting just 60g of the cream would cost the same as a second-hand car.

Roflumilast, a potent phosphodiesterase 4 inhibitor, reduces inflammation and decreases the production of proinflammatory cytokines.

A February study of children aged two-to-five years found that daily application for four weeks resulted in itch stopping within one day and almost half of the patients achieving an EASI of 75 by the end. Studies in older patients aged six and older echoed these findings, Professor Wong said.

“You can apply as much as you want, wherever you want – but 60g will be around $2000 at the moment, so let’s all pray for PBS,” she said.

Immunosuppressives

The 2023 TREAT study compared immunosuppressives in patients aged two-to-16 years and confirmed what doctors already knew clinically, Professor Wong said.

“Cyclosporine: it works fast, works within a couple of days and it is the hare, whereas the tortoise is methotrexate, which takes a while to kick in, sometimes two to three months, but then it has significantly superior efficacy in terms of long-term disease control,” she said.

“If you want something more cost effective, go for methotrexate – it is so much cheaper. But if you want something that works fast, then go for cyclosporine.”

Dupilumab

Data from the BioDay registry, an independent prospective observational cohort study, has shown significant improvements in asthma and airway inflammation in children and teens with severe eczema who took dupilumab.  

The 2024 study found that aeroallergen IgE levels dropped by up to 90% in patients taking the medication.

“Atopic dermatitis is the first in the atopic march. It starts in childhood, and then there’s asthma, and then hay fever,” Professor Wong said.

A 2022 meta-analysis found that dupilumab reduced the risk of new allergies by 37% and reduced the worsening of allergies by 34% compared with placebo.

“The benefits persist even after stopping treatment, but the benefits are greater the younger you are when you start treatment, the earlier your onset of disease, the more severe eczema you have and if you have baseline asthma,” she said.

“So dupilumab could potentially interfere with the atopic march,” she said. “It could attenuate new allergic conditions from developing, and it could stop the worsening of existing allergies.”

Two trials have also shown the treatment led to significant growth spurts in younger patients, highlighting the importance of early and aggressive treatment.

“Three out of 10 children in that younger population gained at least five percentiles in height. That is a massive growth spurt that wasn’t seen in the adolescent population, which speaks to this concept of a window of opportunity,” Professor Wong said.

“So there’s this period of time where if you treat aggressively and you stop skin inflammation, then children have the potential to catch up to where they should be in terms of height and weight.”

Other preliminary and unpublished data found that one in three patients achieved clinical remission after 40 weeks of treatment, with half maintaining remission after stopping the drug, she said. Younger patients were more likely to maintain remission.

Lebrikizumab

Lebrikizumab, a high affinity monoclonal antibody that targets IL-13, has been approved for teens over the age of 12.

The 2023 ADore trial found that fortnightly injections led to 80% of patients achieving an EASI of 75 after a year of treatment, along with quality-of-life improvements. The 2024 follow-up ADjoin trial showed that more patients continued to improve with another year of treatment, and that monthly injections appeared to be as safe and effective.

Nemolizumab

Professor Wong said this “new kid on the block” IL-31 receptor inhibitor significantly reduced itch in adolescents, with half of the study group achieving an EASI of 75 by four months.

Itch meaningfully improved and the treatment had a good safety profile without triggering conjunctival symptoms, according to the ARCADIA 1 and 2 data.

Upadacitinib

“I really like it, because it’s an oral medication that works fast and it works well, but you do need to do blood monitoring that sometimes kids don’t like,” Professor Wong said.

Because upadacitinib has long been available, there was plenty of research into this drug, she added.

Pooled data from three trials found that seven in 10 teens who took the 15mg dose for 76 weeks achieved an EASI of 75, and this rose to eight in 10 who took 30mg.

The Level Up trial published in January found more teens achieved an EASI over 90 at week 16 with upadacitinib than dupilumab.

Professor Wong said the finding wasn’t a surprise, because JAK inhibitors worked fast. Instead, she was waiting to see what the results of the 32 week follow up was, and whether dupilumab caught up.

Another issue was that in Australia, the PBS didn’t cover the higher 30mg dose for teens, which many in the study had to increase to when 15mg was not sufficient, she said.

Nevertheless, by next year Professor Wong hoped to see new data from the same research team in children aged two-to-12 years.

Disease modification

The research now suggested there was a window of opportunity to prevent chronic disease and reduce comorbidities in kids with eczema, Professor Wong said.

“So we all want to advocate for these advanced therapies to be available to our very young population, please.”