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Itching remains the most common symptom experienced by patients with atopic dermatitis (AD), but several new strategies may herald some long-awaited relief.

Patients with AD may experience several different types of itch depending on which nerves or cells are activated by the disease, according to recent studies, and researchers are finding additional evidence that the itch-scratch cycle involves not only the skin, but the immune system, nerves, and brain.

Reducing the itch in AD would improve quality of life not only for patients, but for their families and caregivers, and more research is underway to explore the anti-itch mechanisms of emerging treatments.

In a review article published in May 2023 in the Journal of the American Academy of Dermatology (JAAD), Angelina Labib, BS, Teresa Ju, BS, and Gil Yosipovitch, MD, of the University of Miami, FL, summarized several treatments in phase II and phase III trials that target the elusive itch of AD.1 Of these, tapinarof as a topical and lebrikizumab as a systemic agent are among the farthest along in clinical trials.

“Many of the new available treatments for AD are effective in reducing itch; however, with an abundance of emerging treatments currently being investigated, it is imperative to understand the mechanisms of action and efficacy in reducing pruritus among these novel treatments,” the review authors wrote.

Tapinarof Tests Well

Tapinarof, a topical treatment designed to target the aryl hydrocarbon receptor, showed promise in a recent phase II trial, according to the review authors. Patients with AD who were randomly assigned to tapinarof cream showed significant improvement in the primary endpoint of Investigator Global Assessment compared to placebo at 12 weeks.

In that study, published in JAAD in 2021, Amy S. Paller, MD, and colleagues, approximately one-third of patients in each of four tapinarof dosage groups achieved an improvement in itch of 3 points or more on the pruritus Numeric Rating Scale (30% of those receiving 1% tapinarof twice daily, 32% of those receiving once daily doses, 33% of those receiving 0.5% twice daily, and 29% of those receiving 0.5% once daily) compared to 15% and 5% of patients receiving placebo vehicles once or twice daily, respectively.2

Other topicals under investigation for AD that have shown potential as itch improvers include the phosphodiesterase inhibitor 4 (PDE4) drugs roflumilast, lotamilast, difamilast, and LEO 29102. Other candidates are delgocitinib, a form of janus kinase (JAK) inhibitor, brepocitinib, a TYK2/JAK1 inhibitor, and the transient receptor vanilloid 1 (TRPV1) antagonist known as PAC-14028.1

Lebrikizumab Improves AD and Itch

Lebrikizumab, an emerging systemic treatment for itch, is a monoclonal antibody interleukin (IL)-13 inhibitor under investigation for the treatment of moderate-to-severe AD. Data suggest that the itch-reduction mechanism of lebrikizumab “is directly related to the enhancing effect of IL-13 in neuroactive pathways,” the review authors noted.

Lebrikizumab showed safety and effectiveness in treating moderate-to-severe AD in a pair of phase III trials. In both 52-week studies, published in 2023 in the New England Journal of Medicine, significantly more AD patients met the primary outcome of Investigator’s Global Assessment Scores of at least 2 points after 16 weeks compared to placebo patients.3 The results were published after the review by Labib and colleagues, but were referenced as preliminary.

With regard to itch specifically, lebrikizumab patients also showed significant improvement in a secondary outcome measure of itch, defined as a reduction of 4 points or more on the pruritus NRS, according to Jonathan I. Silverberg, MD, and colleagues. In the two trials, 45.9% and 39.8% of patients randomly assigned to lebrikizumab met the itch improvement outcome, vs. 13.0% and 11.5% of placebo patients, respectively.

Other emerging systemic AD treatments with itch-reducing potential include nemolizumab, an IL-31 inhibitor; etrasimod, a selective Sphingosine-1-phosphate (S1P) agonist, and telazorlimab, and anti-OX-40 monoclonal antibody.1

AD treatments that will relieve the itch aspect of the disease must have “a rapid response that is sustainable regardless of the effect on rash, such lichenified plaques that take longer to resolve,” said Gil Yosipovitch, MD, professor of dermatology at the University of Miami, FL, and director of the Miami Itch Center, in an interview.

Additional challenges for some patients include “severe itch in localized areas that does not respond to topicals, or severe itch with mild rash,” said Dr. Yosipovitich, who served as corresponding author for the JAAD review. He added that, “it is difficult to get approval for new drugs as a treatment for itch because most of the indications are based on body surface area and EASI scores that do not take itch in account.”

“Some of the new treatments targeting itch have rapid effect that is robust,” Dr. Yosipovitch told Practical Dermatology. “Difelikefalin may have some antipruritic effect in AD, but is not the most striking among the drugs.”

The question of whether insurance payers will pay for new treatments remains a major barrier to the use of emerging drugs for itch in AD, said Dr. Yosipovitch. Also, some patients have severe itch but limited body surface area or rash, and therefore fall outside a drug’s indication. Ideally, “severity of itch regardless of AD rash will be recognized by FDA is an indication to treat,” he said, noting that some emerging treatments such as OX-40 inhibitors may have prolonged effect on AD and require treatment every three months in comparison with the biweekly or monthly injections involved in current treatments, which may reduce the barriers to use.

Looking ahead, “more research is needed to better understand the neuroimmune access of itch and how drugs such as biologics affect the nerves,” Dr. Yosipovitch noted.

Many new findings on mechanisms of drugs on nerves and immune interactions will be presented at the 2023 World Congress of Itch, scheduled for November 5-7 in Miami, FL, he added.

Which Itch is Which

When it comes to managing itch, the greatest challenges for patients with AD and their doctors include predicting how much improvement in overall itch a patient will experience, and finding the therapeutic option that rapidly improves itch, according to Brian S. Kim, MD, vice chair of research at the Icahn School of Medicine at Mount Sinai, in New York City, and director of the Mark Lebwohl Center for Neuroinflammation and Sensation, in an interview.

Emerging therapies such as difelikefalin have distinct mechanisms of action, Dr. Kim told Practical Dermatology.

“A major advantage of difelikefalin is that it seems to have very broad activity in suppressing many different kinds of itch,” he said. “Something many people are not aware of is that even within one condition, such as atopic dermatitis, there are different kinds of itch that may or may not be sufficiently targeted with certain therapies. Difelikefalin, rather than simply blocking the itch mediators, acts to stimulate neurologic pathways that are within our body to suppress itch.”

Dr. Kim was the corresponding author on a recent study in which oral difelikefalin improved moderate-to-severe itching in patients with atopic dermatitis.

In that study, published in the Journal of Allergy and Clinical Immunology, difelikefalin at doses of 0.25 mg, 0.5 mg, and 1.0 mg improved itch in patients with moderate-to-severe AD-related pruritus compared to a placebo, although the results were not statistically significant after 12 weeks.4 However, difelikefalin also downregulated pruritus-related genes and TH2-related cytokine pathways, and had a positive impact on genes related to the skin barrier. Difelikefalin’s anti-itch effects may stem from binding to K-opioid receptors (KORs) on keratinocytes, immune cells, and peripheral sensory neurons, the researchers wrote.

Cost is always the number one barrier to widespread use of novel therapies in clinical practice, according to Dr. Kim; however, the costs will likely decrease as the new drugs become generic.

“With the emergence of more competition, one would hope prices can come down as well,” he added.

Other barriers to expanded use of novel AD treatments include concerns about side effects, but these concerns highlight the need for additional research, said Dr. Kim. “We need therapies that are universally effective, safe, and ideally curative; the latter is the next frontier of research in atopic dermatitis,” he said.

1. Labib A et al. Emerging treatments for itch in atopic dermatitis: A review. J Am Acad Dermatol. 2023;89(2):338-344. doi:10.1016/j.jaad.2023.04.057.

2. Paller AS et al. Efficacy and patient-reported outcomes from a phase 2b, randomized clinical trial of tapinarof cream for the treatment of adolescents and adults with atopic dermatitis. J Am Acad Dermatol. 2020;84(3):632-638. doi:10.1016/j.jaad.2020.05.135.

3. Silverberg JI, Guttman-Yassky E, Thaci D, et al. Two phase 3 trials of lebrikizumab for moderate-to-severe atopic dermatitis. N Engl J Med. 2023;388(12):1080-1091. doi: 10.1056/NEJMoa2206714

4. Guttman-Yasky E, Facheris P, Correa Da Rosa J, et al. Oral difelikefalin reduces moderate to severe pruritus and expression of pruritic and inflammatory biomarkers in subjects with atopic dermatitis. J Allergy Clin Immunol. 2023;doi:10.1016/j.jaci.2023.06.023

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