Clinical Challenges: Chronic Itch in Atopic Dermatitis

Atopic dermatitis (AD) is one of the most common chronic inflammatory skin diseases in industrialized nations, affecting an estimated 12% of children and 7.3% of adults in the U.S. Although AD is most often diagnosed in childhood, an estimated one in four adults with the disease experience the onset of initial symptoms after the age of 18.

AD is characterized by eczematous skin lesions, itch, pain, sleep disturbance, and multiple comorbidities, with a chronic or relapsing course. Of those affected, one-third of children and 40% of adults have moderate to severe disease, which is known to negatively impact quality of life (QOL), increasing the risk of anxiety, depression, and even suicide.

Whether AD is mild, moderate, or severe, itch appears to be “the most burdensome symptom overall,” noted Franz J. Legat, MD, of Medical University of Graz in Austria. “Even in severe cases with widespread skin involvement and extensive oozing and crusting, pruritus is still the patients’ major concern and a significant burden of the disease,” Legat wrote in Frontiers in Medicine.

Jashin J. Wu, MD, founder and CEO of the Dermatology Research and Education Foundation in Irvine, California, agreed. “Atopic dermatitis is the ‘itch that rashes,'” he told MedPage Today.

In the absence of biological markers for AD, patients are typically asked to assess the frequency and severity of itch with questionnaires that use a numeric rating scale (NRS), visual analogue scale, verbal rating scale (VRS), and other measures, such as the 5-D itch scale, and Itchy QOL.

A recent study of the Patient-Reported Outcomes Information System (PROMIS) Itch Questionnaire (PIQ), which included multiple NRS, VRS, and frequency-of-itch assessments, demonstrated their validity in adults with AD. Jonathan Silverberg, MD, PHD, MPH, director of Clinical Research at George Washington University School of Medicine and Health Sciences in Washington, D.C., and co-authors found that PIQ, NRS, VRS, and frequency-of-itch measures not only made sense to patients, but also correlated well with each other and were predictive of more severe disease.

“These tools capture what matters most to patients: itch,” Silverberg told MedPage Today. “They also provide rich information that cannot be provided by examining the skin alone.”

In a study of 125 patients with AD, Silverberg and a colleague found that 25% of patients with milder lesions had severe itch. “We describe this group as ‘itch-dominant atopic dermatitis,'” Silverberg said. “This is a very important patient subset that would be entirely missed without incorporating itch outcome measures in clinical practice.”

He said he uses the NRS worst-itch and average-itch questions from the PROMIS Itch Questionnaire to assess itch frequency and severity. “They take a few seconds for patients to complete, provide clinically meaningful information, can easily be incorporated into clinical practice, and are valid for use in AD,” he explained.

“I hope that one day we will have clinically useful objective biomarkers of AD or itch severity. These could help refine the measurement of itch in clinical practice and trials. Alas, we are a long ways off from that time,” he added.

Matthew J. Zirwas, MD, a practicing dermatologist in Columbus, Ohio, manages patients with AD referred by other dermatologists, so all of them have itch. His takeaway? “Treat it aggressively,” Zirwas told MedPage Today.

Currently, dupilumab (Dupixent), an interleukin (IL)-4/13 inhibitor given by injection, is the only FDA-approved systemic or biologic therapy for AD. “The main treatment is to clear the rash, so usually a systemic agent is needed,” said Wu.

Although dupilumab clears the rash and the itch in most patients, the drug’s peak efficacy may occur months after treatment, he explained. In patients who need a “quick fix” or who have poor insurance coverage or both, “prednisone tapered over 4 weeks works well.”

There is evidence that dupilumab can work even more quickly, however. A post-hoc analysis of results from the phase III LIBERTY AD PEDS study, reported at the 2021 Revolutionizing Atopic Dermatitis meeting, showed that in children ages 6-11 with severe AD, a subset had rapid improvement of itch right after the loading dose of dupilumab. “Dupilumab resulted in significant improvements of itch severity within approximately 1-2 weeks and deeper responses of itch by 3-4 weeks,” Silverberg said.

Dupilumab “is a great medication, but we definitely need more options to address unmet needs and tailor therapy to specific patient subsets,” he continued. “We are excited to have multiple new options coming to our toolbox for managing atopic dermatitis.”

Currently, a number of Janus kinase (JAK) inhibitors with variable specificity for the receptor tyrosine kinases JAK1, JAK2, and JAK3 and tyrosine kinase 2, are in the pipeline awaiting FDA approval. These include:

• Abrocitinib, an oral JAK1 inhibitor that reduces IL-4 and IL-13 signaling

• Baricitinib (Olumiant), an oral selective JAK 1/2 inhibitor approved for rheumatoid arthritis

• Upadacitinib (Rinvoq), an oral JAK1 inhibitor also approved for rheumatoid arthritis

• Tralokinumab, a human monoclonal antibody targeting IL-13

“With observed rapidity in itch relief and accompanying dramatic reduction in inflammatory lesion count, JAK inhibitors represent a promising new treatment to revolutionize the management of AD,” said Alexander M. Cartron, MD, of the University of Maryland School of Medicine in Baltimore, and colleagues in Clinical and Experimental Dermatology.

Recently published clinical trials that would appear to bear this out were presented at the 2021 annual meetings of the American Academy of Allergy, Asthma and Immunology and the American Academy of Dermatology (AAD).

In the phase III JADE COMPARE trial, the efficacy of abrocitinib plus topical corticosteroids was compared with dupilumab plus the corticosteroids in adults with moderate to severe AD. The results showed that both provided rapid and effective relief from AD signs and symptoms when compared with placebo. “The 200-mg dose, but not the 100-mg dose, of abrocitinib was superior to dupilumab with respect to itch response at week 2,” Thomas Bieber, MD, PhD, chair and director of the Department of Dermatology and Allergy at the University of Bonn in Germany, and colleagues wrote in the New England Journal of Medicine.

Abrocitinib appeared to have faster onset than dupilumab, but dupilumab had the best safety profile, Silverberg said. “I don’t think we can say that one drug is ‘better’ than another. But there are pros and cons for both. Abrocitinib is an oral medication, with faster onset of effect and more robust efficacy at higher doses. Dupilumab is still highly effective with a very good safety profile and is dosed less frequently. Ultimately, patients can decide which option works best for them.”

In the study reported at the AAD meeting, an analysis of pooled results from two phase III trials of identical design, TRuE-AD1 and TRuE-AD2, looked at the effectiveness of the topical JAK 1/2 inhibitor ruxolitinib in patients randomized to one of two topical ruxolitinib (Jakafi) formulations or to placebo. The results showed that at 8 weeks, 28.0% of patients using 0.7% ruxolitinib cream and 32.7% on 1.5% topical ruxolitinib reported having no days of itch using the Patient-Oriented Eczema Measure, compared with 9.0% of patients on placebo cream. In most patients treated with ruxolitinib, itch was significantly reduced after 36 hours, and in some patients, after 12 hours, reported Kim A. Papp, MD, PhD, founder and CEO of Probity Medical Research in Waterloo, Ontario, and colleagues.

“The results demonstrate the potent anti-inflammatory effects of ruxolitinib cream versus vehicle,” the team wrote. “These results also support the potential of ruxolitinib cream as an effective and well-tolerated topical treatment for atopic dermatitis.”

Zirwas noted that he has found that some patients have itch without a rash. “My go-to treatments are intranasal butorphanol, which is by far the most reliably effective but is difficult to prescribe since it is classified as an opioid, and oral mirtazapine,” he said.

For localized itch, he said he has had “incredible results” with topical ruxolitinib, and has found a new strontium-based over-the-counter topical agent, Dermaleve (aluminum acetate cream), to be “stunningly effective.” For generalized itch, oral nalbuphine (Nubain), an opioid analgesic, and subcutaneous nemolizumab, a first-in-class humanized monoclonal antibody that blocks IL-31 signaling, “are the best drugs in the pipeline,” said Zirwas.