Prurigo Nodularis Treatment Effective in Phase 3 Trial - InventUM

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An article for InventUM | University of Miami Miller School of Medicine

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BY ROCHELLE BRODER-SINGER

Prurigo Nodularis Treatment Effective in Phase 3 Trial

Shortly after the FDA approved the first systemic therapy for the chronic severe itch of prurigo nodularis (PN), researchers have demonstrated the effectiveness of a second systemic treatment in a phase 3 clinical trial.

Gil Yosipovitch, M.D., professor in the Dr. Phillip Frost Department of Dermatology and Cutaneous Surgery, led the studies that resulted in FDA approval of the first treatment and was a collaborator on the phase 3 trials for another treatment, nemolizumab.

“Until recently, PN patients – who also tend to have many comorbidities – were a very difficult-to-treat population,” said Dr. Yosipovitch, also Stiefel Chair of Medical Dermatology and director of the Miami Itch Center. “This targeted treatment, which has minimal side effects, should be another excellent treatment for PN patients.”

PN is a chronic inflammatory skin disease characterized by severe itching. Scratching leads to skin nodules across large areas. The intensity and frequency of PN itch is among the worst of all itch-causing diseases. The itching, pain, stinging and burning are so severe patients struggle to sleep and have higher rates of depression and anxiety than people without the disease.

In a phase 3, double-blind, randomized trial, nemolizumab, a monoclonal antibody that targets the Interleukin-31 receptor for the itchy cytokine IL-31, was shown to rapidly reduce itching. It also significantly diminished pain and reduced the number of firm skin nodules for moderate-to-severe PN patients.

Earlier this year, the FDA approved PN’s first systemic therapy, the monoclonal antibody dupilumab, based on trials led by Dr. Yosipovitch. This subsequent phase 3 trial of nemolizumab points toward another potential treatment that can bring substantial relief to patients who did not respond to existing treatments.

Calming the Immune System

Nemolizumab calms key parts of the immune response that play roles in itching and nodule formation. It blocks signaling of the cytokine interleukin-31—coined “the itchy cytokine”—the levels of which are increased in patients with PN.

Interleukin-31 is believed to be a primary culprit in patients’ itchiness. The higher the level of interleukin-31, the greater the intensity of itchiness. It promotes inflammation and can activate sensory neurons in the skin that make a person more prone to react to any itchy stimulus. It can also stimulate other immune cells, further increasing itchiness, nodule formation and inflammation.

“For the last two decades, our group has studied the role of interleukin-31 in many types of itch, including PN, stasis dermatitis, atopic dermatitis, cutaneous T-cell lymphoma itch, lichen amyloidosis and even COVID-19-related itchy toes,” Dr. Yosipovitch said. “Now that there is a drug targeting this cytokine, we predict it may also be able to help patients with other types of chronic itch.”

Scratching for an Explanation for Psoriatic Itchy Scalp

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Turning an academic research paper into a physician-accessible article for InventUM | University of Miami Miller School of Medicine

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BY ROCHELLE BRODER-SINGER

Scratching for an Explanation for Psoriatic Itchy Scalp

Psoriatic scalp itch may have a larger neural component than previously thought, with neuroimmune mediators — rather than the histamine system — controlling the severity of this type of itch, according to a study led by Miller School of Medicine researchers.

As many as 70% of people with psoriasis report itchy scalps, and treatment is challenging due to the location of scalp lesions and an incomplete understanding of exactly what causes and affects this type of itch. This study was the first of its kind to examine mediators involved in itchy psoriatic scalp and provides some novel insights into how the mechanisms of psoriatic scalp itch are different from psoriatic itch in other locations.

“This study demonstrated that histamine is not a mediator in psoriatic scalp itch, and the use of antihistamines, a common treatment, will not help patients,” said Gil Yosipovitch, M.D., professor, Stiefel Chair of Medical Dermatology, and director of the Miami Itch Center at the Dr. Phillip Frost Department of Dermatology and Cutaneous Surgery. “Inhibitors that block neural channels may better treat this type of itch, and our research indicated specific types of inhibitors to work on in order to help these patients.”

Dr. Yosipovitch was senior author of the study “Neuroimmune Mediators of Pruritus in Hispanic Scalp Psoriatic Itch,” published recently in Acta Dermato-Venereologica and funded by a research grant from LEO Pharma, a dermatological pharmaceutical company. The study’s first author, Leigh A. Nattkemper, Ph.D., is a research assistant professor in the department. Co-authors Zoe M. Lipman, M.D., and Giuseppe Ingrasci, M.D., were Miller School students who are now in their internships. Co-author Enrique Loayza, M.D., was one of Dr. Yosipovitch’s fellows and currently works in the dermatology department at Hospital Luis Vernaza in Guayaquil, Ecuador, where the patient research was conducted.

Mediating a Complex Interplay of Itch’s Causes

The researchers examined scalp biopsies from Hispanic patients with psoriasis who were not receiving treatment or who had stopped treatment prior to the biopsy. The patients were asked to rate the intensity of their scalp itch, which was found not to correlate with the visual severity of their scalp psoriasis.

The group of patients who reported severe scalp itch and the group that reported no scalp itch or mild to moderate itch showed several differences in neuropeptide, transient receptor potential and immune system expression, although they showed no difference in histamine expression.

“Our results indicate that the severity of itching in scalp psoriasis involves both neurogenic and immunogenic inflammation, but itch severity is not mediated by a histaminergic pathway,” Dr. Yosipovitch said, noting that these findings are consistent with prior data on most other types of chronic itch.

The scalp skin of patients with severe itch showed significantly greater expression of protease-activated receptor 2 (PAR2), substance P, the transient receptor potential ion channels TRPV3 and TRPM8 (a cold receptor), and immune-cell activating interleukin-23 (IL-23) cells. The itchier the patient said their scalp was, the higher the expression. All of these are known to make skin more prone to itch and/or to amplify itching sensations.

However, another substance known to increase itchiness — histamine — did not appear to play a role in the level of psoriatic scalp itch in these patients. There was no significant difference in histamine+ cells between the two groups of patients with psoriasis, and no correlation between histamine+ cell levels and itch severity.