Shawn Kwatra, MD: Nemolizumab Modulates Neuroimmune and Epithelial Dysregulation in Patients with Prurigo Nodularis

“It's been my hypothesis for a long time that unchecked inflammation in PN patients can then lead to the development of disease comorbidities,” said Shawn Kwatra, MD, while discussing new prurigo nodularis (PN) and nemolizumab research published recently in JAMA Dermatology. Kwatra, associate professor of dermatology at Johns Hopkins University School of Medicine and director of the Johns Hopkins Itch Center, and his colleagues investigated changes in plasma protein biomarkers associated with clinical response to nemolizumab in patients with PN.

The multicenter cohort study included 38 patients from Austria, France, Germany, Poland, and the US with moderate to severe PN, defined as nodular lesions on the upper extremities, with or without lesions on the trunk or lower extremities, at least 20 nodules on the body, and a distribution of lesions present on both sides of the body.

According to the study results, “Enrichment analysis of canonical pathways, biological functions, and upstream regulators showed downregulation of terms involving inflammation (IL-6, acute-phase response, signal transducer and activator of transcription 3, and interferon γ), neural processes (synaptogenesis signaling and neuritogenesis), tissue remodeling and fibrosis (transforming growth factor β1 and endothelin-1), and epidermal differentiation (epithelial mesenchymal transition) in the plasma of nemolizumab group.” Overall, Kwatra et al found 193 plasma proteins that were differentially expressed at week 4 or week 12 in PN patients treated with nemolizumab compared to placebo.

The authors concluded that their findings, “suggest that IL-31 works through multiple pathways affecting inflammatory, neural, and epithelial regulation to contribute to the pathophysiology of PN. By targeting signaling downstream of IL-31RA, nemolizumab represents a promising potential new approach for the clinical management of PN.”

Transcript

Shawn Kwatra, MD: I'm Shawn Kwatra, and I'm a dermatologist at Johns Hopkins School of Medicine. Our group recently published a paper in JAMA Dermatology, which looked at the treatment of patients with prurigo nodularis with nemolizumab, which is a novel monoclonal antibody targeting IL-31 receptor alpha. And what we did is we followed these patients from a phase 2 trial. And we looked at the changes in blood inflammation. Actually, our group identified systemic blood inflammation in PN patients. And actually, two-thirds of patients are itchy, not only in the skin nodules, but also in normal-appearing skin, highlighting the systemic nature of the disease.

When we followed these patients and correlated their improvement, also with their blood inflammation, we found that there's actually downregulation of many molecules associated with acute inflammation. So, things like IL-6, which is part of the acute phase response. Also, STAT3, interferon gamma, there was downregulation of neural responses. So, synaptogenesis signaling, and nerve growth. Also, factors associated with tissue remodeling, TGF beta, and epithelial differentiation. So, we really found that there's global downregulation of inflammatory proteins. The reason this is so exciting is because emerging data showing that not only prurigo nodularis is associated with comorbidities at baseline, but actually, it's been my hypothesis for a long time that unchecked inflammation in PN patients can then lead to the development of disease comorbidities, and we're starting to see that in a variety of disease comorbidities. It's very important that newer therapeutics are able to modulate this systemic inflammation.

Reference

Deng J, Liao V, Parthasarathy V, et al. Modulation of neuroimmune and epithelial dysregulation in patients with moderate to severe prurigo nodularis treated with nemolizumab. JAMA Dermatol. 2023;159(9):977-985. doi:10.1001/jamadermatol.2023.2609