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. 2023 Sep 1;159(9):977-985.
doi: 10.1001/jamadermatol.2023.2609.

Modulation of Neuroimmune and Epithelial Dysregulation in Patients With Moderate to Severe Prurigo Nodularis Treated With Nemolizumab

Junwen Deng  1 , Viviane Liao  1 , Varsha Parthasarathy  1 , Hannah L Cornman  1 , Anusha Kambala  1 , Madan M Kwatra  2 , Sonja Ständer  3 , Christophe Piketty  4 , Prasad Chaskar  4 , Jayendra Kumar Krishnaswamy  4 , Valerie Julia  4 , Shawn G Kwatra  1
Affiliations

Modulation of Neuroimmune and Epithelial Dysregulation in Patients With Moderate to Severe Prurigo Nodularis Treated With Nemolizumab

Junwen Deng et al. JAMA Dermatol. .

Abstract

Importance: Prurigo nodularis (PN) is a debilitating skin disease characterized by intense pruritus and hyperkeratotic skin nodules. Nemolizumab, a monoclonal antibody targeting interleukin 31 receptor α, is a promising novel therapy for the treatment of moderate to severe PN. The biological mechanisms by which nemolizumab promotes improvement of itch and skin lesions in PN are unknown.

Objective: To characterize changes in plasma protein biomarkers associated with clinical response to nemolizumab in patients with PN.

Design, setting, and participants: This multicenter cohort study included patients recruited from Austria, France, Germany, Poland, and the US from a phase 2 clinical trial. Adults diagnosed with moderate to severe PN with severe pruritus for at least 6 months were included in the original trial. Patients in the nemolizumab group were included in the present study if they achieved at least a 4-point decrease in the Peak Pruritus Numerical Rating Scale (PP-NRS) from baseline to week 12 during nemolizumab treatment. Placebo controls did not experience a 4-point decrease in PP-NRS. Mass spectrometry with tandem mass tags to enrich skin-specific protein detection was used to characterize changes in plasma protein expression in nemolizumab and placebo groups. Data were collected from November 2, 2017, to September 26, 2018, and analyzed from December 6, 2019, to April 8, 2022.

Intervention: As part of the clinical trial, patients were treated with 3 doses of nemolizumab or placebo at 0, 4, and 8 weeks.

Main outcomes and measures: Changes in plasma and epidermal protein expression in nemolizumab-treated patients compared with the placebo group at 0, 4, and 12 weeks.

Results: Among the 38 patients included in the analysis (22 women and 16 men; mean [SD] age, 55.8 [15.8] years), 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.

Conclusions and relevance: In this cohort study, differences between nemolizumab and placebo groups included modulation of inflammatory signaling, neural development, and epithelial differentiation, suggesting a promising potential approach for clinical management of PN.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Ständer reported receiving grant funding and personal fees from Galderma SA during the conduct of the study and grant funding from Kiniksa Pharamceuticals, Trevi Therapeutics, Inc, and Sanofi SA and personal fees from Trevi Therapeutics, Inc, and Sanofi SA outside the submitted work. Dr S. G. Kwatra reported receiving grant funding from Galderma SA, Pfizer Inc, Incyte Corporation, and Sanofi SA and personal fees from Galderma SA, Pfizer Inc, AbbVie Inc, Amgen Inc, Arcutis Biotherapeutics, Inc, Aslan Pharmaceuticals Ltd, Cara Therapeutics, Celldex Therapeutics, Inc, Genzada Pharmaceuticals, Incyte Corporation, Johnson & Johnson, LEO Pharma A/S, Novartis AG, Regeneron Pharmaceuticals, Inc, and Sanofi SA outside the submitted work; and serving on the board of the directors of the Skin of Color Society. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Clinical Efficacy of Nemolizumab
A, Baseline Peak Pruritus Numerical Rating Scale (PP-NRS) scores and percentage of patients with no response to placebo and those with a response to nemolizumab treatment at week 4. A successful response according to the PP-NRS was defined as a decrease (improvement) of 4 points from baseline. Horizontal lines indicate mean. B, Baseline investigator global assessment (IGA) scores and percentage of placebo and nemolizumab group patients with IGA success at week 18. A successful response according to the IGA was defined as a score of 0 or 1 plus a decrease (improvement) of 2 points from baseline. Error bars indicate SD. aP < .001.
Figure 2.
Figure 2.. Exploratory Analysis of Differentially Expressed Proteins in the Pooled Nemolizumab (Nemo) Group vs the Placebo Group
Heat map of mean abundances for the 193 upregulated and downregulated proteins for each time point (baseline [BL], week 4 [W4], and week 12 [W12]) and treatment combination. Protein abundance values shown in the heat map are mean-centered, scaled, and ordered by hierarchical clustering using Euclidian distances. Red colors represent higher-abundance values while blue colors represent lower-abundance values. All treated terms refer to all treatment time points (ie, week 4 and week 12) being jointly considered for the modeling, as opposed to separately considering week 4 and week 12 for the analysis. DEPs indicates differentially expressed proteins.
Figure 3.
Figure 3.. Volcano Plot Representing Selected Upregulated and Downregulated Baseline-Corrected Differentially Expressed Proteins in the Nemolizumab Group vs the Placebo Group
LogFC indicates log2 fold change.
Figure 4.
Figure 4.. Enrichment Analysis of the Differentially Expressed Proteins Using Ingenuity Pathway Analysis
Data were sorted by z scores (z scores ±1) and filtered by adjusted P < .05.
See this image and copyright information in PMC

Comment in

References

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