Can We Finally Decode the Itch: Unraveling the Molecular Mechanisms of Pruritus in Prurigo Nodularis?

🔍 Key Finding Prurigo nodularis (PN) is characterized by intense, chronic itch and is associated with a complex interplay of pruritogens and receptors within the cutaneous neuroimmune network. Targeting these pruritogens, their receptors, and downstream signaling pathways, like JAK-STAT, offers promising therapeutic avenues for alleviating itch and improving PN outcomes.

🔬 Methodology Overview

• Design: Narrative review.
• Data Sources: Published literature.
• Selection Criteria: Focus on pruritogens and their receptors involved in prurigo nodularis (PN).
• Analysis Approach: Qualitative synthesis of findings related to cytokines, neuropeptides, extracellular matrix proteins, vasculogenic substances, ion channels, and intracellular signaling pathways in PN.
• Scope: Molecular mechanisms of pruritus in PN and prospective therapeutic targets.

📊 Results

• IL-4, IL-13, and IL-4R expression increased in prurigo nodularis (PN) lesions. IL-4 expression correlates with itch intensity. Circulating plasma IL-13 is also elevated.
• IL-31 and its receptor (IL-31Ra) are significantly upregulated in PN lesions. Lesional IL-31 levels are 50 times higher than in healthy skin. Pruritus intensity correlates with the number of IL-31+ and IL-31Rx+ cells.
• Oncostatin M (OSM) is upregulated in PN lesions. Itch intensity correlates with the number of OSM+ cells.
• Periostin is abundantly deposited in PN dermis and correlates with pruritus severity. Plasma periostin is also significantly elevated in patients with severe itch.
• Substance P (SP) and its receptor MRGPRX2 are elevated in PN. MRGPRX2 expression correlates with itch severity.
• Dupilumab (anti-IL-4Ra) significantly reduced weekly average worst itch (WI-NRS) in Phase 3 trials. 60% and 18.4% of patients achieved a ≥4-point WI-NRS reduction with dupilumab and placebo, respectively, in the PRIME trial (P < 0.001). Similar results were seen in the PRIME2 trial.
• Nemolizumab (anti-IL-31Ra) demonstrated effectiveness in reducing pruritus and improving nodules in Phase 2 and 3 trials. 56% of nemolizumab-treated patients achieved a ≥4-point reduction in itch (PP-NRS) compared to 21% of the placebo group (P < 0.0001).

💡 Clinical Impact This review elucidates the complex interplay of pruritogens, receptors, and signaling pathways in prurigo nodularis (PN)-associated itch, offering a deeper understanding of its pathogenesis. This knowledge paves the way for developing targeted antipruritic therapies, moving beyond traditional, less effective treatments and improving the quality of life for PN patients.

🤔 Limitations

• Limited long-term efficacy and safety data for dupilumab in PN.
• Lack of large real-world data collections evaluating dupilumab’s efficacy and safety in PN.
• Unclear relationship between IL-17 and pruritus in PN patients.
• Limited evidence regarding the correlation between IL-22 levels and pruritus in PN.
• Lack of direct evidence linking IL-6 and TSLP to pruritus in PN.
• Short-acting efficacy and intense burning side effects of capsaicin limiting its widespread use.
• Need for further investigation into the relationship between extracellular matrix remodeling, fibrosis activation, neural dysfunction, vascular system development, keratinization, and itching in PN.
• Role of topical TRPV1 antagonists in PN treatment requires confirmation through RCTs.
• Role of the endogenous cannabinoid system in PN requires confirmation through double-blind controlled trials.

✨ What It Means For You This review comprehensively summarizes the complex interplay of pruritogens, receptors, and signaling pathways in prurigo nodularis (PN), offering clinicians a deeper understanding of itch mechanisms. This knowledge supports a more targeted approach to treatment, enabling doctors to consider emerging therapies like IL-31, IL-4Rα, and OSMRβ antagonists, JAK inhibitors, and TRP channel modulators alongside established options like dupilumab. Furthermore, the highlighted role of neuro-immune crosstalk encourages clinicians to consider the interplay of immune cells, keratinocytes, fibroblasts, and neurons when managing PN.

Reference Shao Y, Wang D, Zhu Y, Xiao Z, Jin T, Peng L, Shen Y, Tang H. Molecular mechanisms of pruritus in prurigo nodularis. Front Immunol. 2023;14:1301817. https://doi.org/10.3389/fimmu.2023.1301817