IL-33 signaling in sensory neurons promotes dry skin itch.

BACKGROUND: Chronic pruritus, or itch, is common and debilitating, but the neuroimmune mechanisms that drive chronic itch are only starting to be elucidated. Recent studies demonstrate that the IL-33 receptor (IL-33R) is expressed by sensory neurons. However, whether sensory neuron-restricted activity of IL-33 is necessary for chronic itch remains poorly understood. OBJECTIVES: We sought to determine if IL-33 signaling in sensory neurons is critical for the development of chronic itch in 2 divergent pruritic disease models. METHODS: Plasma levels of IL-33 were assessed in patients with atopic dermatitis (AD) and chronic pruritus of unknown origin (CPUO). Mice were generated to conditionally delete IL-33R from sensory neurons. The contribution of neuronal IL-33R signaling to chronic itch development was tested in mouse models that recapitulate key pathologic features of AD and CPUO, respectively. RESULTS: IL-33 was elevated in both AD and CPUO as well as their respective mouse models. While neuron-restricted IL-33R signaling was dispensable for itch in AD-like disease, it was required for the development of dry skin itch in a mouse model that mirrors key aspects of CPUO pathology. CONCLUSIONS: These data highlight how IL-33 may be a predominant mediator of itch in certain contexts, depending on the tissue microenvironment. Further, this study provides insight into future therapeutic strategies targeting the IL-33 pathway for chronic itch.

Treatment of patients with chronic pruritus of unknown origin with dupilumab.

BACKGROUND: Chronic pruritus of unknown origin (CPUO) is a highly debilitating disease that lacks effective treatments. This study explores a new therapeutic strategy with dupilumab. OBJECTIVES: To examine whether patients with CPUO demonstrate clinical response to dupilumab. PATIENTS AND METHODS: This is a retrospective case series examining all patients with CPUO who were treated with dupilumab from March 2017 to December 2019 at a tertiary referral clinic at Washington University School of Medicine in St. Louis, MO. Numerical rating scale (NRS) itch score changes over time were recorded and analyzed. RESULTS: Fifteen patients (67% women; mean [SD] age, 68.7 [12.6] years [range, 42-88 years]) were included in the analysis. All patients had a diagnosis of CPUO for a mean [SD] 2.6 [2.8] years. The median [IQR] pruritus NRS itch score before dupilumab injection was 8 [8-10] and the final median [IQR] NRS itch score was 1 [0-2.5]. The mean [SD] reduction in the NRS itch score was 7.0 [1.9]. Dupilumab was well tolerated with one report of mild injection site reaction that was self-resolving. CONCLUSION: This study suggests that dupilumab may be an effective treatment for patients with CPUO and supports the design of future randomized placebo-controlled trials to prove its efficacy.