Background & Aims

The skin is richly innervated by small sensory fibers encoding pain and itch sensations1. Small fiber neuropathy (SFN) affects thinly myelinated A?- and unmyelinated C-fibers, often resulting in a mixed sensation of itch and pain as observed in patients with atopic dermatitis (AD). AD is a prevalent skin condition characterized by chronic itch and continuous scratching, potentially causing damage to small fibers and sensory alterations. While another pruritic skin condition leads to SFN through chronic scratching, it remains unclear if this also accounts for AD patients.

The diagnosis of SFN relies on symptoms, skin innervation, and quantitative sensory testing, but additional diagnostic tools are needed. Metabolomics analyses have revealed changes in the profiles of patients with pain, yet metabolomic research specific to SFN is limited. Thus, our aim was to identify an SFN in AD patients and explore the potential use of metabolites as diagnostic tools for this condition.

Methods

We did a clinical study in 21 healthy controls (HC) and 18 patients with AD. Each subject attended to a clinical visit to evaluate the sensory profile by Quantitative Sensory Test (QST). Levels of itch and pain were reported using a numerical rating scale (NRS), beside neuropathic descriptors. Blood samples were obtained to evaluate the metabolomic profile by UHPLC-MS/MS. Crude data underwent processing in Metaboscape 4.0 and analysis was done in Qlucore Omics Explorer. Ingenuity Pathways Analysis was used to analyze the interaction networks of the differentially expressed metabolites. Skin biopsies from a chronic lesion (Lesioned skin, L-AD), a contralateral area without dermatitis (non-lesioned skin, NL-AD), and the distal leg (HC) were used to determine the intraepidermal nerve fiber density (IENFD) by PGP 9.5 immunostaining. AD patients were sub-classified with a SFN according to symptomatology, reduced IENFD < 5th quantile and/or alterations on thermal parameters of the QST.

Results

The mean age was 27.8 ± 7.7 years in HC (57.1% females) and 26.7 ± 7.2 years in the AD group (66.6% females). AD patients had higher levels of itch but also pain (p-value<0.001) vs HC, which were described using neuropathic characteristics. L skin was less innervated (p-value<0.05), and IENFD was negatively correlated with the epidermal thickness (p-value<0.01). The QST showed alterations in thermal parameters (CDT and HPT) in L vs NL skin (p-value<0.05). With this, we identified 7 patients (38.8%) with AD and a localized SFN in chronic lesions. We identified 134 metabolites in plasma samples. Of them, 24 metabolites were significantly different in AD vs HC, which were related to Ceramide, Spingosine-1-phosphate, and Endothelial Nitric Oxide Synthase signaling. In patients with AD and SFN, we found 21 metabolites that were significantly different vs AD. Of them, sphingosine-1-phosphate (S1P) was significantly higher in the AD-SFN group compared to AD (Log2 Ratio of 0.58, p-value<0.01).

Conclusions

AD patients not only had higher levels of itch but also had pain with values over the usual cut-off of 4 points, suggesting that this is a symptom to take into consideration. Chronic AD lesions had a reduced IENFD, which was negatively correlated to the epidermal thickness and may be relevant for other skin conditions with lichenification. Besides these alterations, chronic lesions have basal sensory alterations such as thermal hyperalgesia and cold hypoesthesia. With this, one-third of patients with AD fulfill the criteria for SFN, which was localized on chronic lesions and may be secondary to repetitive scratching. As a diagnostic method, S1P levels in serum have been used in patients with bladder pain syndrome/interstitial cystitis. Thereby, this evidence provides a window to explore other skin conditions that may result in SFN using S1P levels as a diagnostic method and also, emphasizes the still unexplored interplay that exists between chronic itch and pain.

References

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Presenting Author

Macarena Tejos-Bravo

Poster Authors

Macarena Tejos

MSc

Pontificia Universidad Catolica de Chile

Lead Author

Jose Luis Cordero

Lead Author

Dixon Cid

Lead Author

Victoria Alfaro

Lead Author

Fernanda Espinoza

Lead Author

Nelson Barrera

PhD

Lead Author

Margarita Calvo

Pontificia Universidad Católica de Chile

Lead Author

Topics

  • Evidence, Clinical Trials, Systematic Review, Guidelines, and Implementation Science