Neuroanatomic Signatures in Brachioradial Pruritus, Chronic Prurigo, and Atopic Dermatitis

We appreciate the interest expressed by J. Wallengren, 2023 Wallengren J. Neuroanatomic signatures in brachioradial pruritus, chronic prurigo, and atopic dermatitis. J Invest Dermatol. 2023; (in press)https://doi.org/10.1016/j.jid.2023.01.035 Abstract Full Text Full Text PDF Scopus (0) Google Scholar in the neuroanatomy of chronic pruritus entities in our article ( Agelopoulos et al., 2023 Agelopoulos K. Renkhold L. Wiegmann H. Dugas M. Süer A. Zeidler C. et al. Transcriptomic, epigenomic, and neuroanatomic signatures differ in chronic prurigo, atopic dermatitis, and brachioradial pruritus. J Investig Dermatol. 2023; 143: 264-272.e3 Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar ). Studies on neuroanatomy are still rare and seem to have discrepant results. For example, there is the interesting fact that Wallengren is also pointing out that more abundant nerve fibers have been reported in different pruritic entities ( Emtestam et al., 2012 Emtestam L. Hagströmer L. Dou Y.C. Sartorius K. Johansson O. PGP 9.5 distribution patterns in biopsies from early lesions of atopic dermatitis. Arch Dermatol Res. 2012; 304: 781-785 Crossref PubMed Scopus (10) Google Scholar ; Järvikallio et al., 2003 Järvikallio A. Harvima I.T. Naukkarinen A. Mast cells, nerves and neuropeptides in atopic dermatitis and nummular eczema. Arch Dermatol Res. 2003; 295: 2-7 Crossref PubMed Scopus (188) Google Scholar ; Kubanov et al., 2015 Kubanov A.A. Katunina O.R. Chikin V.V. Expression of neuropeptides, neurotrophins, and neurotransmitters in the skin of patients with atopic dermatitis and psoriasis. Bull Exp Biol Med. 2015; 159: 318-322 Crossref PubMed Scopus (31) Google Scholar ), although recent papers from our group ( Hidding et al., 2019 Hidding J. Agelopoulos K. Pereira M.P. Conrad H. Hatt H. Lotts T. et al. Sensory qualities point to different structural and functional skin patterns in chronic pruritus patients. A translational explorative study. Acta Derm Venereol. 2019; 99: 668-674 Crossref PubMed Scopus (4) Google Scholar ; Pogatzki-Zahn et al., 2020 Pogatzki-Zahn E.M. Pereira M.P. Cremer A. Zeidler C. Dreyer T. Riepe C. et al. Peripheral sensitization and loss of descending inhibition is a hallmark of chronic pruritus. J Investig Dermatol. 2020; 1: 203-211.e4 Abstract Full Text Full Text PDF Scopus (36) Google Scholar ) and other groups ( Nattkemper et al., 2018 Nattkemper L.A. Tey H.L. Valdes-Rodriguez R. Lee H. Mollanazar N.K. Albornoz C. et al. The genetics of chronic itch: gene expression in the skin of patients with atopic dermatitis and psoriasis with severe itch. J Invest Dermatol. 2018; 138: 1311-1317 Abstract Full Text Full Text PDF PubMed Scopus (180) Google Scholar ; Tan et al., 2019 Tan Y. Ng W.J. Lee S.Z.X. Lee B.T.K. Nattkemper L.A. Yosipovitch G. et al. 3-dimensional optical clearing and imaging of pruritic atopic dermatitis and psoriasis skin reveals downregulation of epidermal innervation. J Invest Dermatol. 2019; 139: 1201-1204 Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar ; Tsutsumi et al., 2016 Tsutsumi M. Kitahata H. Fukuda M. Kumamoto J. Goto M. Denda S. et al. Numerical and comparative three-dimensional structural analysis of peripheral nerve fibres in epidermis of patients with atopic dermatitis. Br J Dermatol. 2016; 174: 191-194 Crossref PubMed Scopus (19) Google Scholar ) showed reduced nerve fiber densities. We think that there is no discrepancy because the different techniques used to describe the nerve fiber anatomy and methods to quantitatively determine the nerve fiber density differ. For the proper determination of nerve fiber numbers, only the number of nerve crossings through the basement membrane is counted. Studies that show an increase in nerve fiber density ( Emtestam et al., 2012 Emtestam L. Hagströmer L. Dou Y.C. Sartorius K. Johansson O. PGP 9.5 distribution patterns in biopsies from early lesions of atopic dermatitis. Arch Dermatol Res. 2012; 304: 781-785 Crossref PubMed Scopus (10) Google Scholar ; Järvikallio et al., 2003 Järvikallio A. Harvima I.T. Naukkarinen A. Mast cells, nerves and neuropeptides in atopic dermatitis and nummular eczema. Arch Dermatol Res. 2003; 295: 2-7 Crossref PubMed Scopus (188) Google Scholar ; Kubanov et al., 2015 Kubanov A.A. Katunina O.R. Chikin V.V. Expression of neuropeptides, neurotrophins, and neurotransmitters in the skin of patients with atopic dermatitis and psoriasis. Bull Exp Biol Med. 2015; 159: 318-322 Crossref PubMed Scopus (31) Google Scholar ) only look at the number (or staining intensity) of nerve fibers or nerve fiber fragments in the epidermis. This is independent of whether a nerve crossing is observed or not. However, taking a comprehensive approach, we combine the different techniques to obtain a complete anatomical picture of the skin nerve fibers. Doing so, we found reduced nerve fiber numbers in the epidermis, with increased nerve fiber branching. This is in line with the published increased nerve fiber count within the epidermis. However, this also highlights that the findings of reduced intraepidermal nerve fiber density and an increased number of free nerve endings in the epidermis are independent of each other. Only the simultaneous determination of intraepidermal nerve fiber density and branching in either two-dimension or three-dimension can show a complete picture and reconcile these two findings.