Image analysis quantification of peptide‐immunoreactive nerves in the skin of patients with Raynaud's phenomenon and systemic sclerosis

Abstract

Image analysis quantification was used to assess the results of immunocytochemistry for a neuronal marker and neuropeptides in digital skin biopsies from Raynaud's phenomenon (RP) and systemic sclerosis (SS) patients, to verify the possibility of a selective quantitative abnormality of immunoreactive nerves. The field area of specific immunostaining and nerve counts were evaluated on coded specimens, and the data compared by statistical analysis. Nerves immunoreactive for protein gene product 9.5 (PGP), a marker for neuronal elements, were decreased significantly in epidermal and subepidermal layers of digital skin in RP patients (P less than 0.0001). This change was paralleled by a decrease of calcitonin gene-related peptide (CGRP) immunoreactive nerves in the epidermis and around capillaries in the dermal papillae (P = 0.005). In the skin of RP patients, these changes were readily demonstrated by image analysis, although they were not always apparent on visual screening. In digital skin of SS patients, there was a generalized and very significant decrease of PGP, CGRP, and VIP immunoreactivities in all areas (P less than 0.0001). These results demonstrate that neuropeptide-containing nerves are involved in the digital pathology of RP and SS, and that image analysis quantification is an accurate and sensitive method for assessing morphological changes in pathological samples.

Primary Raynaud phenomenon and small-fiber neuropathy: is there a connection? A pilot neurophysiologic study

“…However, our results show that it may be more common than generally appreciated. Our results also support the immunocytochemistry results of the skin of patients with primary RP, as well as patients with systemic sclerosis [6,7], who have shown a reduction in calcitonin gene-related peptide immunoreactive neurons, although the reduction is more severe in systemic sclerosis. Therefore, a speculation could be that patients with primary RP and abnormal QSART results may in fact represent a continuum to systemic sclerosis.…”

“…The mechanism responsible for the increased cold sensitivity of vascular 2 -receptors in primary RP has not been determined. Two small studies, both from the same group of investigators, used skin biopsy data in participants with primary RP and scleroderma and found, in both primary RP and scleroderma, a loss of neurons that contain calcitonin generelated peptide [6,7]. These Wndings suggest a small-Wber neuropathy (SFN), particularly because calcitonin generelated peptide not only is a neurotransmitter of the small, unmyelinated sensory aVerent nerves in the skin but also functions as a powerful endogenous vasodilator.…”

Raynaud's phenomenon and scleroderma dysregulated neuroendothelial control of vascular tone

“…There is only one report, by Terenghi et a1 (3 l), that describes a significant general decrease of CGRP and VIP in the epidermis and around capillaries in dermal papillae of patients with SSc. Moreover, a marked decrease of protein gene product 9.5, a marker for neuronal elements in epidermal and subepidermal layers of digital skin, was also noted (31).…”

Primary and secondary Raynaud’s phenomenon: does small neuropathy remain the same?

“…Skin biopsy in SSc with secondary RP showed loss of sensory neuropeptidic fibers sprouting from dermal papillary layer into the epidermis, whereas a similar picture but with less severe loss of fibers was described in primary RP [4,5].…”

“…Peripheral neuropathy is intriguingly common evidence of very different diseases such erythromelalgia [6], connective tissue diseases [2,5,7,8], and RP [1,2,4,5,9]. It seems unlikely that the same postganglionic neuropathy is involved in all these conditions, unless the small fiber neuropathy is considered as a sign of neuropeptidic dysfunction that may manifest in different pathophysiologic ways thereby leading to a different clinical presentation.…”