Nerve growth factor and neuropeptides circulating levels in systemic sclerosis (scleroderma)

Abstract

Objective: To determine the circulating levels of nerve growth factor (NGF), neuropeptide Y (NPY), and vasoactive intestinal peptide (VIP) in systemic sclerosis (SSc), and to correlate these levels with clinical and laboratory features.

Methods: Forty four patients with SSc were evaluated for circulating NGF (immunoenzymatic assay), NPY and VIP (radioimmunoassay), anticentromere and antitopoisomerase I autoantibodies, lung disease (pulmonary function tests with carbon monoxide transfer factor (TLCO), ventilation scintiscan with 99mTc DTPA radioaerosol, high resolution computed tomography (HRCT), pulmonary pressure (echo colour Doppler)), heart disease (standard and 24 ECG, echocardiography), cutaneous involvement (skin score), joint involvement (evidence of tender or swollen joints, or both), peripheral nervous system (PNS) involvement (electromyography), rheumatoid factor, angiotensin converting enzyme (fluorimetric method), von Willebrand factor (ELISA), and erythrocyte sedimentation rate (ESR) (Westergren).

Results: Circulating NGF levels in SSc were significantly increased compared with controls (p<0.00001) and significantly higher in the diffuse than in the limited subset of patients (p<0.01). Patients with articular disease had significantly higher levels of NGF. A significant indirect correlation between NGF levels and TLCO was detected (p<0.01), but no correlation was found between NGF and HRCT, DTPA, skin score, PNS involvement and angiotensin converting enzyme and von Willebrand factor levels, antitopoisomerase or anticentromere antibodies, and ESR. NGF levels increased progressively as the disease worsened. Similarly, VIP circulating levels were significantly increased in patients with SSc (p<0.001), whereas the increase of NPY levels did not reach statistical significance. However, both neuropeptides, following the same trend as NGF, increased as the disease worsened (skin score and lung disease).

Conclusions: The increase of NGF and VIP in patients with SSc, the former in the diffuse subset of the disease, and in patients with prominent articular disease, may suggest a link between neurotransmitters and the disease pathogenesis. Neuropeptide circulating levels seem to increase only in patients with the most severe disease.

Figure 1

(A) Serum levels of nerve growth factor (NGF) (ng/ml) in patients with systemic sclerosis (SSc) and controls (C),*p<0.00001; (B) NGF levels (ng/ml) in limited (lSSc) and diffuse (dSSc) subsets of patients with SSc, *p<0.01; (C) NGF levels (ng/ml) in patients with SSc with joint involvement (JI) and without joint involvement (WJI), *p<0.00002.

Figure 2

Vasoactive intestinal peptide levels (pg/ml) in the sera of patients with systemic sclerosis (SSc) and controls (C), p<0.001.

Figure 3

Data mining elaborations visualised by Trellis graphics (showing relations between different variables in a dataset through a conditioning operation). In the three series of two panels x-y plots are reported, conditioned by a chosen variable. In fig 3A, B, and C are represented, respectively, the conditioning of the two systemic sclerosis (SSc) subsets (diffuse subset (dSSc) and limited subset of the disease (lSSc)) (the range is shown in the x axis, the probability density is shown in y-axis) by neuropeptide Y (NPY), nerve growth factor (NGF), and vasoactive intestinal peptide (VIP). Higher NGF and NPY levels are clustered in patients with the diffuse subset compared with those with the limited subset of the disease.

Figure 4

Data mining elaborations represented by Trellis graphics. In A, B, and C are shown, respectively, the conditioning of the the skin score (the range is shown in the x axis, the probability density is shown in the y axis) by neuropeptide Y (NPY), nerve growth factor (NGF), and vasoactive intestinal peptide (VIP). As the skin score increases, a cluster of patients with higher levels of NGF (A) and NPY (B) is identified. This trend is less evident for VIP (C).

Figure 5

Data mining elaborations represented by Trellis graphics. The involvement of the lung is evaluated with the carbon monoxide transfer factor (TLCO), high resolution computed tomography (HRCT), and DTPA. The sequence of four panels reported in A, B, and C, respectively, shows the conditioning of the NGF density (x axis NGF range, y axis NGF probability density) by different DTPA, HRCT, and TLCO ranges. The parameters showing a worsening of the lung function (increase of HRCT score, decrease of TLCO and DTPA) form a cluster of the group (with diffuse disease) with the highest levels of NGF, NPY, and VIP.