Plasma VEGF as a marker for the diagnosis and treatment of vasculitic neuropathy
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《神经病学神经外科学杂志》
Department of Neurology and Neurobiology of Aging, Kanazawa University Graduate School of Medical Science, Kanazawa 920-8640, Japan
Correspondence to:
Dr K Sakai
ksakai@med.kanazawa-u.ac.jp
Keywords: neuropathy; vascular endothelial growth factor; vasculitis
Vasculitic neuropathy is treatable with immunotherapy. However, histological evidence of vasculitis is not always obtained from nerve and muscle biopsies.1 In particular, in cases of non-systemic vasculitic neuropathy showing no or minimum abnormal findings in serological tests, negative biopsy results cause considerable difficulty in the diagnosis.1
Vascular endothelial growth factor (VEGF) is a potent, multifactorial cytokine.2 VEGF is derived from endothelial cells and pericytes in response to hypoxia, and induces angiogenesis and microvascular hyperpermeability through its binding to VEGF receptors.2 Vascular involvement by vasculitic neuropathy results in hypoxia. It was reported that VEGF was overexpressed in vasculitic lesions in biopsied sural nerves, and that plasma VEGF levels were found to be raised in dermatomyositis with peripheral neuropathy.3 These findings suggest that VEGF levels may be increased in patients with vasculitic neuropathy. Although an increase in plasma or serum VEGF concentrations has been reported in some patients with systemic vasculitis,3 there have been no studies to evaluate plasma VEGF in a series of patients with vasculitic neuropathy. With respect to VEGF levels in neuropathies, a marked increase in serum levels was reported in the Crow-Fukase (POEMS) syndrome.4 In addition, alterations in VEGF are associated with cancer and diabetes mellitus, and VEGF is involved in the angiogenesis of these diseases.
In this study, we investigated the plasma VEGF concentrations in patients with vasculitic neuropathy in comparison with other neuropathies. After obtaining informed consent, samples were obtained from five patients with vasculitic neuropathy confirmed by muscle or sural nerve biopsies. They all presented with neuropathy as a cardinal manifestation, and included three patients with polyarteritis nodosa, one with vasculitic neuropathy associated with Sj?gren syndrome, and one with non-systemic vasculitic neuropathy. None of the patients were on drug treatment at the time of sampling. After disease remission was achieved by treatment with corticosteroids or other immunosuppressants, we analysed plasma VEGF again in three of the patients, including two with polyarteritis nodosa and one with Sj?gren syndrome. As a control group, we used plasma from 18 age matched healthy volunteers, eight patients with Guillain-Barré syndrome, five with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), and seven with amyotrophic lateral sclerosis, after obtaining informed consent. Patients with diabetes mellitus or cancer were not included in the study.
Venous blood was sampled into an EDTA tube with minimal stasis. The sample was centrifuged and the plasma VEGF concentration was determined by a quantitative sandwich-enzyme immunoassay technique using a Quantikine kit (R&D Systems, Minneapolis, Minnesota, USA). As VEGF is secreted by platelets in the clotting process,5 we measured plasma samples, not sera, to evaluate the circulating VEGF level precisely.
Differences between the groups were tested by the Kruskal–Wallis test and the Mann–Whitney U test. Differences were considered significant when the probability (p) value was <0.05. Significance tests for group differences were computed with StatView v5.0 (SAS Institute, Cary, North Carolina, USA).
The mean (SD) plasma VEGF concentrations in patients with vasculitic neuropathy (303 (182) pg/ml) were significantly higher than in the healthy controls (30.9 (31.7) pg/ml) (p<0.01) as well as in patients with Guillain-Barré syndrome (85.7 (57.3) pg/ml) (p<0.05), CIDP (49.9 (48.3) pg/ml) (p<0.05), and amyotrophic lateral sclerosis (88.1 (55.7) pg/ml) (p<0.05) (fig 1). There was no statistical difference in plasma VEGF concentrations between healthy controls and patients with CIDP, Guillain-Barré syndrome, or amyotrophic lateral sclerosis. The plasma VEGF concentrations in patients with vasculitic neuropathy before treatment (423 (97.1) pg/ml) decreased significantly after successful treatment with corticosteroids or other immunosuppressants, to 150 (114) pg/ml (p<0.05). One case with polyarteritis nodosa and the patients with vasculitic neuropathy associated with Sj?gren syndrome had a marked decrease in plasma VEGF after treatment (from 461 to 91.3 pg/ml and from 496 to 77.8 pg/ml, respectively). In the other patient with polyarteritis nodosa, the plasma VEGF levels decreased mildly, from 313 to 281 pg/ml.
Figure 1 Plasma levels of vascular endothelial growth factor (VEGF) in patients with vasculitic neuropathy (VN), healthy controls, Guillain-Barré syndrome (GBS), chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), and amyotrophic lateral sclerosis (ALS).
COMMENT
Our results indicated that increased plasma VEGF could be a useful marker for the diagnosis of vasculitic neuropathy and for monitoring a therapeutic effect.
This is the first report to show a significant increase in plasma VEGF levels in patients with vasculitic neuropathy compared with other neuropathies. As our patients with vasculitic neuropathy did not have cancer or diabetes mellitus, and as the plasma VEGF concentrations were significantly decreased after treatment, we consider that VEGF would be secreted into blood by the vasculitic lesions in this conditions. We could find no significant increase in plasma VEGF levels in CIDP, Guillain-Barré syndrome, or amyotrophic lateral sclerosis. Vasculitic neuropathy may present with clinical manifestations similar to CIDP or other peripheral neuropathies.1 The increase in plasma VEGF could be a helpful marker to distinguish vasculitic neuropathy from CIDP and other peripheral neuropathies in such patients.
Although our results indicate the potential value of plasma VEGF as a marker in the diagnosis and treatment of vasculitic neuropathy, the significance of the results is limited by the relatively small number of patients. Further studies with a larger study population are necessary to confirm our results.
References
Collins MP, Periquet MI, Mendell JR, et al. Nonsystemic vasculitic neuropathy insights from a clinical cohort. Neurology 2003;61:623–30.
Nomura M, Yamaguchi S, Harada S, et al. Possible participation of autocrine and paracrine vascular endothelial growth factors in hypoxia-induced proliferation of endothelial cells and pericytes. J Biol Chem 1995;270:28316–24.
Matsui N, Mitsui T, Endo I, et al. Dermatomyositis with peripheral nervous system involvement: activation of vascular endothelial growth factor (VEGF) and VEGF receptor (VEGFR) in vasculitic lesions. Intern Med 2003;42:1233–9.
Watanabe O, Arimura K, Kitajima I, et al. Greatly raised vascular endothelial growth factor in POEMS syndrome. Lancet 1996;347:702.
Maloney JP, Silliman CC, Ambruso DR, et al. In vitro release of vascular endothelial growth factor during platelet aggregation. Am J Physiol 1998;275:1054–61.(K Sakai, K Komai, D Yanas)
Correspondence to:
Dr K Sakai
ksakai@med.kanazawa-u.ac.jp
Keywords: neuropathy; vascular endothelial growth factor; vasculitis
Vasculitic neuropathy is treatable with immunotherapy. However, histological evidence of vasculitis is not always obtained from nerve and muscle biopsies.1 In particular, in cases of non-systemic vasculitic neuropathy showing no or minimum abnormal findings in serological tests, negative biopsy results cause considerable difficulty in the diagnosis.1
Vascular endothelial growth factor (VEGF) is a potent, multifactorial cytokine.2 VEGF is derived from endothelial cells and pericytes in response to hypoxia, and induces angiogenesis and microvascular hyperpermeability through its binding to VEGF receptors.2 Vascular involvement by vasculitic neuropathy results in hypoxia. It was reported that VEGF was overexpressed in vasculitic lesions in biopsied sural nerves, and that plasma VEGF levels were found to be raised in dermatomyositis with peripheral neuropathy.3 These findings suggest that VEGF levels may be increased in patients with vasculitic neuropathy. Although an increase in plasma or serum VEGF concentrations has been reported in some patients with systemic vasculitis,3 there have been no studies to evaluate plasma VEGF in a series of patients with vasculitic neuropathy. With respect to VEGF levels in neuropathies, a marked increase in serum levels was reported in the Crow-Fukase (POEMS) syndrome.4 In addition, alterations in VEGF are associated with cancer and diabetes mellitus, and VEGF is involved in the angiogenesis of these diseases.
In this study, we investigated the plasma VEGF concentrations in patients with vasculitic neuropathy in comparison with other neuropathies. After obtaining informed consent, samples were obtained from five patients with vasculitic neuropathy confirmed by muscle or sural nerve biopsies. They all presented with neuropathy as a cardinal manifestation, and included three patients with polyarteritis nodosa, one with vasculitic neuropathy associated with Sj?gren syndrome, and one with non-systemic vasculitic neuropathy. None of the patients were on drug treatment at the time of sampling. After disease remission was achieved by treatment with corticosteroids or other immunosuppressants, we analysed plasma VEGF again in three of the patients, including two with polyarteritis nodosa and one with Sj?gren syndrome. As a control group, we used plasma from 18 age matched healthy volunteers, eight patients with Guillain-Barré syndrome, five with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), and seven with amyotrophic lateral sclerosis, after obtaining informed consent. Patients with diabetes mellitus or cancer were not included in the study.
Venous blood was sampled into an EDTA tube with minimal stasis. The sample was centrifuged and the plasma VEGF concentration was determined by a quantitative sandwich-enzyme immunoassay technique using a Quantikine kit (R&D Systems, Minneapolis, Minnesota, USA). As VEGF is secreted by platelets in the clotting process,5 we measured plasma samples, not sera, to evaluate the circulating VEGF level precisely.
Differences between the groups were tested by the Kruskal–Wallis test and the Mann–Whitney U test. Differences were considered significant when the probability (p) value was <0.05. Significance tests for group differences were computed with StatView v5.0 (SAS Institute, Cary, North Carolina, USA).
The mean (SD) plasma VEGF concentrations in patients with vasculitic neuropathy (303 (182) pg/ml) were significantly higher than in the healthy controls (30.9 (31.7) pg/ml) (p<0.01) as well as in patients with Guillain-Barré syndrome (85.7 (57.3) pg/ml) (p<0.05), CIDP (49.9 (48.3) pg/ml) (p<0.05), and amyotrophic lateral sclerosis (88.1 (55.7) pg/ml) (p<0.05) (fig 1). There was no statistical difference in plasma VEGF concentrations between healthy controls and patients with CIDP, Guillain-Barré syndrome, or amyotrophic lateral sclerosis. The plasma VEGF concentrations in patients with vasculitic neuropathy before treatment (423 (97.1) pg/ml) decreased significantly after successful treatment with corticosteroids or other immunosuppressants, to 150 (114) pg/ml (p<0.05). One case with polyarteritis nodosa and the patients with vasculitic neuropathy associated with Sj?gren syndrome had a marked decrease in plasma VEGF after treatment (from 461 to 91.3 pg/ml and from 496 to 77.8 pg/ml, respectively). In the other patient with polyarteritis nodosa, the plasma VEGF levels decreased mildly, from 313 to 281 pg/ml.
Figure 1 Plasma levels of vascular endothelial growth factor (VEGF) in patients with vasculitic neuropathy (VN), healthy controls, Guillain-Barré syndrome (GBS), chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), and amyotrophic lateral sclerosis (ALS).
COMMENT
Our results indicated that increased plasma VEGF could be a useful marker for the diagnosis of vasculitic neuropathy and for monitoring a therapeutic effect.
This is the first report to show a significant increase in plasma VEGF levels in patients with vasculitic neuropathy compared with other neuropathies. As our patients with vasculitic neuropathy did not have cancer or diabetes mellitus, and as the plasma VEGF concentrations were significantly decreased after treatment, we consider that VEGF would be secreted into blood by the vasculitic lesions in this conditions. We could find no significant increase in plasma VEGF levels in CIDP, Guillain-Barré syndrome, or amyotrophic lateral sclerosis. Vasculitic neuropathy may present with clinical manifestations similar to CIDP or other peripheral neuropathies.1 The increase in plasma VEGF could be a helpful marker to distinguish vasculitic neuropathy from CIDP and other peripheral neuropathies in such patients.
Although our results indicate the potential value of plasma VEGF as a marker in the diagnosis and treatment of vasculitic neuropathy, the significance of the results is limited by the relatively small number of patients. Further studies with a larger study population are necessary to confirm our results.
References
Collins MP, Periquet MI, Mendell JR, et al. Nonsystemic vasculitic neuropathy insights from a clinical cohort. Neurology 2003;61:623–30.
Nomura M, Yamaguchi S, Harada S, et al. Possible participation of autocrine and paracrine vascular endothelial growth factors in hypoxia-induced proliferation of endothelial cells and pericytes. J Biol Chem 1995;270:28316–24.
Matsui N, Mitsui T, Endo I, et al. Dermatomyositis with peripheral nervous system involvement: activation of vascular endothelial growth factor (VEGF) and VEGF receptor (VEGFR) in vasculitic lesions. Intern Med 2003;42:1233–9.
Watanabe O, Arimura K, Kitajima I, et al. Greatly raised vascular endothelial growth factor in POEMS syndrome. Lancet 1996;347:702.
Maloney JP, Silliman CC, Ambruso DR, et al. In vitro release of vascular endothelial growth factor during platelet aggregation. Am J Physiol 1998;275:1054–61.(K Sakai, K Komai, D Yanas)