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Pentraxin-3 and VEGF in POEMS syndrome: A 2-year longitudinal study

https://doi.org/10.1016/j.jneuroim.2014.09.021Get rights and content

Highlights

  • VEGF is a diagnostic marker of POEMS syndrome responsible for many symptoms.

  • Anti-VEGF therapy fails to treat POEMS syndrome. Other factors might be involved.

  • Pentraxin 3 (PTX3), involved in vessel homeostasis, is often associated with VEGF.

  • No correlation was found between PTX3 and VEGF levels in POEMS syndrome patients.

  • The data confirm the non-inflammatory pathogenic mechanisms of POEMS syndrome.

Abstract

Circulating Pentraxin 3 (PTX3) and vascular endothelial growth factor (VEGF) levels were measured longitudinally (mean follow-up 2 years) by ELISA in 6 patients with polyneuropathy, organomegaly, endocrinopathy, M-protein, skin changes (POEMS) syndrome and 16 controls. Expression of PTX3 was also assessed (immunohistochemistry) on sural nerve biopsies from POEMS and vasculitic neuropathy patients.

No correlation was found between PTX3 and VEGF levels in POEMS or controls.

Sural nerve biopsies from vasculitic neuropathy patients, but not those from POEMS syndrome, showed strong PTX3 staining.

PTX3, expression of vessel inflammation/remodeling, and VEGF, crucial pro-angiogenic cytokine, appear to be independently regulated in POEMS syndrome.

Introduction

Polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes (POEMS) syndrome is a multisystem disorder associated with plasma cell dyscrasia. Elevated serum level of vascular endothelial growth factor (VEGF), which strongly promotes neovascularization and vessel permeability, has been considered to have a key role in many clinical manifestations of POEMS syndrome (e.g. ascites, papilloedema, extravascular volume overload), and is included among the major diagnostic criteria (Dispenzieri, 2014). VEGF reliably mirrors disease activity and response to treatment (Scarlato et al., 2005). However anti-VEGF therapy, in spite of dramatically reducing VEGF systemic levels, does not control the disease (Sekiguchi et al., 2013) suggesting a more complex pathogenesis. Various angiogenic factors (Yamada et al., 2013) and inflammatory cytokines (Kanai et al., 2012, Arimura, 2013) are up-regulated in POEMS syndrome, but their role is uncertain. Pentraxin 3 (PTX3), a soluble pattern recognition receptor, is the prototypic long pentraxin and is involved in vessel homeostasis and inflammation (Monach, 2014). Very high level of PTX3 has been associated with recent optic ischemia in patients with giant cell arteritis (Baldini et al., 2012) and is increased in large and small vessels vasculitis (Fazzini et al., 2001). PTX3 production reflects vessel injury, inflammation and repair and is often associated with the generation of VEGF, which contributes to restore angiogenesis.

Sural nerve from POEMS syndrome patients show increased thickness of the basal lamina and narrowing of the endoneurial vessels lumina and, at electron microscopy, proliferation of endothelial cells and opening of tight junctions likely reflecting VEGF-mediated angiogenic and vessel permeability effects (Scarlato et al., 2005).

In the present study we assessed whether local and systemic expression of PTX3, which is increased in systemic vasculitis (Fazzini et al., 2001, Dagna et al., 2011, Baldini et al., 2012), is modulated in POEMS syndrome and whether these changes reflect those of VEGF levels and of clinical activity.

Section snippets

Patients and controls

Six patients (4 men, 2 women, mean age 56 yrs, 42–70 range) with POEMS syndrome, diagnosed according to the revised diagnostic criteria (Dispenzieri, 2014) were enrolled. The mean disease duration was 62 months. All patients underwent serial consecutive blood sampling every two months parallel to neurological and hematological evaluations for an approximate follow-up period of 24 months (median 20.5 months, range 4–24). Clinical severity was quantified using the INCAT disability scale (Merkies et

Results

Median plasma PTX3 levels at first sampling (as stated in the Methods, only one patient was therapy naïve, the others had previously been treated) were 1.10 ng/mL (range 0.33–19.94, SD 3.40). Median serum VEGF levels were 733 pg/mL (range 136–2679, SD 573.39). In controls median plasma PTX3 level was 0.57 ng/mL (range 0.25–2.1, SD 0.4759) and median VEGF level was 239 pg/mL (range 64.–940, SD 269). No correlation was found between plasma PTX3 levels and VEGF serum levels in POEMS (p 0.17; r 0.19)

Discussion

PTX3 is a marker of inflammation, which is locally expressed at sites of inflammatory vessel injury and whose systemic levels in general correlate with those of VEGF (Baldini et al., 2012).

Despite the relatively high levels of serum VEGF (this study) and of other pro-inflammatory cytokines (Kanai et al., 2012, Arimura, 2013), we failed to detect evidence of primary inflammatory mechanisms in POEMS syndrome. Inflammatory leukocytes in POEMS patients do not in general infiltrate sural nerves (

Acknowledgments

We are in debt to Susanna Ruggero and Elisabetta Tofffanin for technical assistance and to Mario Ermani for statistical analysis. We thank Barbara Bottazzi and Alberto Mantovani for kindly providing rat anti-human PTX3 antibodies.

The study was not supported by any fund.

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