INTRODUCTION

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POEMS syndrome is a rare multisystem disorder. It is a complication of plasma cell dyscrasia, mainly of osteosclerotic myeloma and solitary plasmocytoma, and it is characterized by five main features, polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (1, 2). Arteriolar and capillary wall thickening typical of an occluding microvascular disorder has been observed in histologic studies. This has led to the suggestion that microangiopathic lesions cause various clinical manifestations of POEMS syndrome (3). The pathogenesis of POEMS syndrome is not understood, but overproduction of proinflammatory cytokines (tumor necrosis factor- [TNF-], interleukin-1 [IL-1], and IL-6) and vascular endothelial growth factor (VEGF) has been reported and could be very important in POEMS syndrome (7, 8).

We studied five patients suffering from POEMS syndrome with symptomatic precapillary pulmonary hypertension (PH), High serum levels of TNF-, IL-1, IL-6, and VEGF were detected in all tested patients. The PH occurring with POEMS syndrome may be associated with the overproduction of these cytokines, as suggested for primary PH (9).

	METHODS

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Patients

Twenty patients with POEMS syndrome were studied in our institution over a 10-yr period. PH was observed in five of them (four women and one man 37 to 58 yr of age). All patients had five or more symptoms of POEMS syndrome (Table 1).

Pulmonary hypertension was defined as pulmonary-artery systolic pressure greater than 25 mm Hg measured by pulsed Doppler echocardiography. Cardiac catheterization was also performed in two patients. The diagnosis required that several secondary causes of PH were absent (10). Congenital or acquired valvular and myocardial disease were ruled out by echocardiography in the five patients. Pulmonary thromboembolic disease was excluded either by lung perfusion scan (n = 4) or by pulmonary angiogram (n = 1). Pulmonary function testing and chest radiography were performed in the five patients to rule out obstructive and interstitial lung disease. No patient had collagen vascular disease (antinuclear antibodies were negative), sickle cell anemia, parasitic disease affecting the lungs, portal hypertension, or human immunodeficiency virus infection. They did not use exogenous substances such as anorexic agents, L-tryptophan, or crack cocaine.

Serum Cytokine Levels

Serum sampling. Peripheral blood was collected in dry tubes at 8:00 A.M. in the absence of fever, shock, or overt infection and centrifuged within 1 h. Sera were stored frozen at 70° C until analysis.

Measurements of proinflammatory cytokines. The levels of TNF-, IL-1, and IL-6 were measured in serum samples. Commercially available kits for enzyme-linked immunosorbent assays (ELISA) were used. ELISA kits from Immunotech (Marseille, France) were used for four patients. The upper limit for the TNF- serum concentration as measured using these kits in healthy subjects was 15 pg/ml. The upper limit for IL-1 was 5 pg/ml, and for IL-6 it was 10 pg/ml. ELISA kits from R&D Systems (Minneapolis, MN) were used for the last patient. TNF-, IL-1, and IL-6 were undetectable in healthy subjects using these kits.

Measurement of VEGF. Levels of VEGF were determined in serum samples (n = 3) or in plasma samples (n = 2), using ELISA kits from R&D Systems. The normal concentration of VEGF as measured by these kits in healthy subject serum was 224 pg/ml (range, 62 to 707), and VEGF was undetectable in plasma from most healthy subjects (range, 0 to 115).

Levels of proinflammatory cytokines and VEGF were compared with those found in 11 patients with POEMS syndrome who had no evidence of PH by echocardiography. Concentrations are expressed as the median value. Statistical analysis was performed using the Mann-Whitney U test. A p value less than 0.05 was considered significant.

	RESULTS

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Echocardiography was performed in 15 of the 20 patients with POEMS syndrome. PH was diagnosed in five (33%) of these 15 patients. Characteristics of PH in these five patients are shown in Table 2.

Patient 1

A 56-yr-old woman suffering from POEMS syndrome was admitted 15 mo after diagnosis because of exacerbation of her disease (polyneuropathy and anasarca). The patient had suffered chest pain and dyspnea for 2 wk. An echocardiogram showed enlargement of the right atrium and ventricle with tricuspid regurgitation. Catheterization of the right side of the heart showed that mean pulmonary artery pressure was 32 mm Hg. Pulmonary capillary wedge pressure was 12 mm Hg, and cardiac index was 4.3 L/min/m². The dose of prednisone was increased (50 mg/d), and the dyspnea and anasarca gradually disappeared over 3 mo. Pulmonary-artery systolic pressure decreased to 28 mm Hg, as assessed by echocardiogram. The dose of prednisone was gradually decreased to 20 mg/d. Four years later, a marked improvement in the neuropathy was noted and there was no recurrence of PH.

Patient 2

A 37-yr-old woman presented with dyspnea, ascites, edema, and Raynaud's phenomenon that had persisted for 9 mo. An echocardiogram showed enlargement of the right atrium and ventricle with tricuspid regurgitation. Catheterization of the right side of the heart showed that mean pulmonary artery pressure was 32 mm Hg. Pulmonary capillary wedge pressure was 6 mm Hg. Cardiac index was 3 L/min/m², and pulmonary vascular resistance was 462 dynes/s/cm. Corticosteroid therapy (prednisone, 1 mg/kg/d) improved the dyspnea and ascites over a 3-mo period. Pulmonary-artery systolic pressure decreased to 25 mm Hg, as assessed by echocardiogram. However, the patient's state deteriorated as neuropathy and progressive renal failure developed. She died 5 mo after diagnosis of POEMS syndrome. Autopsy showed changes in both lungs characteristic of PH, including eccentric intimal fibrosis, medial hypertrophy, and marked dilatation of arteries and arterioles. Fibrous thickening of the arteriolar walls were also found in the kidneys and lymph nodes.

Patient 3

A 58-yr-old woman was referred with a 6-mo history of paresthesia of the legs and dyspnea. Peripheral edema was noted on physical examination. An echocardiogram showed enlargement of the right atrium and ventricle with tricuspid regurgitation. She was treated with prednisone, plasmapheresis and six courses of cyclophosphamide. This resulted in partial relief of the neuropathy, and the dyspnea was completely cured 11 mo later. She was admitted to hospital 3 yr later because of exacerbation of POEMS syndrome. An echocardiogram showed a relapse of PH, with pulmonary-artery systolic pressure at 65 mm Hg. The POEMS syndrome was treated with intermittent courses of cyclophosphamide and plasmapheresis, and the dose of prednisone was maintained at 30 mg/d. The neuropathy stabilized 5 yr after diagnosis of POEMS syndrome. Several echocardiograms showed complete absence of PH (pulmonary-artery systolic pressure  25 mm Hg).

Patient 4

A 54-yr-old woman with a 10-mo history of POEMS syndrome presented with exacerbation of her disease and progressive dyspnea that had persisted for 3 mo. There was a systolic murmur typical of tricuspid regurgitation and peripheral edema. An echocardiogram showed tricuspid regurgitation without enlargement of the right atrium or ventricle. The neuropathy and dyspnea worsened despite prednisone therapy (60 mg/d), intermittent courses of melphalan, and anticoagulation. The patient died 6 mo after diagnosis of PH.

Patient 5

A 58-yr-old man was admitted for evaluation of his POEMS syndrome, which had been diagnosed 4 mo earlier. The patient had suffered exacerbation of the neuropathy and dyspnea for 1 mo. An echocardiogram showed enlargement of the right atrium and ventricle with tricuspid regurgitation. The POEMS syndrome was treated by all transretinoid acid and local irradiation of a solitary plasmocytoma. This improved the neuropathy and cured the dyspnea. However, pulmonary-artery systolic pressure remained high (40 mm Hg), as assessed by echocardiogram. The patient died 1 yr later of an acute arterial obliteration related to POEMS syndrome.

Serum Cytokine Levels

Serum cytokines concentrations are reported in Table 3. The level of IL-1 was high (as much as 50 times higher than normal values) in all five patients with PH. High circulating levels of VEGF (as much as 28 times higher than normal) and TNF- (as much as 17 times higher than normal) were recorded in four of the five patients. High levels of IL-6 (two to nine times higher than normal) were found in three patients.

The median serum concentrations of cytokines were higher in patients with PH than in control patients, but the difference was not statistically significant: IL-1 (PH, 129 pg/ml; control, 61.5 pg/ml), IL-6 (PH, 47 pg/ml; control, 36.5 pg/ml), TNF- (PH, 71 pg/ml; control 16 pg/ml), and serum VEGF (PH [n = 3], 6,086 pg/ml; control [n = 6], 2,046 pg/ml).

Clinical Correlations

A two-point evaluation before and during treatment of POEMS was performed in three patients (Table 4). Serum samples from a single patient were tested simultaneously with the same kit. Decrease of IL-1 and TNF- levels were observed in Patient 1 after complete improvement of the PH. Patient 3 had no detectable circulating IL-1 level when PH was cured, but she did have a moderately elevated level of TNF-. A dramatic decrease of IL-1, IL-6, and TNF- serum levels was observed in Patient 5 at the time of resolution of the dyspnea.

	DISCUSSION

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Symptomatic PH was found in five patients with POEMS syndrome who had dyspnea and the typical echocardiographic signs of PH, with right ventricular and atrial enlargement, tricuspid insufficiency and high pulmonary-artery systolic pressure. PH was confirmed by cardiac catheterization in only two patients, but there was a strong correlation between pulsed Doppler-determined pulmonary arterial pressure and pressure measured by cardiac catheterization (11).

There are several reasons to suspect that the PH was related to POEMS syndrome: (1) No other explanation for PH was found in the five patients, and there was no evidence of left ventricular dysfunction of pulmonary thromboembolic disease, as assessed by echocardiography and ventilation-perfusion scintigraphy. (2) The clinical courses of PH and POEMS syndrome coincided; PH symptoms appeared during an exacerbation of POEMS in all of these patients, and PH improved with the treatment of POEMS syndrome in three patients. (3) An unusually high frequency of PH occurred among the 20 patients with POEMS syndrome studied in our institution. The estimates of the incidence of primary PH are one to two cases per million people in the general population (12).

There are two major differences between PH in POEMS syndrome and primary PH. First, the clinical course of PH was benign in our patients, whereas the evolution of primary PH is usually progressive and severe. None of our patients had predictive indicators of severe PH (13). However, the rate of progression of PH was difficult to establish because of the overall poor prognosis of POEMS syndrome. Second, corticosteroid therapy for POEMS syndrome may improve PH, whereas primary PH is unresponsive to corticosteroids.

Precapillary PH has never been described in patients with POEMS syndrome. No cases were reported in the three largest studies, which included 165 patients (2, 14, 15). PH has been reported in two patients with left-side cardiac dysfunction (16, 17). Myocardial disease was systematically ruled out by echocardiography in all our patients, and capillary wedge pressure was normal at catheterization in two patients.

Lung specimens obtained from one patient in our series showed pulmonary arteriopathy similar to the pathologic changes seen in lung tissue obtained from patients with primary PH. These are medial hypertrophy, intimal proliferation and fibrosis, plexiform lesions and in situ microthrombosis (18). Microangiopathic lesions are also observed in affected organs of patients with POEMS syndrome. These include fibrous thickening of arteriolar and capillary walls in nerve, muscle, spleen, and lymph nodes, fibrous thickening of the media and endothelial proliferation in small dermal arteries, mesangial proliferation and thickening of glomerular capillaries, and angiofollicular lymph node hyperplasia (3).

As no other cause of PH was found in our five patients, the proinflammatory cytokines implicated in pathogenesis of systemic symptoms of POEMS syndrome may also be involved in the pulmonary vascular changes. We found high serum concentrations of IL-1, IL-6, and TNF- in our patients. A correlation was found in three patients between proinflammatory cytokine serum levels and disease activity assessed by both clinical and echographic severity of the PH. Patients with primary PH have higher IL-1 and IL-6 serum concentrations than do patients with PH secondary to chronic obstructive pulmonary disease, who have normal levels (9). The same profile of high cytokine levels is observed in the plasma of patients infected with human immunodeficiency virus (HIV) (19). There is strong evidence for HIV-associated PH that is histologically indistinguishable from primary PH (20). This suggests that patients with POEMS syndrome, primary PH, and HIV infection may all have large changes in the regulation of the cytokine cascade, contributing to pulmonary vascular lesions.

The pathogenesis of primary PH is not understood, but three factors combine to produce increased vascular resistance: vasoconstriction, vascular-wall remodeling, and thrombosis in situ (12). The cytokine overproduction observed in our patients could affect these physiopathologic mechanisms (21). The imbalance between vasodilators (prostacyclin, nitric oxide) and vasoconstrictors (thromboxane, endothelin, and platelet-derived growth factor [PDGF]) is important in pathogenesis (22, 23). Endothelin and PDGF production is upregulated by IL-1, and PDGF promotes IL-1 synthesis by macrophages (24, 25). PDGF and IL-1 are potent growth factors that cause the underlying smooth-muscle cells to migrate and replicate (25). They may mediate medial hypertrophy of PH. Plexiform lesions in primary PH result from deregulated growth of endothelial cells, and are a unique form of active angiogenesis. Among the multiple factors that regulate angiogenesis, vascular endothelial growth factor (VEGF) is a selective and potent mitogen for endothelial cells (21). Proinflammatory cytokines could be involved in overproduction of VEGF, as both IL-1 and IL-6 promote expression of VEGF by monocytes and smooth-muscle cells (26, 27). IL-1 and TNF- increase procoagulant activity in endothelial cells, and they could be responsible for the local imbalance between procoagulant and anticoagulant factors that cause thromboses in situ in PH (28). A beneficial effect of IL-1 receptor antagonist has been reported in an animal model of PH induced by inflammation (32).

Our results suggest a close relationship between POEMS syndrome and PH. Overproduction of proinflammatory cytokines is probably involved in the pathophysiology of PH observed in our patients. Treatment of the plasma cell dyscrasia may improve the pulmonary vascular symptoms, as has been shown for the other features of POEMS syndrome.