Patients with POEMS Syndrome Have High Bone Turnover and Increased Circulating Angiogenic Cytokines; Should Angiopoietin-2 and Bone-Specific Alkaline Phosphatase Be Used As Minor Criteria for the Diagnosis of the Disease?

Abstract 806^FN2

POEMS syndrome is defined by the presence of peripheral neuropathy (P), monoclonal plasma cell disorder (M), organomegaly (O), endocrinopathy (E) and skin changes (S). The majority of patients have sclerotic bone lesions, although the underlying mechanisms are still unclear. Increased circulating vascular endothelial growth factor (VEGF) is another feature of the disease. However, there is almost no information on the role of other angiogenic molecules in POEMS biology. The aim of the study was to evaluate bone metabolism and angiogenic cytokines in POEMS and compare the results with multiple myeloma (MM) and osteosclerotic patients of other etiology.

We retrospectively studied 61 POEMS patients (40M/21F, median age 52 years) who were diagnosed between 1996 and 2010 and were treated and followed in Mayo Clinic Rochester (MN, USA), Hôpital Saint-Louis, Paris (France) and in Alexandra Hospital, Athens (Greece). We evaluated the following indices of bone remodeling and angiogenesis in all patients at diagnosis and in 22 of them one month after front-line treatment: i) osteoclast regulators [sRANKL and osteoprotegerin (OPG)]; ii) osteoblast inhibitor dickkopf-1 (Dkk-1); iii) bone resorption marker CTX; iv) bone formation markers [bone-specific alkaline phosphatase (bALP) and osteocalcin]; and v) angiogenic cytokines [VEGF, angiogenin (ang), angiopoietin (angp)-1 and -2]. These molecules were also measured in 60 newly diagnosed, untreated MM patients (34M/26F, median age: 54 years) and 44 healthy controls. Bone markers were also evaluated in 24 patients with HbS/beta-thalassemia (10M/14F, median age: 43 years) who presented with osteosclerosis, defined as osteosclerotic bone lesions in plain radiography and high T-score of lumbar spine DXA (median: +3.6, range: +2 to +7.9).

All POEMS patients presented with P and M, while 90% had E, 83% had S, 61% had O and 32% had papilloedema. One or more documented sclerotic bone lesions in plain X-rays were observed in 78% of patients (diffuse lesions in 44%), while 43% of patients had also an osteolytic component. Seven patients had Castleman disease.

At diagnosis, compared to controls, POEMS patients had increased levels of bALP (mean ± SD: 48.3 ± 22.9 IU/L vs. 21.6 ± 8.2 IU/L; p<0.001), CTX (0.97 ± 0.94 ng/ml vs. 0.33 ± 0.24 ng/ml; p<0.001), Dkk-1 (p<0.001), sRANKL (p<0.001) and sRANKL/OPG ratio (p<0.001). Patients with diffuse osteosclerosis had increased levels of Dkk-1 compared to others (p = 0.05), suggesting a balance effect to increased formation activity. Patients with POEMS had increased levels of bALP and decreased levels of CTX compared to MM patients (p<0.001 and p = 0.03, respectively), while they had increased levels of CTX and sRANKL/OPG ratio compared to HbS/beta-thal patients (p = 0.001 for both comparisons). There were no other differences regarding bone markers among studied groups.

Regarding angiogenic cytokines, at diagnosis, POEMS patients had elevated VEGF (1232 ± 565 pg/ml vs. 195 ± 211 pg/ml; p<0.001), ang (266 ± 82 ng/ml vs. 190 ± 45; p<0.001) and angp-2 (3.5 ± 2.2 ng/ml vs. 1.2 ± 0.6 ng/ml; p<0.001) and decreased angp-1 (p =0.05) and angp-1/angp-2 ratio (reflects increased angiogenic capacity; 9.1 ± 8.8 vs. 44.8 ± 76.1; p<0.001) compared to normal controls. We found no strong correlations between the levels of VEGF, ang and angps. When compared to MM patients, POEMS patients had increased circulating VEGF (p = 0.001) without any difference regarding the other angiogenic cytokines. Response to therapy was accompanied by a dramatic reduction of VEGF only (551 ± 541 pg/ml compared to baseline 1800 ± 1510 pg/ml; p = 0.003).

Receiver-operating characteristic (ROC) curve analysis showed that high levels of angiopoietin-2 (≥ 2.3 ng/ml) and high bALP (≥ 38 IU/l) each have a 95% specificity for patients with POEMS syndrome.

These results suggest that patients with POEMS syndrome have high bone turnover with increased bone formation as compared to healthy subjects, to MM patients, who have reduced bone formation, and to osteosclerotic HbS/beta-thal patients, who have diminished bone resorption. Importantly, our analysis supports the use of angp-2, bALP along with VEGF as minor criteria for the diagnosis of POEMS. Successful treatment reduced VEGF, which seems to be a suitable marker for the follow-up of POEMS patients. Furthermore the imbalance of angp-1/angp-2 pathway may indicate possible targets for the development of novel agents against POEMS.