Measurement of β-isomerized C-terminal telopeptide of type I collagen in patients with POEMS syndrome: diagnostic, prognostic, and follow-up utilities

polyneuropathy, organomegaly, endocrinopathy, monoclonal

POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and skin changes) syndrome is a paraneoplastic disorder, of which most clinical manifestations are attributed to elevated vascular endothelial growth factor (VEGF). Osteosclerosis, although well described in the majority of patients, has an obscure mechanism. Although conventional imaging methods, including plain radiography and computed tomography, can be informative, these techniques are neither sensitive nor specific enough to Comparisons between patients with higher and lower levels of serum β-CTX at baseline. b Castleman's disease was diagnosed in 16 of 25 patients who underwent lymph node biopsies. c Novel-agent group should include IMiDs (thalidomide and lenalidomide) and PIs (bortezomib); the others group included those patients using conventional chemotherapy (that is, CHOP).
detect the sclerotic changes. 1,2 Markers of bone turnover are easily measured, and when interpreted in the context of appropriate clinical design can provide valuable information. Indeed, increased bone turnover markers were reported in POEMS patients, and have even been suggested for inclusion into the diagnostic criteria. 3,4 Carboxy-terminal telopeptide (CTX) is formed during type I collagen degradation in the bone, and an isomerization reaction occurs subsequently under physiological conditions. The resulting β-isomerized CTX (β-CTX) can be measured automatically in most clinical laboratories, and is used to assess bone diseases. 5,6 Except for the aforementioned studies concerning the diagnostic performance of bone turnover markers in POEMS syndrome, there is nearly no information about their levels in response to effective treatment. Moreover, their potential utility in therapeutic evaluation and follow-up is also poorly understood.
The current study included 146 POEMS patients who were diagnosed and treated at Peking Union Medical College Hospital (Beijing, China) between January 2011 and March 2016. All met the diagnostic criteria proposed by Dispenzieri. 2 Clinical and laboratory information was collected, as described previously. 1,7 Serum β-CTX and N-terminal propeptide of type I collagen (PINP) levels were measured using an automatic analyzer (Roche Cobas E601; Holliston, MA, USA) with Elecsys reagent kits (Roche Diagnostics, Basel, Switzerland). Serum VEGF was measured with a human Quantikine ELISA Kit (normal o 600 pg/ml; R&D Systems,  Table 1. In the beginning of our study, we measured both serum β-CTX and P1NP in 43 POEMS patients and observed a statistically significant linear correlation between these two markers (Spearman ρ = 0.341, P = 0.025; Online Supplementary Figure 1), indicating that bone formation and resorption processes are well coupled in these patients. Considering both the assay stability and patients' financial reasons, we chose to measure β-CTX alone in the following study. 8 There is no significant difference in clinical characteristics between patients with (n = 43) and without PINP (n = 103), indicating a good representativeness of the early cohort.
When dividing patients into two subgroups according to the median levels in each gender, we found high β-CTX levels at baseline were associated with several POEMS manifestations ( Table 1). As serum β-CTX is a bone turnover marker, we also compared its levels in patients with (n = 98) and without (n = 48) osteosclerosis. No statistical difference was found (median, 1.030 vs 1.000 ng/ml, P = 0.473).
We have demonstrated that serum β-CTX levels are elevated in POEMS patients and correlate with the well-characterized disease marker, VEGF. The two have similar diagnostic accuracies.
However, β-CTX is routinely measured in most hospitals, whereas the VEGF assay is typically performed in reference laboratories only, and results take several days or even longer. The availability and relatively short turnaround time may help spread the clinical use of β-CTX. Furthermore, we have shown the utility of serum β-CTX in disease monitoring, and its normalization after therapy could predict superior OS and less relapse. It is noteworthy that β-CTX levels could still be abnormal, even in patients who achieved VEGF normalization, suggesting that disease activity in POEMS syndrome is multifaceted. Responses in different categories, although always strongly associated, do not completely overlap, and have separate roles in therapeutic evaluation. These findings may prompt the clinical usage of this easily measured bone turnover marker in POEMS syndrome management.