Increased angiogenesis and enhanced bone formation in patients with IgM monoclonal gammopathy and urticarial skin rash: new insight into the biology of Schnitzler syndrome

Abstract

Schnitzler syndrome is a rare plasma cell disorder the pathogenesis of which is still not fully understood. We evaluated the circulating levels of four major angiogenic cytokines (VEGF, angiogenin, angiopoietin-1 and angiopoietin-2) and six bone remodeling markers (sRANKL, osteoprotegerin, dickkopf-1, CTX, osteocalcin and bone-specific alkaline phosphatase-bALP) in 13 patients with Schnitzler syndrome. At diagnosis, patients had elevated angiogenic cytokines. The mean VEGF levels were almost 3.5-fold higher in Schnitzler syndrome compared to controls, while 10 of 13 patients had higher VEGF than the upper control value. Successful treatment led to a significant reduction in VEGF. Patients with Schnitzler syndrome had increased bone formation (high bALP, osteocalcin and osteoprotegerin) which was not balanced by an increase in bone resorption (normal CTX and sRANKL). These data support a role for VEGF as a new minor criterion in the diagnosis and follow up of Schnitzler syndrome, while the uncoupling of bone remodeling in favor of bone formation justifies the presence of bone densification.

Figure 1.

Clinical features of patients with Schnitzler syndrome (except chronic urticarial rash and IgM monoclonal protein).

Figure 2

At diagnosis patients with Schnitzler syndrome had increased circulating levels of VEGF (A) and angiogenin (B) compared to healthy controls and decreased angiopoietin-1 (C) and angiopoietin-1/angiopoietin-2 ratio (D) suggesting increased angiogenic activity. After successful treatment with pefloxacin or anakinra, VEGF levels decreased (387±207 pg/mL) compared to baseline values (P=0.04). (E) Three patients who progressed to overt WM had decreased levels of angiopoietin-1 to angiopoietin-2 ratio at diagnosis compared to all other patients (5.3±4.6 vs. 16.5±8.0; P=0.04, F).

Figure 3.

At diagnosis patients with Schnitzler syndrome had elevated serum bALP (A), osteocalcin (B), OPG (C) and Dkk-1 (D). The increase in bone formation markers (bALP, osteocalcin and OPG) in combination with normal bone resorption is responsible for the bone densification observed in Schnitzler syndrome.