Increased Angiogenesis and Enhanced Bone Formation in Patients with IgM Monoclonal Gammopathy and Urticarial Skin Rash: New Insight Into the Biology of the Schnitzler Syndrome

Abstract 1802

Schnitzler syndrome is a rare plasma cell disorder which is characterized by the presence of a monoclonal IgM component in association with a chronic urticarial skin rash and at least 2 of the following criteria: fever, joint and/or bone pain, organomegaly (enlarged lymph nodes, spleen and/or liver), increased neutrophil counts and increased ESR. Abnormal bone findings with imaging evidence of osteosclerosis are also frequent. The pathogenesis of this syndrome is unclear and there is no information on bone remodeling and angiogenesis in these patients. To address this issue we studied 13 patients (12M/1F, median age 55 years, range: 39–79 years) with a well characterized Schnitzler syndrome. Patients were diagnosed between 1989 and 2009 and were treated and followed in Hôpital Saint-Louis, Paris (France) and in the University of Athens (Greece). We evaluated the following serum indices of bone remodeling and angiogenesis at diagnosis and after treatment: i) osteoclast regulators [soluble receptor activator of nuclear factor kappa-B ligand (sRANKL) and osteoprotegerin (OPG)]; ii) osteoblast inhibitor dickkopf-1 (Dkk-1); iii) bone resorption marker C-telopeptide of collagen type-1 (CTX); iv) bone formation markers [bone-specific alkaline phosphatase (bALP) and osteocalcin (OC)]; and v) angiogenic cytokines [vascular endothelial growth factor (VEGF), angiogenin (ang), angiopoietin (angp)-1 and -2]. The above molecules were also measured in 24 gender- and age-matched controls.

All patients presented with urticaria and monoclonal IgM(kappa) component (median M-peak 0.79 g/dl; range 0.1–2.36 g/dl), while 10 (76%) patients had fever, 9 (69%) had joint and/or bone pain, 5 (38%) had lymphadenopathy and 2 (15%) had splenomegaly. Four patients had documented sclerotic bone lesions in plain X-rays. A technetium bone scintigraphy was performed in 11 patients; all of them had high uptake in at least one site. At diagnosis, 11/13 patients received various symptomatic therapies, including low dose corticosteroids that were ineffective. Two patients at diagnosis and 6 after initial symptomatic therapy were treated with the quinolone antibiotic pefloxacin, while 7 patients were treated with the interleukin-1 inhibitor anakinra (including 3 previously treated by pefloxacine) usually with a complete and sustained efficacy on clinical manifestations of the disease. In a median follow up time of 10 years (range 1–20 years), 3 patients developed overt Waldenström macroglobulinemia (WM) at 5, 7 and 20 years post diagnosis.

At diagnosis patients had increased serum levels of bALP (mean±SD: 36.5±15.0 IU/L vs. 26.8±7.1 IU/L; p=0.049), osteocalcin (20.5±18.6 ng/ml vs. 7.4±3.5 ng/ml; p<0.001), Dkk-1 (49.9±13.0 pmol/L vs. 30.9±11.1 pmol/L; p<0.001) and OPG (6.7±1.3 pmol/L vs. 3.5±1.8; p<0.001) compared to controls, while there were no differences between patients and controls for sRANKL and CTX. The increase of Dkk-1 may suggest a balance effect on osteoblast increased activity, while the lack of increase in osteoclast function is in accordance with data on idiopathic osteosclerosis.

At diagnosis, patients had also elevated VEGF (809±598 pg/ml vs. 263±257 pg/ml; p=0.001) and ang (221±96 ng/ml vs. 169±33; p=0.013) and decreased angp-1 (18.7±9.1 ng/ml vs. 25.4±10.9 ng/ml; p=0.048) and angp-1/angp-2 ratio (13.9±8.7 vs. 63.4±102.1; p=0.005). Patients presenting with fever had reduced angp-1 levels (14.8±5.2 ng/ml) compared to others (32.7±10.3 ng/ml; p=0.03). Interestingly, patients who progressed to WM had also decreased levels of angp-1 (10.2±7.5 ng/ml) compared to others (21.2±8.2 ng/ml; p=0.04) and angp-1/angp-2 ratio (5.3±4.6 vs. 16.5±8.0; p=0.04), suggesting that low angp-1/angp-2 ratio at diagnosis, which reflects increased angiogenesis, may indicate a predisposition for evolution of the gammopathy towards an overt WM. After successful treatment, VEGF levels decreased (387±207 pg/ml) compared to baseline (770±456 pg/ml; p=0.04).

In conclusion our analysis shows increased serum levels of angiogenic cytokines in Schnitzler syndrome and documents enhanced bone formation which appears not to be balanced by a comparable increase in bone resorption; this result may explain the presence of sclerotic bone lesions in this entity. Successful therapy with either anakinra or pefloxacin is associated with reduction of the major angiogenic cytokine VEGF.