PF433 SOLUBLE MANNOSE RECEPTOR IS A POTENTIAL NEW BIOMARKER FOR PLASMA CELL DYSCRASIAS AND OTHER SKELETAL COMPLICATIONS IN GAUCHER DISEASE
Authors: Beaton B. , Hughes D. 
Published: June 2019

Background:Gaucher Disease (GD) is a rare autosomal recessive lysosomal storage disorder caused by deficient activity of the lysosomal enzyme beta‐glucocerebrosidase (GBA). Clinical features of disease are heterogeneous as is response to treatment. Skeletal disease is complex and a proportion of patients do not respond or progress, despite GD‐specific therapy. Determinants of skeletal non‐response are not known. Polyclonal gammopathy, monoclonal gammopathy of undeterminded significance (MGUS) and Plasma Cell Myeloma (PCM) are features of GD. Progression from MGUS to PCM is difficult to predict. Biomarkers currently used to assess overall disease burden are not specific to GD and do not reliably reflect individual domains of organ involvement. Soluble mannose receptor (sMR) has been assessed as a biomarker in various diseases where alternatively activated macrophages have been implicated, and shows promise in predicting transformation of MGUS to PCM.Aims:To assess sMR in relation to domains of clinical features of GD. To compare sMR to known biomarkers of GD.Methods:The diagnosis of GD was confirmed in our patients by assessing enzyme activity and genotype, which also excluded GD in our controls. Pertinent clinical data was collected from patient records retrospectively. ELISA analysis of biomarkers were undertaken as per kit instructions: Human sMR (Hycult Biotech); PARC (Life Technologies); human osteoactivin GPNMB (Invitrogen by Thermo Fisher Scientific); CCL3 and CCL4 (Invitogen by Thermo Fisher Scientific); progranulin (Ray Biotech). Chitotriosidase, ferritin, ACE, haemoglobin, platelets, IgA, IgG, and IgM were determined by the diagnostic laboratory at The Royal Free hospital. Spleen volumes and liver volumes were calculated from MRI images of patients.Results:16 treatment naïve type 1 GD patients, 14 with paired post‐treatment sera and 10 non‐GD controls had sMR measured by ELISA. Mean sMR in treatment naïve sera was 291.2 +/‐ 178.8 ng/ml compared to post‐treatment 200.5 ng/ml +/‐ 103.1 (p = 0.02). Mean sMR of the control group was 182.1 +/‐ 48.0 ng/ml. There was no statistical significance between control and post‐treatment groups. Median treatment time was 27 months (range: 11–124). There is good correlation with all domains of GD clinical features: platelet count (rho = 0.47, p = 0.009), haemoglobin (rho = 0.77, p = <0.0001), spleen volume (rho = 0.68, p = 0.002), liver volume (rho = 0.64, p = 0.002), bone marrow burden (BMB) score (rho = 0.78, p = 0.0009). There was strong correlation with immunoglobulin levels: IgA (rho = 0.54, p = 0.002), IgG (rho = 0.58, p = 0.0007), IgM (rho = 0.86, p = <0.0001). sMR correlated well with other biomarkers: PARC (rho = 0.65, p = <0.0001), osteoactivin (rho = 0.58, p = 0.0006), chitotriosidase (rho = 0.52, p = 0.0003), ferritin (rho = 0.71, p = <0.0001), CCL3 (rho = 0.66, p = <0.0001). sMR did not correlate with these biomarkers: angiotensin converting enzyme (ACE) (rho = 0.27, p = 0.13), progranulin (rho = 0.071, p = 0.7), CCL4 (rho = 0.048, p = 0.79).Summary/Conclusion:sMR has been studied as a marker in diseases of alternatively activated macrophages previously, but not in GD to date. sMR is elevated in GD patients measured at baseline (prior to treatment) and reduces with Gaucher‐directed treatment. sMR correlates with all domains of clinical features of GD. sMR is strongly correlated with increased immunoglobulin levels in GD patients. sMR correlates with many established clinically used biomarkers and those in development. Future work will assess sMR over time in patients with polyclonal gammopathy and MGUS who develop PCM to assess its utility to predict evolution to PCM.