Changes in bone density and bone turnover in patients with rheumatoid arthritis treated with rituximab, a B cell depleting monoclonal antibody

Abstract

Background The role of B-lymphocytes regarding bone turnover is controversial (1). Some studies showed that treatment with tumor necrosis factor alpha (TNFα) blockers could prevent structural bone damage and improve bone mineral density (BMD) in RA (2). Hence, we set up this study to determine rituximab will have similar effect on bone turnover and the possible mechanisms. Aim To assess the effect of rituximab on bone turnover and to correlate these changes with circulating B cells in RA. Materials & Methods 45 RA patients starting rituximab were assessed over 5 visits for one year. Patients were treated with two courses of rituximab. Patients were assessed clinically using DAS28, BMD using DXA scan, bone formation markers (BAP, P1NP), osteocyte markers (DKK1 and sclerostin), resorption markers (TRAP5b and CTX) and flow cytometry of peripheral blood CD19+ cells including subsets. Results Subjects were 59.3±12.1 years old mostly females (80%). 57.8% were postmenopausal. Patients had severe active disease at baseline DAS28=6.1±1.3. 68.9% of patients had vitamin D deficiency at baseline. 15(33.3%) of patients took prednisolone 11.2±9.8 mg. DAS28 score at 12 months decreased to 4.7±1.4 compared to 6.1±1.3 at baseline (P<0.001). Median (95%CI) P1NP levels increased from 41.9 (34.1-46.4) to 47.7 (42.0-61.4) after 12 months. Yet, the change was not statistically significant. BAP increased significantly from 19.0±6.5 to 21.3±7.7 (P=0.007). There was insignificant small reduction in TRAP5b and CTX levels during follow up. Osteocyte markers (sclerostin and DKK1) were stable during follow up. After performing Bonferroni correction, the increase in sclerostin levels between 6 and 12 months was found to be statistically significant (p=0.019). Depletion of most of CD19 B cells following baseline with increase at 6th month then continued to decrease following the second course of rituximab. After 12 months, BMD slightly decreased at all sites. However, the reduction was statistically significant only at total hip (p=0.041). There was significant positive independent association of BMD L2-L4 at 12 months with CD19 B-lymphocytes at baseline. Conclusion Based on results obtained from bone markers, B cell depletion using rituximab increased bone formation and slightly reduced bone resorbtion markers. However, sclerostin slightly increased from 6th to 12 month. BMD results were inconsistent with bone markers findings, as there was a reduction in all sites mostly at total hip. Furthermore, CD19+ B cells were found to have a direct positive association with BMD at LS suggesting that B cell depletion is not protective for bone metabolism as previously expected. II Key Words: “bone markers”, “bone resorption”, “bone formation”, “osteocyte biomarkers”, “bone mineral density”, “bone turnover”, “rheumatoid arthritis” and “disease activity indices”.