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Rosuvastatin for Tocilizumab, an Interleukin-6 Receptor Antibody-induced Dyslipidemia in a Diabetic Patient Hidekatsu Yanaia, b, e, Hiroshi Kanekoc, Yuji Hirowararid tor monoclonal antibody, used as monotherapy or in com- Abstract
bination with methotrexate for rheumatoid arthritis (RA) therapy, leads to a decrease of RA disease activity and an im- Tocilizumab, which blocks interleukin-6 binding to interleukin-6 provement in joint function [1-3]. Although hyperlipidemia receptor, is now approved for the treatment of rheumatoid arthri- has been reported as one of common adverse effects of tocili- tis (RA). Hyperlipidemia has been reported to be one of the most zumab [1- 3], the precise mechanisms remain unknown. To common adverse effects of tocilizumab, however, the underlying understand lipid metabolism precisely, we measured plasma mechanisms remain unknown. To understand lipid metabolism cytokines, small dense low-density lipoprotein (LDL) (sd- precisely, we measured plasma cytokines, small dense low-density LDL), oxidized LDL (ox-LDL) and cholesterol level in each lipoprotein (LDL), oxidized LDL and cholesterol level in each lipo- lipoprotein fraction using the high-performance liquid chro- protein fraction using the high-performance liquid chromatography method before and after the tocilizumab treatment, and also studied matography (HPLC) method before and after the treatment the effect of rosuvastatin on tocilizumab-induced dyslipidemia in a using tocilizumab [4], and also studied the effect of rosu- diabetic patient complicated with RA. We found that rosuvastatin vastatin on tocilizumab-induced dyslipidemia in a diabetic signifi cantly ameliorated the tocilizumab-induced dyslipidemia.
Keywords: Diabetes; Interleukin-6; Small dense low-density lipo-
Case Report
A 74-year-old woman developed RA and type 2 diabetes, in 2002 and 2004, respectively. Her RA has been treated by non-steroidal anti-infl ammatory drugs and methotrexate Introduction
(4mg / week), and her diabetes has been treated by dietary therapy. In 2010, the treatment using tocilizumab for RA was Tocilizumab, a newly developed interleukin-6 (IL-6) recep- introduced because her RA disease activity increased. Her body weight was 51.9 kg and height 154.0 cm (BMI 21.9 kg/m2). Fasting plasma glucose and HbA levels were 108 mg/ After one month of tocilizumab use, serum high-sensi- tivity C-reactive protein (hs-CRP) signifi cantly decreased Manuscript accepted for publication Oct 12, 2011 and serum adiponectin and interleukin-6 increased (Fig. 1). HbA level decreased from 7.3 to 6.8%. Serum levels of to- Department of Internal Medicine, National Center for Global Health tal cholesterol (TC) and high-density lipoprotein cholesterol and Medicine, Kohnodai Hospital, Chiba, JapanbClinical Research Center, National Center for Global Health and (HDL-C) slightly increased, and LDL-C level decreased, Medicine, Kohnodai Hospital, Chiba, Japan and serum triglyceride (TG) levels signifi cantly increased cDepartment of Rheumatology, National Center for Global Health and after the tocilizumab treatment (Fig. 2). In the HPLC study, Medicine, Kohnodai Hospital, Chiba, Japand very low-density lipoprotein cholesterol (VLDL-C) signifi - Bioscience Division, Tosoh Corporation, Kanagawa, Japan cantly increased and HDL-C decreased (Fig. 3). The sd-LDL corresponding author: Department of Internal Medicine, National Center for Global Health and Medicine, Kohnodai Hospital, Kohnodai and ox-LDL levels were increased (Fig. 4). After two weeks 1-7-1, Ichikawa, Chiba 272-8516, Japan. of rosuvastatin use, serum levels of LDL-C, intermediate low-density lipoprotein (IDL)-C, VLDL-C, chylomicron (CM)-C, sd-LDL and ox-LDL were signifi cantly decreased, and HDL-C remarkably increased (Fig. 3, 4).
Articles The authors | Journal compilation J Endocrinol Metab and Elmer Press™ | www.jofem.org Figure 1. Effects of tocilizumab and rosuvastatin on serum interleukin (IL)-6 (A), high-sensitivity C-reactive pro-
tein (hs-CRP) (B) and adiponectin (C). a, before the tocilizumab treatment; b, one month after the tocilizumab
treatment and before the rosuvastatin use; c, two weeks after the rosuvastatin use.
Figure 2. Effects of tocilizumab and rosuvastatin on serum total cholesterol (TC) (A), triglyceride (TG) (B),
low-density lipoprotein-cholesterol (LDL-C) (C) and high-density lipoprotein-cholesterol (HDL-C) (D). a, before
the tocilizumab treatment; b, one month after the tocilizumab treatment and before the rosuvastatin use; c, two
weeks after the rosuvastatin use.
Articles The authors | Journal compilation J Endocrinol Metab and Elmer Press™ | www.jofem.org Figure 3. Effects of tocilizumab and rosuvastatin on serum low-density lipoprotein-cholesterol (LDL-C) (A),
very low-density lipoprotein-cholesterol (VLDL-C) (B), intermediate-density lipoprotein-cholesterol (IDL-C) (C),
chylomicron-cholesterol (CM-C) (D) and high-density lipoprotein-cholesterol (HDL-C) (E), determined by the
high-performance liquid chromatography method. a, before the tocilizumab treatment; b, one month after the
tocilizumab treatment and before the rosuvastatin use; c, two weeks after the rosuvastatin use.
Figure 4. Effects of tocilizumab and rosuvastatin on serum oxidized low-density lipoprotein (ox-LDL) (A) and
small dense low-density lipoprotein (sd-LDL) (B). a, before the tocilizumab treatment; b, one month after the
tocilizumab treatment and before the rosuvastatin use; c, two weeks after the rosuvastatin use.
Articles The authors | Journal compilation J Endocrinol Metab and Elmer Press™ | www.jofem.org Discussion
Conclusion
Tocilizumab, which blocks IL-6 binding to IL-6 receptor, is Rosuvastatin signifi cantly ameliorated the tocilizumab-in- now approved for the treatment of RA [1-3]. In the system- duced dyslipidemia. To confi rm our fi ndings, further studies, atic review of MEDLINE (1998 - June 2008) and Interna- preferably with larger numbers of subjects, will be needed.
tional Pharmaceutical Abstracts (1970 - June 2008), hyper-lipidemia has been reported to be one of the most common adverse effects of tocilizumab [2]. In another systematic re- Acknowledgments
view including eight randomized controlled trial with 3,334 participants, 2,233 treated with tocilizumab and 1,101 con- This work was supported by the Grant of National Center for trols, signifi cant increases in TC, HDL-C, LDL-C and TG Global Health and Medicine (22-120).
were observed in the tocilizumab treated patients [3]. How-ever, the underlying mechanisms for tocilizumab-induced hyperlipidemia remain unknown.
Tocilizumab decreased hs-CRP and increased adipo- nectin in our patient, which is favorable for serum lipid Written informed consent was obtained from a patient for metabolism [5, 6], however, tocilizumab remarkably in- creased TG-rich lipoprotein such as VLDL and athero-genic lipoproteins such as sd-LDL and ox-LDL, and decreased HDL. In our study, serum IL-6 level was in- Authors’ Contributions
creased after the tocilizumab treatment due to the block-ade of interleuikin-6 receptor. IL-6 is a cytokine that All authors were involved in study design, drafting the man- appears to act as an important systematic regulatory hor- uscript and read and approved the fi nal manuscript.
mone in response to infl ammation. Serum IL-6 has been reported to increase in RA patients and to be associated with disease activity of RA [7]. Plasma levels of IL-6 cor- Competing Interests
relate positively with insulin resistance and plasma free fatty acids (FFA) levels [8, 9]. Administration of IL-6 to The authors declare that they have no competing interests.
humans induces elevation of plasma FFA and increased plasma FFA appearance, consistent with increased adipo-cyte lipolysis of TG [10, 11]. IL-6 has been also reported References
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