 |
|
|
 |
Increase in Plasma Levels of Adiponectin After Administration of Anti-Tumor Necrosis Factor Agents in Patients with Rheumatoid Arthritis To the Editor: Adiponectin, a fat-derived adipocytokine, is abundantly expressed in adipose tissue. It exhibits antiatherogenic, antidiabetic, and antiinflammatory effects1. Blood adiponectin levels are low in subjects with metabolic syndrome and/or cardiovascular diseases, and its lowered levels in sera are closely associated with increased cardiovascular mortality in metabolic syndrome. Cardiovascular events are the most important cause of death also in patients with rheumatoid arthritis (RA), and improvement in mortality among patients with RA after the introduction of anti-tumor necrosis factor (TNF) agents2 could be related to changes in the levels of adipocytokines. We evaluated plasma levels of adiponectin before and after treatment with anti-TNF agents in Japanese patients with RA. Patients' characteristics are shown in Table 1. Infliximab was infused at 3 mg/kg body weight at Weeks 0, 2, and 6, and blood samples were obtained just before the first and third infusions. Etanercept was injected subcutaneously 25 mg twice weekly for more than 3 months. Blood samples were collected at baseline, 2 months after treatment, and at the latest visits, with a mean interval of 7.2 (SD 3.0) months (range 3–13 mo) after the first injection. Levels of total and high molecular weight (HMW) adiponectin were measured using ELISA kits (R&D Systems, Minneapolis, MN; and Linco Research, St. Charles, MO, USA, respectively). Total adiponectin levels were also measured in 37 patients with RA who were anti-TNF-naive and whose disease activities were stable, and in 19 healthy controls [11 men, 8 women, mean age 36.3 ± 9.3 years (range 26–55)]. The Wilcoxon signed-rank test was employed for statistical analysis. Multiple regression analysis was performed to examine the relationship between adiponectin levels and baseline characteristics [sex, disease duration, age, body mass index, prednisolone dosage, methotrexate use, C-reactive protein, and Disease Activity Score (DAS28)]. A p value < 0.05 was considered significant.
The results are shown in Figure 1. Adiponectin levels of healthy controls (female, 13.5 ± 2.7 µg/ml; male, 7.8 ± 4.5 µg/ml) did not differ significantly from those of patients with RA at baseline (female, 12.9 ± 5.1 µg/ml; male, 8.6 ± 5.6 µg/ml). In both infliximab- and etanercept-treated groups, the levels of total and HMW adiponectin increased significantly only in female patients (Figure 1, A, C, and D, respectively). In patients with RA who were naive to anti-TNF agents and in healthy controls, there were no changes in total adiponectin levels (Figure 1, E and F). Multiple regression analysis showed female sex and DAS28 were statistically significant independent variables (data not shown).
Serum levels of adiponectin are reported to be higher in patients with RA than in healthy controls3 and it is suggested that adiponectin could be proinflammatory in vitro4. However, these variables did not differ significantly in our population. The precise reason for the contradictory results is unknown, but it could be due to the differences in patients' demographics and/or ethnicity. Etanercept increases serum levels of total adiponectin, but not HMW adiponectin, in patients with metabolic syndrome5. However, we found significant increases in plasma levels of both total and HMW adiponectin after treatment with infliximab and etanercept in Japanese women with RA. TNF and adiponectin mutually inhibit the production of each other in adipose tissue6, therefore, blockage of the action of TNF by anti-TNF agents is a reasonable explanation. Alleviation of joint inflammation per se by treatment might be another explanation for the increase in plasma adiponectin; insulin resistance is improved by anti-TNF agents in patients with inflammatory diseases such as RA and ankylosing spondylitis7, but not in the obese and patients with type 2 diabetes5,8. Härle, et al reported no influence on the serum levels of adiponectin in patients with RA treated with adalimumab9, which contradicts our results. In our results, adiponectin tended to increase more in the etanercept-treated group. Etanercept was administered much more frequently than infliximab; adalimumab came in between. Blood was collected immediately before the next administration of anti-TNF agents and the adiponectin-increasing effects could have waned by that time. Another explanation is the difference between Härle's patient population and ours. Interestingly, the increase of adiponectin was observed only in women in our study. The major reason for this could be that the number of men studied was too small, 8 and 4 male patients in the infliximab and etanercept groups, respectively. Sex differences might be fundamentally important to this issue; testosterone replacement therapy suppresses total and HMW adiponectin in hypogonadal men10. Recently, it was reported that TNF inhibitors reduce mortality only in women with RA2. This coincides well with our results that only female patients showed increases in plasma adiponectin levels after treatment with anti-TNF agents. Whether this indicates cause and effect or is just a coincidence needs to be addressed in the future. TAKAO NAGASHIMA, MD, PhD; HIKARU OKUBO-FORNBACHER, MD; YOKO AOKI, MD; YASUYUKI KAMATA, MD; HIROTAKA KIMURA, MD; TAKESHI KAMIMURA, MD, PhD; HIROYUKI NARA, MD; MASAHIRO IWAMOTO, MD, PhD, Assistant Professor; TAKU YOSHIO, MD, PhD, Associate Professor; HITOAKI OKAZAKI, MD, PhD, Associate Professor; SEIJI MINOTA MD, PhD, Professor of Medicine, Division of Rheumatology and Clinical Immunology, Department of Medicine, Jichi Medical University, Yakushiji 3311-1, Shimotsuke-shi, Tochigi, 329-0498, Japan. Address reprint requests to Dr. T. Nagashima. E-mail: naga4ma@jichi.ac.jp Supported in part by a Jichi Medical University Young Investigator Award. 2. Jacobsson LT, Turesson C, Nilsson JA, et al. Treatment with TNF blockers and mortality risk in patients with rheumatoid arthritis. Ann Rheum Dis 2007;66:670-5. [MEDLINE] 3. Otero M, Lago R, Gomez R, et al. Changes in plasma levels of fat-derived hormones adiponectin, leptin, resistin and visfatin in patients with rheumatoid arthritis. Ann Rheum Dis 2006;65:1198-201. [MEDLINE] 4. Ehling A, Schaffler A, Herfarth H, et al. The potential of adiponectin in driving arthritis. J Immunol 2006;176:4468-78. [MEDLINE] 5. Lo J, Bernstein LE, Canavan B, et al. Effects of TNF-alpha neutralization on adipocytokines and skeletal muscle adiposity in the metabolic syndrome. Am J Physiol Endocrinol Metab 2007;293:E102-9. [MEDLINE] 6. Maeda N, Shimomura I, Kishida K, et al. Diet-induced insulin resistance in mice lacking adiponectin/ACRP30. Nat Med 2002;8:731-7. [MEDLINE] 7. Kiortsis DN, Mavridis AK, Vasakos S, Nikas SN, Drosos AA. Effects of infliximab treatment on insulin resistance in patients with rheumatoid arthritis and ankylosing spondylitis. Ann Rheum Dis 2005;64:765-6. [MEDLINE] 8. Dominguez H, Storgaard H, Rask-Madsen C, et al. Metabolic and vascular effects of tumor necrosis factor-alpha blockade with etanercept in obese patients with type 2 diabetes. J Vasc Res 2005;42:517-25. [MEDLINE] 9. Härle P, Sarzi-Puttini P, Cutolo M, Straub RH. No change of serum levels of leptin and adiponectin during anti-tumour necrosis factor antibody treatment with adalimumab in patients with rheumatoid arthritis. Ann Rheum Dis 2006;65:970-1. [MEDLINE] 10. Xu A, Chan KW, Hoo RL, et al. Testosterone selectively reduces the high molecular weight form of adiponectin by inhibiting its secretion from adipocytes. J Biol Chem 2005;280:18073-80. [MEDLINE]
|
