Rheumatoid Arthritis: Asanuma Y

Yokota K, Akiyama Y, Asanuma Y, Miyoshi F, Sato K, Mimura T. · Department of Rheumatology and Applied Immunology, Faculty of Medicine, Saitama Medical University, Iruma-gun, Saitama, Japan. · Rheumatol Int. · Pubmed #18802706 No free full text.

Abstract: We report a Japanese male patient with intractable rheumatoid arthritis (RA), in whom tacrolimus was effective ultimately. Five years before the admission he was diagnosed as RA, which was resistant to various disease-modifying anti-rheumatic drugs (DMARDs). Two years before, administration of infliximab was initiated although the medicine failed to control RA. In spite of the multiple joint replacement, the RA disease activity worsened. Tacrolimus (1.5 mg/day) was administered. Twenty-four weeks of tacrolimus treatment reduced the disease activity score for 28 joints-erythrocyte sedimentation rate from 7.44 to 3.65. Herein, we present a patient with RA, who was successfully treated by tacrolimus, and in whom infliximab was not effective. Tacrolimus may be one of the drugs for RA patients refractory to the conventional treatments including methotrexate or tumor necrosis factor inhibitors.

Yokota K, Miyoshi F, Miyazaki T, Sato K, Yoshida Y, Asanuma Y, Akiyama Y, Mimura T. · Division of Rheumatology and Applied Immunology, Department of Internal Medicine, Saitama Medical University, Saitama, Japan. · J Rheumatol. · Pubmed #18203325 No free full text.

Abstract: OBJECTIVE: We previously reported that 10 mg/day of simvastatin significantly reduced clinical scores of rheumatoid arthritis (RA) in patients with active RA with hypercholesterolemia. We have also reported that a certain pharmacological concentration of simvastatin, i.e., 0.05-0.1 microM, inhibits the production of interleukin 6 (IL-6) and IL-8 and the cell proliferation induced by tumor necrosis factor-alpha (TNF-alpha) in fibroblast-like synoviocytes (FLS) derived from patients with RA in vitro. We investigated other effects of simvastatin on FLS from the standpoint of cell viability and apoptosis. METHODS: RA FLS were cultured with or without 0.05-50 microM simvastatin for 48 h. Cell viability was determined using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Apoptosis was measured by flow cytometric analysis using propidium iodide and annexin-V. Caspase-3 and -9 activities were analyzed by colorimetric assays. RESULTS: High concentrations of simvastatin, i.e., 1.0-50 microM, reduced cell viability and induced prominent apoptosis in FLS in a dose-dependent manner. The apoptosis induced by simvastatin was caspase-3- and caspase-9-dependent. These effects were completely reversed in the presence of mevalonic acid or geranylgeranyl-pyrophosphate, but not in the presence of farnesyl-pyrophosphate. Further, a geranylgeranyl transferase inhibitor and a RhoA kinase inhibitor mimicked the effect of simvastatin. CONCLUSION: These data, together with our previous report, suggest that low (pharmacological range) and high concentrations of simvastatin affect FLS differently: (1) at a low concentration, it inhibits IL-6 and IL-8 production and the cell proliferation of FLS induced by TNF-alpha (2) at high concentrations, it induces apoptosis in FLS. Understanding this dose-dependent biphasic effect of simvastatin may prove important for its clinical applications in the treatment of RA.

Asanuma Y, Chung CP, Oeser A, Solus JF, Avalos I, Gebretsadik T, Shintani A, Raggi P, Sokka T, Pincus T, Stein CM. · Saitama Medical University, Saitama, Japan. · Atherosclerosis. · Pubmed #17570371 links to  free full text

Abstract: Osteoprotegerin (OPG), a soluble decoy receptor for receptor activator of nuclear factor kappaB ligand, is implicated in the pathogenesis of atherosclerosis. Patients with rheumatoid arthritis (RA) have inflammation and increased atherosclerosis. We examined the hypothesis that OPG concentrations are increased in patients with RA and are associated with coronary-artery atherosclerosis. Serum OPG concentrations were measured by ELISA and coronary-artery calcification by electron-beam computer tomography in 157 patients with RA and 87 control subjects. OPG concentrations were higher in patients with long-standing RA (n=67) [median (interquartile range)]: [1895 (1337-2847) pg/mL, and early RA (n=90): [1340 (1021-1652) pg/mL, than controls 1068 (692-1434) pg/mL; (p<0.001)]. In patients with RA, OPG concentrations were associated with erythrocyte sedimentation rate (p<0.001), homocysteine (p=0.001), disease duration (p=0.02), coronary calcium score (p=0.03), and cumulative dose of corticosteroids (p=0.04) after adjustment for age and sex. In patients with long-standing RA, OPG was associated with coronary-artery calcification independently of cardiovascular risk factors and disease activity [OR for every increase in 500 pg/mL of OPG=2.22 (1.43-3.34), p<0.001]. In conclusion, OPG concentrations are increased in patients with RA and are associated with inflammation. In patients with long-standing disease, OPG is independently associated with coronary-artery calcification.

Asanuma Y, Kawai S, Aoshima H, Kaburaki J, Mizushima Y. · St. Marianna University School of Medicine, Kawasaki, Japan. · Arthritis Rheum. · Pubmed #10088766 links to  free full text

Abstract: OBJECTIVE: To determine serum lipoprotein(a) (Lp[a]) concentrations and to analyze the apolipoprotein(a) (Apo[a]) phenotype in patients with rheumatoid arthritis (RA). METHODS: The subjects included 131 patients with RA and 200 healthy control subjects. Serum Lp(a) concentrations were measured by enzyme-linked immunosorbent assay, and the Apo(a) phenotype was determined by immunoblotting. HLA-DR typing was also done. RESULTS: The mean serum Lp(a) level was significantly higher (P < 0.001) in the RA patients (27.5 mg/dl) than in the controls (15.0 mg/dl). The S3 allele was found in 70.0% of the patients versus 39.5% of the controls (P < 0.001). There was no significant difference in HLA-DR4 positivity between patients with and without the S3 phenotype. CONCLUSION: The serum Lp(a) level was increased in patients with RA, possibly partly because of S3 phenotype predominance.