A Single-Center Retrospective Observational Study Evaluating the Favorable Predictive Factors for the Disease Control Time of Treatment with Tocilizumab in Patients of Rheumatoid Arthritis.

BACKGROUND: Tocilizumab (TCZ) is humanized monoclonal antibody against the interleukin-6 (IL-6) and receptor that has prominent efficacy for the treatment of rheumatoid arthritis (RA). We conducted a retrospective observational study to determine how long TCZ controls RA. PATIENTS AND METHODS: We retrospectively reviewed the medical records of RA patients treated with TCZ. The aim of this study was to evaluate the contribution of clinical parameters to disease control time (DCT) in RA patients. RESULTS: Overall, 144 patients were enrolled in the study. The median age of patients was 66 years (range: 34-85 years). In univariate analysis, DCT was significantly increased in patients who had never received previous biologic disease-modifying anti-rheumatic drugs treatment (P = 0.0064). We also analyzed the contribution of the base line value of C-reactive protein (CRP) to DCT. We divided the patients with RA into two groups according to a cutoff value of 1.000 mg/dl. The median control times were 77.5 months (95% confidence interval [CI]: 44.8-not reached to median) and 34.5 months (95% CI: 17.0-79.3) for patients with high and low CRP value, respectively. In univariate analysis, DCT was significantly increased in patients with a high CRP value (P = 0.0283). Multivariate analysis clearly revealed that a high baseline CRP value was an independent favorable predictive factor for longer DCT (hazard ratio, 0.608, 95% CI: 0.378-0.981, P = 0.0416). CONCLUSION: These data clearly demonstrate that the baseline value of CRP was closely associated with long time DCT in patients of RA treated with TCZ.

Mycophenolic acid, the active form of mycophenolate mofetil, interferes with IRF7 nuclear translocation and type I IFN production by plasmacytoid dendritic cells.

BACKGROUND: Both humoral and cellular immune mechanisms are involved in the onset and progression of autoimmune responses in systemic lupus erythematosus (SLE). Plasmacytoid dendritic cells (pDCs) play a central role in the pathogenesis of SLE via the dysregulation of type I interferon (IFN) production; these cells act together with activated myeloid DCs (mDCs) to amplify the vicious pathogenic spiral of autoimmune disorders. Therefore, control of aberrant DC activation in SLE may provide an alternative treatment strategy against this disease. Mycophenolate mofetil (MMF), which has been used to treat lupus nephritis, specifically blocks the proliferation of B and T lymphocytes via inhibition of inosine-5-monophosphate dehydrogenase. Here, we focus on the effects of MMF in targeting DC functions, especially the IFN response of pDCs. METHODS: We isolated human blood pDCs and mDCs by flow cytometry and examined the effect of mycophenolic acid (MPA), which is a metabolic product of MMF, on the toll-like receptor (TLR) ligand response of DC subsets. Additionally, we cultured pDCs with serum from SLE patients in the presence or absence of MPA and then examined the inhibitory function of MPA on SLE serum-induced IFN-α production. RESULTS: We found that treatment with 1-10 µM of MPA (covering the clinical trough plasma concentration range) dose-dependently downregulated the expression of CD80 and CD86 on mDCs (but not pDCs) without inducing apoptosis, in response to R848 or CpG-ODN, respectively. Notably, in pDCs, MPA significantly suppressed IFN-α production with IRF7 nuclear translocation and repressed the AKT activity. In addition, MPA inhibited IL-12 production with STAT4 expression in mDCs. We further identified that MPA had an inhibitory effect on SLE serum-induced IFN-α production by pDCs. CONCLUSIONS: Our data suggest that MPA can interrupt the vicious pathogenic spiral of autoimmune disorders by regulating the function of DC subsets. This work unveiled a novel mechanism for the therapeutic ability of MMF against SLE.

Immunohistochemical analysis of NANOG expression and epithelial-mesenchymal transition in pulmonary sarcomatoid carcinoma.

Pulmonary sarcomatoid carcinomas (PSCs) are defined as a group of poorly differentiated non-small cell lung cancers that demonstrate sarcoma-like differentiation. The mechanism of mesenchymal differentiation in PSC is epithelial-mesenchymal transition (EMT). The expression of homeobox protein NANOG (NANOG), which regulates the pluripotency of embryonic stem cells, is associated with the EMT process. Therefore, the present study aimed to assess the expression level of NANOG and the status of the EMT process in PSC. The data of patients with PSC were retrospectively reviewed and immunohistochemical analyses were performed on patient samples to examine the expression of NANOG and EMT-associated proteins. The comparator group included randomly selected patients with matched clinicopathological characteristics who had pulmonary adenocarcinoma (PA). In the present study, 12 patients with PSC (4 females and 8 males) were enrolled; their median age was 65 years (range, 36-79 years), and the number of patients with stage IB, IIB, IIIA, IIIB and IV disease were 1, 1, 1, 1 and 8, respectively. The immunoreactive score (IRS) for E-cadherin was significantly lower in the PSC group compared with the PA group (P<0.0001), whereas the IRS for vimentin was significantly higher in the PSC group compared with the PA group (P<0.0001). However, the IRS for NANOG was significantly decreased in the PSC group compared with the PA group (P<0.0001), which suggests that NANOG does not serve an essential role in EMT in PSC. In addition, the overall survival of patients with PSC was significantly lower compared with that of patients with PA (median survival time, 7.0 vs. 35.6 months, respectively; P=0.0256). However, no significant difference was observed in the OS of patients who expressed low compared with high levels of NANOG (P=0.4416). In conclusion, it was clearly demonstrated that cytoplasmic NANOG expression was significantly lower in PSC compared with PA, and that the EMT process in PSC was accelerated, compared with that in PA.

Anti-atherosclerotic effects of sitagliptin in patients with type 2 diabetes mellitus.

BACKGROUND: Advanced glycation end products, selectins, and adiponectin play important roles in the development of atherosclerosis in individuals with diabetes. Sitagliptin has been shown to reduce the concentration of glycated hemoglobin in diabetic patients. However, its effects on soluble receptor for advanced glycation end products (sRAGEs), selectins, and adiponectin in these patients are poorly understood. This study was conducted to assess the effects of sitagliptin on the circulating levels of sRAGEs, monocyte chemoattractant protein-1 (MCP-1), selectins, and adiponectin in patients with type 2 diabetes. METHODS: Diabetic patients eligible for sitagliptin monotherapy or combination therapy (eg, sitagliptin plus a sulfonylurea) were administered sitagliptin (50 mg/day) for 6 months. Levels of soluble P-selectin (sP-selectin), soluble E-selectin (sE-selectin), soluble vascular cell adhesion molecule-1 (sVCAM-1), MCP-1, sRAGEs, and adiponectin were measured by ELISA at baseline and after 3 and 6 months of treatment. RESULTS: At baseline, the levels of MCP-1, sP-selectin, sE-selectin, and sVCAM-1 were higher and the level of adiponectin was lower in diabetic patients than in nondiabetic patients. Sitagliptin therapy for 3 and 6 months significantly reduced plasma levels of sP-selectin, sE-selectin, sVCAM-1, and MCP-1 relative to baseline, while significantly increasing adiponectin levels. sRAGEs did not exhibit a statistical significance, although there was an increasing tendency. Furthermore, the reductions in sP-selectin, sE-selectin, sVCAM-1, and MCP-1 during sitagliptin therapy were significantly greater in responders, defined as patients with a significant increase in adiponectin levels, than in nonresponders. In contrast, responders showed a significant increase in the plasma concentration of sRAGEs. CONCLUSION: Sitagliptin shows an adiponectin-dependent anti-atherothrombotic effect, which may be beneficial for primary prevention of atherothrombosis, in patients with type 2 diabetes.

Effects of febuxostat on platelet-derived microparticles and adiponectin in patients with hyperuricemia.

Platelet-derived microparticles (PDMPs) and adiponectin play an important role in the development of atherothrombosis. We investigated the effect of febuxostat on circulating PDMP levels and adiponectin in hyperuricemic patients. Levels of PDMP and biomarkers were measured using an ELISA at baseline and after 2 and 6 months of treatment. Plasma levels of PDMPs and biomarkers were higher, while those of adiponectin were lower in hyperuricemic patients than in normouricemic controls. Uric acid and interleukin (IL)-6 levels decreased significantly in hyperuricemic patients after 2 months of febuxostat treatment. However, PDMP and biomarkers decreased significantly in hyperuricemic patients after only 6 months of febuxostat treatment and adiponectin increased significantly. These results suggest that the effects of febuxostat for PDMPs seen may be the effect on xanthine oxidase but not the decrease of uric acid, and febuxostat may be beneficial for primary prevention of atherothrombosis in hyperuricemic patients.

Combined use of ursodeoxycholic acid and bosentan prevents liver toxicity caused by endothelin receptor antagonist bosentan monotherapy: two case reports.

INTRODUCTION: Pulmonary arterial hypertension is a fatal disease characterized by progressive remodeling of the pulmonary arteries and an increase in pulmonary vascular resistance. Up to 50% of patients with systemic sclerosis have pulmonary arterial hypertension, which significantly affects the prognosis. The endothelin receptor antagonist bosentan is used for the treatment of pulmonary arterial hypertension and shows a great beneficial effect. However, the most frequent side effect of bosentan is liver toxicity, which often requires dose reduction and discontinuation. CASE PRESENTATION: We report two cases (a 64-year-old Japanese woman and a 69-year old Japanese woman) of systemic sclerosis, both with severe Raynaud's phenomenon and pulmonary arterial hypertension. Both patients had initially received bosentan monotherapy, which caused liver toxicity as indicated by increased levels of alanine aminotransferase, alkaline phosphatase, and gamma-glutamyltransferase. After dose reduction or discontinuation of bosentan, these liver function abnormalities were normalized and the patients subsequently received retreatment with a combination of bosentan and ursodeoxycholic acid. The results of liver function tests did not show any abnormalities after this combination therapy. CONCLUSIONS: These reports suggest the usefulness of ursodeoxycholic acid for preventing liver toxicity caused by bosentan. Thus, the addition of ursodeoxycholic acid to the treatment protocol is expected to be useful when liver toxicity emerges as a side effect of bosentan.

Serum interleukin 6 before and after therapy with tocilizumab is a principal biomarker in patients with rheumatoid arthritis.

OBJECTIVE: Biologic treatments including the humanized anti-interleukin 6 (anti-IL-6) receptor antibody tocilizumab (TCZ) provide therapeutic options for patients with rheumatoid arthritis (RA). We investigated useful biomarkers to predict the responsiveness to TCZ by measurement of serum proinflammatory cytokine concentrations. METHODS: Serum samples were collected from 61 patients with RA before biologic treatment and at 4 weeks after initial administration of either TCZ (n = 32) or infliximab (IFX; n = 29) and from 13 healthy serum donor controls. Disease Activity Score of 28 joints (DAS28) was determined at baseline and after treatment. RESULTS: Although IL-1ß, IL-2, IL-6, IL-17A, IL-17F, interferon-α, and tumor necrosis factor-α (TNF-α) were all increased in sera from patients with RA compared with controls, only the IL-6 level was significantly correlated with DAS28 before treatment. The IL-6 level before treatment was positively correlated with DAS28 after TCZ treatment, and was significantly lower in TCZ-responsive patients (as judged by a post-treatment DAS28 < 3.2) than in TCZ-resistant patients (post-treatment DAS28 ≥ 3.2). DAS28 after TCZ was significantly lower than after administration of IFX in patients with low pretreatment IL-6 (< 51.5 pg/ml, the mean baseline value of IL-6 in all RA patients), but not in those with high pretreatment IL-6. These results indicate that low serum IL-6 is associated with a favorable response to TCZ. CONCLUSION: Although both TNF-α and IL-6 are major targets of therapeutic intervention in RA, baseline serum IL-6 but not baseline TNF-α level is a potential biomarker reflecting disease activity. Measurement of serum IL-6 in RA before treatment may be useful to estimate residual disease activity after TCZ treatment and to predict responsiveness to TCZ treatment.