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Objective: To examine the incidence of hepatitis B virus (HBV) reactivation in patients with rheumatoid arthritis (RA) receiving biological disease-modifying antirheumatic drugs (DMARDs)., Methods: We retrospectively reviewed RA patients treated with biological DMARDs at our institution from July 2010 to December 2012. Patients with antibodies for hepatitis B core antigen and/or hepatitis B surface antigen were regarded as having prior HBV infection. Clinical data on these patients, including HBV-DNA levels, were retrieved from the medical records., Results: During the study period, 251 patients were administered various biological DMARDs. Six patients with a history of HBV vaccination and one patient with positive HBV surface antigen were excluded from the study. Fifty-seven of the remaining 244 patients (23.4%) had prior HBV infection. These patients were followed for a median of 18 months (range: 2-27 months) and HBV-DNA was examined a median of seven times (range: 2-27). HBV-DNA was detected in three patients (5.3%), comprising two receiving tocilizumab and one receiving etanercept. However, HBV-DNA levels were below the quantitation limit (<2.1 log copies mL(-1) ) in all three patients. HBV-DNA became negative again within several months in all three patients, while biological DMARDs were continued and liver function tests remained normal throughout., Conclusion: HBV-DNA reactivation occurred in 5.3% of RA patients with prior HBV infection during treatment with biological DMARDs, but there were no associated clinical manifestations. Accordingly, it seems that biological DMARDs can be used safely in patients with RA., (© 2014 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd.)

Objective: To investigate the influence of biologics on mortality and risk factors for death in rheumatoid arthritis (RA) patients., Methods: RA patients treated with at least one dose of biologics in daily practice in six large rheumatology institutes ("biologics cohort") were observed until 15 May 2010 or death, whichever occurred first. Mortality of the biologics cohort and the "comparator cohort" (comprising patients among the IORRA cohort who had never been treated with biologics) was compared to that of the Japanese general population. Factors associated with mortality were assessed by a Cox model., Results: Among 2683 patients with 6913.0 patient-years of observation, 38 deaths were identified in the biologics cohort. The probability of death in patients lost to follow-up, calculated using the weighted standardized mortality ratio (SMR), was 1.08 [95 % confidence interval (CI) 0.77-1.47] in the biologics cohort and 1.28 (95 % CI 1.17-1.41) in the comparator cohort. Pulmonary involvement was the main cause of death (47.4 %), and the disease-specific SMR of pneumonia was 4.19 (95 % CI 1.81-8.25). Risk factors for death included male gender [hazard ratio (HR) 2.78 (95 % CI 1.24-6.22)], advanced age (HR 1.07, 95 % CI 1.03-1.11), and corticosteroid dose (HR 1.08, 95 % CI 1.01-1.17)., Conclusion: Mortality in RA patients exposed to biologics did not exceed that in patients not exposed to biologics, but death from pulmonary manifestations was proportionally increased in RA patients exposed to biologics.

We investigated the influence of antibodies against infliximab and etanercept on the serum trough levels of these agents and the influence of these antibodies on the effectiveness of treatment in patients with rheumatoid arthritis treated with these agents. Forty patients treated with infliximab for 54 weeks and 40 patients treated with etanercept for 32 weeks were enrolled. They were divided into responder and non-responder groups. Serum trough levels of and antibodies against these agents were measured by enzyme-linked immunosorbent assay or radioimmunoassay. Of the 40 patients treated with infliximab, 14 (35%) had anti-infliximab antibodies. Serum trough levels were significantly lower in the non-responder group (14 patients) than in the responder group (26 patients) 6 weeks after initiation of infliximab (p < 0.05). Conversely, titers of anti-infliximab antibody were significantly higher in the non-responder group than in the responder group between 6 and 38 weeks after initiation of infliximab (p < 0.05). Anti-etanercept antibodies were not detected in any patients on etanercept. Serum trough levels of etanercept were not significantly different between the responder (31 patients) and non-responder groups (9 patients). It seems that the appearance of anti-infliximab antibodies might decrease infliximab serum concentrations and, thereby, reduce the agent's effectiveness. The clinical efficacy of etanercept does not appear to be affected by the serum concentrations if it is administered at standard doses.

Although TNF inhibitors have dramatically improved the outcome of patients with rheumatoid arthritis, 30-40% of patients do not respond well to them and treatment needs to be changed. In an effort to discriminate good and poor responders, we focused on the change in serum and synovial fluid levels of interleukin (IL-) 33 before and after treatment with TNF inhibitors. They were also measured in synovial fluids from 17 TNF inhibitor-naïve patients, and fibroblast-like synoviocytes (FLS) in-culture from 6 patients and correlated with various pro-inflammatory cytokines. Serum levels of IL-33 at 6 months after treatment decreased significantly in responders, while they did not change in non-responders. Synovial fluid levels of IL-33 in 6 patients under treatment with TNF inhibitors stayed high in 3 who were refractory and slightly elevated in 2 moderate responders, while they were undetectable in one patient under remission. Among inflammatory cytokines measured in 17 synovial fluids from TNF inhibitor-naïve patients, levels of IL-33 showed a significant positive correlation only to those of IL-1β. IL-1β increased IL-33 expression markedly in FLS in vitro, compared to TNF-α. IL-1β might be inducing RA inflammation through producing pro-inflammatory IL-33 in TNF inhibitor-hypo-responders. Sustained elevation of serum and/or synovial levels of IL-33 may account for a poor response to TNF inhibitors, although how TNF inhibitors affect the level of IL-33 remains to be elucidated.

Objective: To determine levels of interleukin 33 (IL-33) in serum and synovial fluid (SF) and their clinical associations in patients with rheumatoid arthritis (RA). To evaluate the ability of activated peripheral blood mononuclear cells (PBMC) and fibroblast-like synoviocytes (FLS) from RA patients to release IL-33., Methods: Sera were obtained from 59 patients with RA, 10 patients with infectious diseases, and 42 healthy volunteers. SF samples were obtained from 15 patients with RA and 13 with osteoarthritis. IL-33 levels were measured using a sandwich ELISA after removal of rheumatoid factor with protein A-Sepharose beads. FLS were stimulated with IL-1beta and tumor necrosis factor, and treated with or without chemical damage. PBMC were stimulated with anti-CD3/CD28 antibodies. The levels of IL-33 were measured in the culture supernatants and cell lysates by ELISA or immunoblotting., Results: Serum IL-33 levels were significantly higher in RA patients, especially in the high disease activity group compared to the moderate or low activity group. IL-33 levels in SF were elevated in all 15 RA patients measured. IL-33 levels were higher in SF samples than in sera in 7 RA patients measured simultaneously. The 30-kDa IL-33 precursor was detected in the culture supernatants of damaged FLS but was not detected in those of activated PBMC and non-damaged FLS., Conclusion: IL-33 levels were elevated in sera and SF samples from patients with RA, and correlated with disease activity. IL-33 was produced mainly in inflamed joints; IL-33/ST2L signaling might play an important role in joint inflammation of human RA.

Objective: Rheumatoid arthritis (RA) is the most common systemic autoimmune disease and is characterized mainly by symmetric polyarticular joint disorders. The pathologic processes are mediated by a number of cytokines, chemokines, cell adhesion molecules, and matrix metalloproteinases. The expression of most of these molecules is controlled at the transcriptional level. In addition, activation of NF-kappaB is involved in RA pathogenesis. This study was performed to explore the role of a novel serine/threonine kinase inhibitor, fasudil, in the control of the NF-kappaB activation pathway and to investigate the therapeutic effects of fasudil on arthritis development in a rat model of RA., Methods: Fibroblast-like synoviocytes (FLS) from RA patients and human endothelial cells (ECs) were established and maintained. To study the role of fasudil on cytokine expression, various cytokines expressed in the RA FLS and human ECs were measured by enzyme-linked immunosorbent assay following stimulation of the cells with interleukin-1beta (IL-1beta) in the presence of various concentrations of fasudil. The role of fasudil on NF-kappaB activation was studied using a reporter gene assay, Western blotting of IkappaBalpha, immunofluorescence analysis of the p65 subunit of NF-kappaB, and electrophoretic mobility shift assay. The in vivo effects of fasudil on arthritis were studied in a rat adjuvant-induced arthritis (AIA) model., Results: Fasudil inhibited cytokine expression in RA FLS and human ECs and also inhibited the activation of ECs, in a dose-dependent manner. Fasudil inhibited IL-1beta-induced activation of NF-kappaB independent of the inhibition of IkappaBalpha degradation and nuclear translocation of NF-kappaB, and inhibited IL-1beta-induced DNA binding of NF-kappaB. Finally, in vivo, fasudil ameliorated arthritis in rats with AIA, without any adverse effects., Conclusion: Serine/threonine kinase inhibitor fasudil inhibits the development of arthritis in a rat model of RA, and also inhibits the NF-kappaB signaling required for binding of NF-kappaB to specific DNA sequences through, for example, the phosphorylation of p65, suggesting that a specific target of fasudil might be a novel NF-kappaB kinase. Thus, fasudil serves as a novel strategy for the treatment of RA.