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OBJECTIVE: To assess safety of baricitinib in Japanese patients with rheumatoid arthritis in real-world clinical practice. METHODS: This all-case post-marketing surveillance study included patients initiating baricitinib for rheumatoid arthritis from September 2017 to April 2019. Treatment duration was recorded. Safety data were collected for up to 3 years from baricitinib initiation (up to 4 weeks post discontinuation in discontinuing patients). RESULTS: Safety analyses included 4720 patients; 2580 (54.7%) were ≥65 years old. Baricitinib persistence rate was 45.4% (3 year Kaplan-Meier analysis); the most common discontinuation reason was insufficient effectiveness (n = 1005, 21.3%). Serious adverse events occurred in 600 patients (incidence rate 10.42/100 patient-years; 95% confidence interval, 9.76-11.09). There were 39 deaths (incidence rate 0.43 [0.30-0.57]/100 patient-years). Incidence rate per 100 patient-years for adverse events of special interest were herpes zoster 4.68 (4.22-5.14), serious infection 3.05 (2.68-3.41), malignancy 1.09 (0.87-1.30), major adverse cardiovascular events 0.35 (0.23-0.48) and venous thromboembolism 0.25 (0.15-0.36). Incidence rates did not increase with prolonged exposure. CONCLUSIONS: No new safety concerns were identified during this 3 year post-marketing surveillance study of baricitinib in Japanese patients with rheumatoid arthritis. Patients and clinicians should be cognizant of herpes zoster and other serious infection risks during baricitinib treatment, especially in the first 6 months.
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OBJECTIVES: To assess the safety and effectiveness of baricitinib treatment for rheumatoid arthritis (RA) in real-world clinical practice. METHODS: This ongoing all-case post-marketing surveillance study (starting September 2017) includes all patients with RA treated with baricitinib in Japan. Safety and effectiveness (disease activity) were assessed for 24 weeks. RESULTS: Safety analyses to February 2021 included 4731 patients (initial baricitinib dose: 4 mg/day, n = 3058; 2 mg/day, n = 1661; other, n = 12); 1059 (22.38%) were ≥75 years and 3362 (71.06%) previously received biologic therapy. The overall observational period was 1863.14 patient-years; 1174 (24.82%) patients discontinued baricitinib before Week 24, mostly for lack of effectiveness (n = 478; 10.10%). Adverse events occurred in 1271 (26.87%) patients [serious: 203 (4.29%); death: 18 (0.38%)]. The incidence of herpes zoster, hepatic function disorder, and serious infection was 3.09%, 2.77%, and 1.90%, respectively. Malignancy occurred in 17 patients (0.36%) and major adverse cardiovascular events in seven patients (0.15%). Among patients with effectiveness data, at least 26.57% (Boolean) achieved remission at Week 24. CONCLUSIONS: This large nationwide surveillance study evaluated the safety and effectiveness of 24 weeks of baricitinib for RA in real-world clinical practice. Continued surveillance of long-term safety is ongoing.
Subject(s)
Antirheumatic Agents , Arthritis, Rheumatoid , Humans , Antirheumatic Agents/adverse effects , Arthritis, Rheumatoid/drug therapy , East Asian People , Product Surveillance, Postmarketing , Treatment Outcome , AgedABSTRACT
There has been continuing discussion regarding the treatment strategy for acute type A intramural hematoma (IMH). Most patients are treated conservatively in Japan; hence, predicting fatal events and stratifying risks based on results normally obtained on hospital arrival are important. We aimed to examine the incidences and risk factors of death or need for surgery for acute type A IMH in patients receiving medical treatment and to identify high-risk patients using clinical findings on hospital arrival. From 2011 to 2016, 57 consecutive patients (mean age 72.5 years; male 36.8%) diagnosed with acute type A IMH who were receiving treatment at Shizuoka City Shizuoka Hospital were retrospectively included. Primary endpoint was a composite of cardiovascular death and operation within 1 year after onset. To evaluate sensitivity and specificity of the risk factors and risk score, we estimated the area under the receiver operating characteristic (ROC) curve. Mean follow-up duration was 621 days. Mean systolic blood pressure (SBP) was 129 mmHg. Computed tomography (CT) on arrival showed a mean ascending aorta diameter of 46 mm. Ulcer-like projection (ULP) in the ascending aorta and pericardial effusion (PE) were seen in 33% and 42% of cases, respectively. Twenty-eight patients (49.1%) reached the primary endpoint (cardiovascular death, 7 cases [12.3%]; operation, 21 cases [36.8%]). In univariate analysis of admission values, the primary endpoint group had significantly lower SBP (113.0 ± 28.5 vs 144.3 ± 33.5 mmHg), higher ascending aorta diameter (49.5 ± 8.1 vs 43.6 ± 5.9 mm), and higher frequency of ULP (53.8% vs 13.8%) and PE (58.6% vs 25.0%) than the event-free group. Multivariate analysis showed that ULP on admission CT was a significant predictor of the primary endpoint. The risk score was considered using these risk factors. On admission, the primary endpoint could be predicted with 89.7% sensitivity and 75% specificity (area under the ROC curve 0.823) if the patient had ULP and/or > 2 of the following factors: SBP < 120 mmHg, ascending aorta diameter > 45 mm, and PE. SBP and CT findings on arrival were significantly associated with cardiovascular death and the need for surgery in patients with acute type A IMH receiving initial medical therapy. The novel risk score was useful for predicting cardiovascular death and surgery.
Subject(s)
Aortic Diseases/therapy , Clinical Decision Rules , Conservative Treatment , Emergency Service, Hospital , Hematoma/therapy , Patient Admission , Vascular Surgical Procedures , Aged , Aged, 80 and over , Aortic Diseases/diagnostic imaging , Aortic Diseases/mortality , Clinical Decision-Making , Conservative Treatment/adverse effects , Conservative Treatment/mortality , Female , Hematoma/diagnostic imaging , Hematoma/mortality , Humans , Japan , Male , Middle Aged , Predictive Value of Tests , Retrospective Studies , Risk Assessment , Risk Factors , Treatment Outcome , Vascular Surgical Procedures/adverse effects , Vascular Surgical Procedures/mortalityABSTRACT
OBJECTIVE: To evaluate the longterm safety of tocilizumab (TCZ) for the treatment of rheumatoid arthritis (RA) in a real-world clinical setting in Japan. METHODS: In this longterm extension of a single-arm, observational postmarketing surveillance study, a total of 5573 patients who initiated intravenous TCZ between April 2008 and July 2009 were observed for 3 years, regardless of its continuation, for incidence of fatal events, serious infections, malignancy, gastrointestinal perforations, and serious cardiac dysfunction. RESULTS: Of the 5573 patients who were enrolled, 4527 patients (81.23%) completed 3 years of followup. There were no increases in the proportions of patients with fatal events, serious infection, malignancy, GI perforation, or serious cardiac dysfunction over 3 years. The all-cause mortality rate during followup was 2.58% (0.95/100 patient-yrs), and the standardized mortality ratio was 1.27 (95% CI, 1.08 to 1.50). Patients who were older with longer disease duration and respiratory comorbidities were more likely to discontinue TCZ treatment following serious infection during the first year. Among patients who completed 3 years of TCZ treatment, serious infection developed at a constant rate during the 3-year treatment period. The proportion of malignancy during followup was 2.24% (0.83/100 patient-yrs), and the standardized incidence ratio was 0.79 (95% CI, 0.66 to 0.95). CONCLUSION: The safety profile of TCZ was consistent over time regarding mortality, serious infections, malignancy, gastrointestinal perforation, and serious cardiac dysfunction. These data confirm the longterm safety of TCZ use in patients with RA in a real-world clinical setting.
Subject(s)
Antibodies, Monoclonal, Humanized/adverse effects , Antirheumatic Agents/adverse effects , Arthritis, Rheumatoid/drug therapy , Adolescent , Adult , Aged , Aged, 80 and over , Antibodies, Monoclonal, Humanized/therapeutic use , Antirheumatic Agents/therapeutic use , Female , Humans , Japan , Male , Middle Aged , Severity of Illness Index , Time Factors , Young AdultABSTRACT
To investigate changes in the risk for serious infections (SIs) over time in Japanese rheumatoid arthritis (RA) patients treated with tumor necrosis factor inhibitors (TNFIs). This prospective cohort study included Japanese RA patients who began treatment with a TNFI from 2005 to 2007 (2005 group, n = 716, 634.2 patient years [PY]) and from 2008 to 2011 (2008 group, n = 352, 270.1 PY) at the time or after their enrollment in the registry of Japanese RA patients on biologics for long-term safety (REAL) database. Patients were observed for 12 months or until discontinuation of their initial TNFI in the REAL database. Drug discontinuation reasons and retention rates were analyzed. Incidence rates of serious adverse events (SAEs) were calculated with 95 % confidence intervals (CIs). The Cox proportional hazard model was applied to estimate the risk for SIs. The retention rate in the 2008 group was significantly lower than the 2005 group (p < 0.001). Discontinuation rates due to lack of efficacy or good control for the 2008 group were significantly higher than the 2005 group (p < 0.001). The crude incidence rate ratios comparing the 2008 group with the 2005 group for SAEs were 0.93 (95 % CI 0.65-1.34) and for SIs were 0.50 (0.24-1.03). The 2008 group had significantly lower risk for SIs than the 2005 group after adjusting for covariates (hazard ratio: 0.43 [0.20-0.93]). These results indicate significant decrease of the risk for SIs with TNFI treatment over time; this may be explained by evidence-based risk management of RA patients given TNFIs.
Subject(s)
Antirheumatic Agents/adverse effects , Arthritis, Rheumatoid/drug therapy , Immunocompromised Host , Opportunistic Infections/chemically induced , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Adult , Aged , Arthritis, Rheumatoid/diagnosis , Arthritis, Rheumatoid/epidemiology , Arthritis, Rheumatoid/immunology , Female , Humans , Japan/epidemiology , Kaplan-Meier Estimate , Male , Middle Aged , Opportunistic Infections/diagnosis , Opportunistic Infections/epidemiology , Opportunistic Infections/immunology , Proportional Hazards Models , Prospective Studies , Registries , Risk Assessment , Risk Factors , Time Factors , Treatment Outcome , Tumor Necrosis Factor-alpha/immunologyABSTRACT
OBJECTIVE: To compare the incidence and risk factors of serious adverse events (SAEs) in rheumatoid arthritis (RA) patients treated with etanercept (ETN) or adalimumab (ADA) between Korean and Japanese registries. METHODS: We recruited 416 RA patients [505.2 patient-years (PYs)] who started ETN or ADA from Korean registry and 537 RA patients (762.0 PY) from Japanese registry. The patient background, incidence rate (IR) of SAE in 2 years, and risk factors for SAEs were compared. RESULTS: Korean patients were younger and used more nonbiologic DMARDs, higher doses of methotrexate, and lower doses of prednisolone (PSL). The IR of SAEs (/100 PY) was higher in the Japanese registry compared to the Korean [13.65 vs. 6.73]. In both registries, infection was the most frequently reported SAE. The only significant risk factor for SAEs in Korean registry was age by decade [1.45]. In Japanese registry, age by decade [1.54], previous use of nonbiologic DMARDs ≥ 4 [1.93], and concomitant use of oral PSL ≥ 5 mg/day [2.20] were identified as risk factors for SAEs. CONCLUSIONS: The IR of SAE in Japan, especially infection, was higher than that of Korea, which was attributed to the difference of demographic and clinical characteristics of RA patients and treatment profiles.
Subject(s)
Antibodies, Monoclonal, Humanized/adverse effects , Antirheumatic Agents/adverse effects , Arthritis, Rheumatoid/drug therapy , Drug-Related Side Effects and Adverse Reactions/epidemiology , Immunoglobulin G/adverse effects , Adalimumab , Age Factors , Antibodies, Monoclonal, Humanized/therapeutic use , Antirheumatic Agents/therapeutic use , Etanercept , Female , Humans , Immunoglobulin G/therapeutic use , Incidence , Japan/epidemiology , Male , Middle Aged , Receptors, Tumor Necrosis Factor/therapeutic use , Registries , Republic of Korea/epidemiology , Risk Factors , Treatment OutcomeABSTRACT
INTRODUCTION: Intravascular large B-cell lymphoma is a rare aggressive disseminated disease characterized by the presence of lymphoma cells in small vessels without lymphadenopathy. Rituximab, a novel monoclonal antibody against the CD20 B-cell antigen, has been reported to be effective in treating intravascular large B-cell lymphoma. However, adverse events have been reported in association with rituximab infusion. CASE PRESENTATION: We report the case of a 54-year-old Japanese man diagnosed with Asian variant intravascular large B-cell lymphoma who died within five hours of the initiation of a first course of chemotherapy including rituximab. Autopsy results suggested that the patient died of severe systemic inflammatory response syndrome. A literature review revealed that rituximab administered during the second course of chemotherapy (instead of during the first course) appears to reduce the incidence of infusion reactions (from 48% to 15%) without altering the frequency of complete remission outcomes. CONCLUSIONS: Our data indicate that the incidence of adverse reactions to rituximab can be markedly decreased if the tumor load is first reduced with an initial course of chemotherapy excluding rituximab. Future prospective studies of the timing of rituximab administration are warranted.
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OBJECTIVE: To compare reasons for discontinuation and drug retention rates per reason among anticytokine therapies, infliximab, etanercept and tocilizumab, and the risk of discontinuation of biological agents due to adverse events (AE) in patients with rheumatoid arthritis (RA). METHOD: This prospective cohort study included Japanese RA patients who started infliximab (n=412, 636.0 patient-years (PY)), etanercept (n=442, 765.3 PY), or tocilizumab (n=168, 206.5 PY) as the first biological therapy after their enrolment in the Registry of Japanese Rheumatoid Arthritis Patients for Long-term Safety (REAL) database. Drug retention rates were calculated using the Kaplan-Meier method. To compare risks of drug discontinuation due to AE for patients treated with these biological agents, the Cox proportional hazard model was applied. RESULTS: The authors found significant differences among the three therapeutic groups in demography, clinical status, comorbidities and usage of concomitant drugs. Development of AE was the most frequent reason for discontinuation of biological agents in the etanercept and tocilizumab groups, and the second most frequent reason in the infliximab group. Discontinuation due to good control was observed most frequently in the infliximab group. Compared with etanercept, the use of infliximab (HR 1.69; 95% CI 1.14 to 2.51) and tocilizumab (HR 1.98; 95% CI 1.04 to 3.76) was significantly associated with a higher risk of discontinuation of biological agents due to AE. CONCLUSIONS: Reasons for discontinuation are significantly different among biological agents. The use of infliximab and tocilizumab was significantly associated with treatment discontinuation due to AE compared with etanercept.
Subject(s)
Antibodies, Monoclonal, Humanized/adverse effects , Antirheumatic Agents/adverse effects , Arthritis, Rheumatoid/drug therapy , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Antibodies, Monoclonal/adverse effects , Etanercept , Female , Humans , Immunoglobulin G/adverse effects , Infliximab , Kaplan-Meier Estimate , Male , Middle Aged , Proportional Hazards Models , Prospective Studies , Receptors, Tumor Necrosis Factor , Registries , Risk Factors , Survival Rate , Withholding TreatmentABSTRACT
OBJECTIVE: To investigate associations between continuous treatments with tumor necrosis factor (TNF) antagonists and risk for developing serious infections (SIs) over 3 years in Japanese patients with rheumatoid arthritis (RA) enrolled in the Registry of Japanese RA Patients for Long-Term Safety (REAL) database. METHODS: We analyzed 727 RA patients who had started either infliximab or etanercept (the anti-TNF group; 1,480.1 patient-years [PY]) and 571 RA patients who had started conventional nonbiologic disease-modifying antirheumatic drugs (the unexposed group; 1,104.1 PY) at the time of enrollment in the REAL. We assessed the occurrence of SIs within a 3-year observation period, including the period after switching to other TNF antagonists, and all SIs, unlimited to the first one in each patient as reported in other studies, to evaluate the real safety of TNF antagonists in daily practice. RESULTS: The incidence rate of SIs per 100 PY was 5.54 (95% confidence interval [95% CI] 4.44-6.84) in the anti-TNF group and 2.72 (95% CI 1.87-3.83) in the unexposed group. Poisson regression analysis revealed that the relative risk (RR) of continuous use of TNF antagonists for SIs after adjusting for baseline and time-dependent covariates was significantly elevated both overall (1.97, 95% CI 1.25-3.19) and for the first year (2.40, 95% CI 1.20-5.03), but not for the second and third years combined (1.38, 95% CI 0.80-2.43). The adjusted RR for SIs of etanercept compared to infliximab was not significantly elevated. CONCLUSION: Continuous anti-TNF therapy was significantly associated with increased risks for developing SIs during, but not after, the first year.
Subject(s)
Antibodies, Monoclonal/adverse effects , Arthritis, Rheumatoid/drug therapy , Arthritis, Rheumatoid/epidemiology , Communicable Diseases/epidemiology , Immunoglobulin G/adverse effects , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Adult , Aged , Cohort Studies , Communicable Diseases/chemically induced , Etanercept , Female , Follow-Up Studies , Humans , Infliximab , Japan/epidemiology , Male , Middle Aged , Prospective Studies , Receptors, Tumor Necrosis Factor , Risk Factors , Severity of Illness Index , Time FactorsABSTRACT
OBJECTIVE: To compare tumor necrosis factor-α (TNF-α) inhibitors to nonbiological disease-modifying antirheumatic drugs (DMARD) for the risk of serious infection in Japanese patients with rheumatoid arthritis (RA). METHODS: Serious infections occurring within the first year of the observation period were examined using the records for patients recruited to the Registry of Japanese Rheumatoid Arthritis Patients for Longterm Safety (REAL), a hospital-based prospective cohort of patients with RA. The analysis included 1144 patients, 646 of whom were treated with either infliximab or etanercept [exposed group: 592.4 patient-years (PY)]. The remaining 498 patients received nonbiological DMARD with no biologics (unexposed group: 454.7 PY). RESULTS: In the unexposed group, the incidence rate for all serious adverse events (SAE) was 9.02/100 PY and for serious infections, 2.64/100 PY. In the exposed group, SAE occurred in 16.04/100 PY and serious infections in 6.42/100 PY. The crude incidence rate ratio comparing serious infections in the exposed group with the unexposed group was 2.43 (95% CI 1.27-4.65), a significant increase. A multivariate analysis revealed that the use of TNF inhibitors is a significant independent risk factor for serious infection (relative risk 2.37, 95% CI 1.11-5.05, p = 0.026). CONCLUSION: Our study has provided the first epidemiological data on Japanese patients with RA for the safety of TNF inhibitors compared to nonbiological DMARD for up to 1 year of treatment. Anti-TNF therapy was associated with a significantly increased risk for serious infections, compared to treatment with nonbiological DMARD.
Subject(s)
Antibodies, Monoclonal/adverse effects , Antibodies, Monoclonal/therapeutic use , Arthritis, Rheumatoid/drug therapy , Immunoglobulin G/adverse effects , Immunoglobulin G/therapeutic use , Infections/epidemiology , Receptors, Tumor Necrosis Factor/therapeutic use , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Aged , Antirheumatic Agents/adverse effects , Antirheumatic Agents/therapeutic use , Cohort Studies , Etanercept , Female , Gastrointestinal Diseases/chemically induced , Gastrointestinal Diseases/epidemiology , Humans , Incidence , Infections/chemically induced , Infliximab , Japan/epidemiology , Longitudinal Studies , Male , Middle Aged , Prospective Studies , Registries , Respiratory Tract Infections/chemically induced , Respiratory Tract Infections/epidemiology , Risk FactorsABSTRACT
We experienced a case with a falsely low value by a blood MMP-3 measuring reagent employing a recently structured new latex immunoturbidity. The case involved duplicate orders for one patient in a single day, and the blood collection amounts and measured values were approximately 6.0 mL and 206.6 ng/mL and approximately 1.0 mL and 107.5 ng/mL. The latter MMP-3 concentration was 48% of the former, showing a low tendency. Therefore, an experiment was conducted by adding serum to the blood collection tubes with or without a serum-separating agent of four different manufacturers (Terumo, Sekisui Medical, Nipro, and Becton Dickinson), and similar results as our experienced case were obtained with the Terumo tube with serum-separating agent, which had been used in this case. The amount of whole blood was obtained by conversion assuming a hematocrit value of 40%, and the addition ratio was calculated relative to the predetermined amount of the tube showing a falsely low value. Falsely low values were observed at < or = 56%, < or = 21%, < or = 20%, and , or = 33% for Terumo, Sekisui Medical, Nipro, and Becton Dickinson, with tubes containing a serum-separating agent, and at < or =10%, < or =8%, < or =19%, and < or =14% for Terumo, Sekisui Medical, Nipro, and Becton Dickinson, respectively, with plain tubes. Falsely low values were not observed with the 10-ml plain tube of Terumo and the 9-ml plain tube of Nipro (untreated tube). Based on these results, care should be taken if samples are below the predetermined amount of the blood collection tube to determine the serum MMP-3 by this method.
Subject(s)
Antigens , Immunoassay/instrumentation , Matrix Metalloproteinase 3/blood , Nephelometry and Turbidimetry/instrumentation , Aged , Female , HumansSubject(s)
Antirheumatic Agents/administration & dosage , Arthritis, Rheumatoid/drug therapy , Bacterial Infections/epidemiology , Methotrexate/administration & dosage , Opportunistic Infections/epidemiology , Adult , Aged , Antirheumatic Agents/adverse effects , Databases, Factual , Female , Humans , Japan , Male , Methotrexate/adverse effects , Middle Aged , Risk AssessmentABSTRACT
INTRODUCTION: Accumulation of B cells in the rheumatoid arthritis (RA) synovium has been reported, and it has been thought that these cells might contribute to the pathogenesis of RA by antigen presentation, autoantibody production, and/or inflammatory cytokine production. Chemokines could enhance the accumulation of B cells in the synovium. The aims of this study were to determine chemokine receptor expression by B cells both in the peripheral blood of normal donors and subjects with RA, and at the inflammatory site in RA, and the effects of chemokines on B cell activation. METHODS: Cell surface molecule expression was analyzed by flow cytometry. Cellular migration was assessed using chemotaxis chambers. Cellular proliferation was examined by 3H-thymidine incorporation. Tumor necrosis factor (TNF) production was assayed by enzyme-linked immunosorbent assay. RESULTS: Significant numbers of peripheral blood B cells of healthy donors and subjects with RA expressed CC chemokine receptor (CCR)5 and CXCR3, and most B cells expressed CCR6, CCR7, CXCR4 and CXCR5. CCR5 expression was more frequent on CD27+ than CD27- peripheral blood B cells of healthy donors and RA. Synovial B cells more frequently expressed CCR5, but less often expressed CCR6, CCR7 and CXCR5 compared to peripheral blood in RA. Further functional analyses were performed on peripheral blood B cells from healthy donors. Migration of peripheral blood B cells, especially CD27+ B cells, was enhanced by CC chemokine ligand (CCL)20, CCL19, CCL21 and CXCL12. All four chemokines alone induced B cell proliferation; with CCL21 being the most effective. CCL21 also enhanced the proliferation of anti-immunoglobulin (Ig)M-stimulated B cells and blockade of CCR7 inhibited this effect. CCL20, CCL21 and CXCL12 enhanced TNF production by anti-IgM mAb-stimulated B cells. Finally, stimulation with CXCL12, but not CCL20, CCL19 and CCL21, enhanced inducible costimulator-ligand (ICOSL) expression by peripheral blood B cells of healthy donors and RA, but did not increase B cell-activating factor receptor or transmembrane activator and CAML-interactor. CONCLUSIONS: The data suggest that CCR5, CCR6, CCR7, CXCR3, CXCR4 and CXCR5 may be important for the B cell migration into the synovium of RA patients, and also their local proliferation, cytokine production and ICOSL expression in the synovium.
Subject(s)
Arthritis, Rheumatoid/immunology , B-Lymphocytes/metabolism , Lymphocyte Activation/immunology , Receptors, Chemokine/biosynthesis , Antigens, CD/biosynthesis , Arthritis, Rheumatoid/metabolism , B-Cell Activation Factor Receptor/biosynthesis , B-Lymphocytes/immunology , Cell Proliferation , Chemotaxis, Leukocyte/immunology , Enzyme-Linked Immunosorbent Assay , Flow Cytometry , Humans , Inducible T-Cell Co-Stimulator Ligand , Receptors, Chemokine/immunology , Transmembrane Activator and CAML Interactor Protein/biosynthesis , Tumor Necrosis Factor-alpha/biosynthesisABSTRACT
We previously reported that during total knee arthroplasty in rheumatoid arthritis (RA) patients, the use of tourniquet might promote local release of neutrophil elastase (NE) from neutrophils, which may contribute to the development of pulmonary thromboembolism (PTE) and tissue injury. The aim of this study was to develop PTE by the use of NE in a mouse model of collagen-induced arthritis (CIA) and investigate the relationship between thrombus and endothelial cells as well as the effect of recombinant human soluble thrombomodulin (rhs-TM) in reducing the risk of PTE. Male DBA/1J mice were injected intracutaneously at several sites with an emulsion containing bovine collagen and later a booster shot to produce CIA mice. Subsequently, NE was injected intravenously 2 times a day for 3 days and after a further 4 days, mice were sacrificed. A group of mice received rhs-TM injections prior to NE injections. We divided the mice into four groups of normal, CIA control, CIA + NE, and CIA + rhs-TM + NE mice and evaluated thrombus formation status. All CIA + NE mice developed PTE. In contrast, no thrombosis was found in normal control, CIA control and CIA + rhs-TM + NE mice. Plasma thrombin level, fibrinogen expression and neutrophil count were increased in CIA + NE mice. Double staining for anticoagulant TM and procoagulant von Willebrand factor (vWF) in pulmonary endothelial cells in normal mice showed a TM-dominant expression while in both CIA control and CIA + NE mice a vWF-dominant expression compatible with coagulant status was observed. Injection of rhs-TM into CIA + NE mice resulted in a phenotypic conversion of endothelial cells from vWF-dominant to TM-dominant expression and a reduction in fibrinogen deposition. These findings demonstrate that by repeated use of NE in CIA mice, it is feasible to produce PTE and to study its pathogenesis and that rhs-TM reduces the risk of PTE. We suggest that in surgical operations of upper and lower extremities in RA patients, the use of a tourniquet should be avoided as it may trigger NE release.
Subject(s)
Arthritis, Experimental/enzymology , Leukocyte Elastase/metabolism , Pulmonary Embolism/prevention & control , Recombinant Proteins/therapeutic use , Thrombomodulin/therapeutic use , Animals , Arthritis, Experimental/surgery , Cattle , Endothelial Cells/metabolism , Endothelial Cells/pathology , Humans , Injections, Intravenous , Leukocyte Elastase/toxicity , Lung/metabolism , Lung/pathology , Male , Mice , Mice, Inbred DBA , Pulmonary Embolism/enzymology , Pulmonary Embolism/etiology , Recombinant Proteins/administration & dosage , Thrombomodulin/administration & dosage , Tourniquets/adverse effects , von Willebrand Factor/metabolismABSTRACT
Postoperative results and complications of total elbow arthroplasty (TEA) conducted for rheumatoid arthritis (RA) patients at our institute were studied. Primary TEAs were performed in 72 patients. The mean follow-up period was 3.5 years. Three types of prostheses were implanted: JACE prosthesis in 34 elbows, STABLE prosthesis in 13 elbows, and KUDO prosthesis (type 5) in 32 elbows. The outcome was evaluated by the change in the range of motion and the Japanese Orthopaedic Association functional evaluation score for the elbow joint (JOA score). The arc of motion and the JOA score at discharge and at final examination significantly improved in patients with the three types of prosthesis. The loosening rates for the JACE, STABLE and KUDO prostheses were 15, 23, and 0%, respectively, although the follow-up periods were different. The loosening rate decreased to 2.5% when the humeral component was fixed with cement. Intraoperative fractures occurred in eight (10.1%) elbows and ulnar nerve palsy in six. Deep infection developed in three (4.8%) elbows and was treated by removing the prosthesis. Although there were considerable complications, the marked improvements in pain and function favor TEA in patients with rheumatoid elbow.
Subject(s)
Arthroplasty, Replacement/instrumentation , Arthroplasty, Replacement/rehabilitation , Elbow Joint/surgery , Joint Prosthesis/adverse effects , Activities of Daily Living , Adult , Aged , Arthritis, Rheumatoid/surgery , Arthroplasty, Replacement/adverse effects , Cohort Studies , Equipment Design , Female , Follow-Up Studies , Humans , Male , Middle Aged , Prospective Studies , Range of Motion, Articular , Recovery of FunctionABSTRACT
TNF-like weak inducer of apoptosis (TWEAK) is a type II membrane protein belonging to the TNF family that regulates apoptotic cell death, cellular proliferation, angiogenesis, and inflammation. However, the role of TWEAK in the pathogenesis of rheumatoid arthritis (RA) remains unclear. In this study, we have investigated the effect of neutralizing anti-TWEAK mAb on the development of collagen-induced arthritis (CIA), a well-established murine model of RA. Administration of anti-TWEAK mAb significantly ameliorated paw swelling, synovial hyperplasia, and infiltration of inflammatory cells. The levels of proinflammatory chemokines such as MCP-1 and MIP-2 in serum and knee joints were reduced by this treatment. Consistently, recombinant TWEAK enhanced the proliferation of MCP-1 and MIP-2 production by synovial cells from CIA mice in vitro. Histological examination also revealed that the treatment with anti-TWEAK mAb suppressed the development of small vessels in synovial tissues. These results indicated anti-inflammatory and antiangiogenic effects of the TWEAK blockade in CIA, which may be also beneficial for the treatment of RA.
Subject(s)
Apoptosis , Arthritis, Experimental/etiology , Tumor Necrosis Factors/metabolism , Animals , Antibodies, Monoclonal/pharmacology , Arthritis, Experimental/metabolism , Arthritis, Experimental/pathology , Cell Proliferation/drug effects , Chemokine CCL2/analysis , Chemokine CCL2/blood , Chemokine CXCL2 , Chemokines/analysis , Chemokines/blood , Collagen/toxicity , Cytokine TWEAK , Knee Joint/chemistry , Knee Joint/pathology , Male , Mice , Mice, Inbred DBA , Neovascularization, Physiologic/drug effects , Synovial Membrane/pathology , Tumor Necrosis Factor Inhibitors , Tumor Necrosis Factors/pharmacologyABSTRACT
Rheumatoid arthritis (RA) is a common autoimmune disease characterized by persistent inflammation of joints resulting in progressive destruction of cartilage and bone. Recently, biological agents that suppress the activities of proinflammatory cytokines have shown efficacy as antirheumatic drugs, but require frequent administration, and often result in systemic immune suppression. Thus, gene transfer approaches are being developed as an alternative approach for targeted, more efficient, and sustained delivery of inhibitors of inflammatory cytokines as well as other therapeutic agents. Several gene therapy approaches have been established in preclinical animal models. In these models, autoantigen-specific T cells have been demonstrated to be ideal gene delivery vehicles for the local delivery of "immunoregulatory molecules" because these cells have tissue-specific homing and retention properties. Indeed, bioluminescence studies in an animal model of inflammatory arthritis revealed that these cells accumulated in and remained in inflamed joints. Transfer of genetically modified dendritic cells (DCs) may also have interesting effects. We conclude that modifying antigen-specific T cells or autologous DCs by retroviral transduction for local expression of regulatory proteins is a promising therapeutic strategy for the treatment of RA.
Subject(s)
Arthritis, Rheumatoid/therapy , Gene Transfer Techniques , Genetic Therapy/methods , T-Lymphocytes/immunology , Adoptive Transfer , Animals , Autoantigens , Cell Transplantation , Genetic Vectors , HumansABSTRACT
Receptor activator of NF-kappaB (RANK) and its ligand (RANKL) are pivotal regulators of osteoclast differentiation. RANK and RANKL also mediate T cell/dendritic cell (DC) interaction. Previous study has shown that RANK/RANKL interaction induces prolonged DC survival and antigen presentation. In the present study, we have newly established a hybridoma which produces neutralizing anti-RANKL monoclonal antibody (IK22-5). By treating collagen-induced arthritis (CIA) mice with IK22-5, we have investigated the role of RANKL in the pathogenesis of CIA. Although IK22-5 had no effect on immune responses or inflammation, it ameliorated bone loss at the site of inflammation. Histological analyses revealed that osteoclast formation was impaired at the site of joint inflammation in IK22-5-treated CIA mice. These results suggest the utility of anti-RANKL mAb for the prevention of osteoporosis associated with joint inflammation in RA.
Subject(s)
Antibodies, Monoclonal/administration & dosage , Arthritis/immunology , Arthritis/prevention & control , Bone Resorption/immunology , Bone Resorption/prevention & control , Carrier Proteins/immunology , Membrane Glycoproteins/immunology , Animals , Antibodies, Monoclonal/immunology , Arthritis/chemically induced , Arthritis/pathology , Bone Resorption/chemically induced , Bone Resorption/pathology , Collagen , Male , Mice , Mice, Inbred DBA , RANK Ligand , Receptor Activator of Nuclear Factor-kappa B , Treatment OutcomeABSTRACT
The tumor necrosis factor (TNF) antagonist etanercept is an antirheumatic agent which was approved by Japanese regulatory authorities in January 2005. In Japan, the cost-effectiveness of this therapy for patients with rheumatoid arthritis (RA) has not previously been evaluated. This study models the cost-utility of etanercept in comparison with standard therapy with disease-modifying antirheumatic drugs (DMARDs) among adult Japanese RA patients who have failed a previous course of the DMARD bucillamine. A Markov model with 6-month cycles was constructed to compare two therapeutic strategies: etanercept versus standard therapy. For each cycle, one of three options was possible: a patient could (i) remain on current therapy if American College of Rheumatology criteria for 20% clinical improvement (ACR20) were achieved, (ii) switch to another drug in the therapeutic pathway if ACR20 was not achieved or if side effects severe enough to cause treatment discontinuation occurred, or (iii) they could die. The therapeutic pathway for the etanercept strategy was etanercept, methotrexate (MTX), sulfasalazine (SSZ), combination therapy (MTX + SSZ) and, finally, no DMARD. The pathway for standard therapy was identical except the initial therapy was MTX (etanercept was excluded). Results from clinical trials in U.S. and European patient populations were used to derive model probabilities for disease progression, response to drug therapy, and relationships between ACR20 response and functional improvement as measured by the Health Assessment Questionnaire (HAQ) disability index. An equation was developed to predict utility from HAQ scores of Japanese patients. Costs for drugs and medical services in Japan were obtained for April 2003. Analysis was conducted from a societal perspective, including lost productivity costs due to RA disability and premature mortality. Costs were discounted at 6% annually, and quality-adjusted life years (QALYs) at 1.5% annually. Model parameters were varied by 20% above and below base-case values in sensitivity analyses. Compared to standard therapy, the etanercept strategy was yen6.39 million more costly per patient but yielded an additional 2.56 QALYs. The incremental cost-utility ratio was yen 2.50 million/QALY. Sensitivity analyses revealed that cost-utility was most strongly influenced by the acquisition cost of etanercept and the percentage of etanercept recipients who achieved ACR20. Using commonly applied thresholds for acceptable cost-effectiveness in the United States ($50 000 = yen 5.5 million/QALY) and the United Kingdom (pound 30 000 = yen 5.7 million/QALY), etanercept therapy in Japan can be considered cost-effective. Cost-utility ratios did not exceed these thresholds in any sensitivity analysis. Further analyses should be conducted once clinical and epidemiologic data for Japanese patients become available.