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ID PMID Title PublicationDate abstract
25603545 Rituximab for rheumatoid arthritis. 2015 Jan 20 BACKGROUND: Rituximab is a selective, B-cell depleting, biologic agent for treating refractory rheumatoid arthritis (RA). It is a chimeric monoclonal antibody targeted against CD 20 that is promoted as therapy for patients who fail to respond to other biologics. There is evidence to suggest that rituximab is effective and well tolerated when used in combination with methotrexate for RA. OBJECTIVES: To evaluate the benefits and harms of rituximab for the treatment of RA. SEARCH METHODS: We conducted a search (until January 2014) in electronic databases (The Cochrane Library, MEDLINE, EMBASE, CINAHL, Web of Science), clinical trials registries, and websites of regulatory agencies. Reference lists from comprehensive reviews were also screened. SELECTION CRITERIA: All controlled trials comparing treatment with rituximab as monotherapy or in combination with any disease modifying anti-rheumatic drug (DMARD) (traditional or biologic) versus placebo or other DMARD (traditional or biologic) in adult patients with active RA. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed the risk of bias and abstracted data from each study. MAIN RESULTS: We included eight studies with 2720 patients. For six studies selection bias could not be evaluated and two studies were considered to have low risk of bias. The level of evidence ranged from low to high, but was rated as moderate for most outcomes. We have prioritised reporting of rituximab (two 1000 mg doses) in combination with methotrexate since this is the approved dose and most commonly used combination. We also reported data on other combinations and doses as supplementary information in the results section of the review.American College of Rheumatology (ACR) 50 response rates were statistically significantly improved with rituximab (two 1000 mg doses) in combination with methotrexate compared with methotrexate alone at 24 to 104 weeks. The RR for achieving an ACR 50 at 24 weeks was 3.3 (95% CI 2.3 to 4.6); 29% of patients receiving rituximab (two 1000 mg doses) in combination with methotrexate achieved the ACR 50 compared to 9% of controls. The absolute treatment benefit (ATB) was 21% (95% CI 16% to 25%) with a number needed to treat (NNT) of 6 (95% CI 4 to 9).At 52 weeks, the RR for achieving clinical remission (Disease Activity Score (DAS) 28 joints < 2.6) with rituximab (two 1000 mg doses) in combination with methotrexate compared with methotrexate monotherapy was 2.4 (95% CI 1.7 to 3.5); 22% of patients receiving rituximab (two 1000 mg doses) in combination with methotrexate achieved clinical remission compared to 11% of controls. The ATB was 11% (95% CI 2% to 20%) with a NNT of 7 (95% CI 4 to 13).At 24 weeks, the RR for achieving a clinically meaningful improvement (CMI) in the Health Assessment Questionnaire (HAQ) (> 0.22) for patients receiving rituximab combined with methotrexate compared to patients on methotrexate alone was 1.6 (95% CI 1.2 to 2.1). The ATB was 24% (95% CI 12% to 36%) with an NNT of 5 (95% CI 3 to 13). At 104 weeks, the RR for achieving a CMI in HAQ (> 0.22) was 1.4 (95% CI 1.3 to 1.6). The ATB was 24% (95% CI 16% to 31%) with a NNT of 5 (95% CI 3 to 7).At 24 weeks, the RR for preventing radiographic progression in patients receiving rituximab (two 1000 mg doses) in combination with methotrexate was 1.2 (95% CI 1.0 to 1.4) compared to methotrexate alone; 70% of patients receiving rituximab (two 1000 mg doses) in combination with methotrexate had no radiographic progression compared to 59% of controls. The ATB was 11% (95% CI 2% to 19%) and the NNT was 10 (95% CI 5 to 57). Similar benefits were observed at 52 to 56 weeks and 104 weeks.Statistically significantly more patients achieved a CMI on the physical and mental components of the quality of life, measured by the Short Form (SF)-36, in the rituximab (two 1000 mg doses) in combination with methotrexate-treated group compared with methotrexate alone at 24 to 52 weeks (RR 2.0, 95% CI 1.1 to 3.4; NNT 4, 95% CI 3 to 8 and RR 1.4, 95% CI 1.1 to 1.9; NNT 8, 95% CI 5 to 19, respectively); 34 and 13 more patients out of 100 showed an improvement in the physical component of the quality of life measure compared to methotrexate alone (95% CI 5% to 84%; 95% CI 7% to 8%, respectively).There was no evidence of a statistically significant difference in the rates of withdrawals because of adverse events or for other reasons (that is, withdrawal of consent, violation, administrative, failure to return) in either group. However, statistically significantly more people receiving the control drug withdrew from the study compared to those receiving rituximab (two 1000 mg doses) in combination with methotrexate at all times (RR 0.40, 95% CI 0.32 to 0.50; RR 0.61, 95% CI 0.40 to 0.91; RR 0.48, 95% CI 0.28 to 0.82; RR 0.58, 95% CI 0.45 to 0.75, respectively). At 104 weeks, 37% withdrew from the control group and 20% withdrew from the rituximab (two 1000 mg doses) in combination with methotrexate group. The absolute risk difference (ARD) was -20% (95% CI -34% to -5%) with a number needed to harm (NNH) of 7 (95% CI 5 to 11).A greater proportion of patients receiving rituximab (two 1000 mg doses) in combination with methotrexate developed adverse events after their first infusion compared to those receiving methotrexate monotherapy and placebo infusions (RR 1.6, 95% CI 1.3 to 1.9); 26% of those taking rituximab plus methotrexate reported more events associated with their first infusion compared to 16% of those on the control regimen with an ARD of 9% (95% CI 5% to 13%) and a NNH of 11 (95% CI 21 to 8). However, no statistically significant differences were noted in the rates of serious adverse events. AUTHORS' CONCLUSIONS: Evidence from eight studies suggests that rituximab (two 1000 mg doses) in combination with methotrexate is significantly more efficacious than methotrexate alone for improving the symptoms of RA and preventing disease progression.
26928373 Methotrexate is not associated with increased liver cirrhosis in a population-based cohort 2016 Mar 1 A few studies showed that long-term methotrexate (MTX) use exacerbates liver fibrosis and even leads to liver cirrhosis in rheumatoid arthritis (RA) patients. We therefore conducted a population-based cohort study to investigate the impact of long-term MTX use on the risk of chronic hepatitis B (CHB)-related cirrhosis among RA patients. We analyzed data from the National Health Insurance Research Database in Taiwan and identified 631 incident cases of RA among CHB patients (358 MTX users and 273 MTX non-users) from January 1, 1998 to December 31, 2007. After a median follow-up of more than 6 years since the diagnosis of CHB, a total of 41 (6.5%) patients developed liver cirrhosis. We did not find an increased risk of liver cirrhosis among CHB patients with long-term MTX use for RA. Furthermore, there was no occurrence of liver cirrhosis among 56 MTX users with a cumulative dose ≧3 grams after 97 months' treatment. In conclusion, our data showed that long-term MTX use is not associated with an increased risk for liver cirrhosis among RA patients with CHB. However, interpretation of the results should be cautious due to potential bias in the cohort.
27494516 Intra-articular glucocorticoid injections should not be neglected in the remission targete 2016 Nov OBJECTIVES: To study the effects of neglecting intra-articular glucocorticoid injections (IAGCIs) into swollen joints in early rheumatoid arthritis (RA). METHODS: Ninety-nine patients with early, DMARD naive RA were treated, aiming at remission, with methotrexate, sulfasalazine, hydroxychloroquine, low-dose oral prednisolone and, when needed, IAGCIs for 2 years, and randomised to receive infliximab or placebo from weeks 4 to 26. During each of the 15 study visits, patients were scored retrospectively 0.2-0.4 points (depending on the number of non-injected joints) if IAGCIs to all swollen joints were not given. Patients were divided into tertiles by their cumulative scores for neglected injections (CSNI) over 24 months. 28-joint disease activity score (DAS28) area under the curve (AUC) between 0-24 months, remission rates, changes in quality of life, and radiological changes during the follow-up were assessed. Trends across tertiles of CSNI were tested with generalised linear models. RESULTS: Higher CSNI was associated with lower strict remission rates (p=0.005), and lower quality of life (p=0.004) at 24 months, and higher DAS28 AUC (p<0.001) during the follow-up. At 24 months, DAS28 remission rates were 90%, 93% and 76% (p=0.081), and strict remission rates were 74%, 77% and 39% by tertiles of CSNI. No significant differences were observed in radiological progression (p=0.089). IAGCIs were well tolerated. CONCLUSIONS: Neglecting IAGCIs into swollen joints is associated with lower remission rates, higher disease activity, and lower quality of life. Hence, IAGCIs should be used as an integral part of the targeted treatment of early RA.
25834204 Longterm efficacy and safety of abatacept in patients with rheumatoid arthritis treated in 2015 May OBJECTIVE: Our study aimed to evaluate the longterm efficacy and safety of abatacept (ABA), and to explore factors that increase its longterm efficacy in patients with rheumatoid arthritis (RA) treated in routine clinical practice. METHODS: There were 231 participants with RA treated with ABA who were prospectively registered in a Japanese multicenter registry. They were followed up for at least 52 weeks. RESULTS: Mean age of the patients was 64.3 years, mean disease duration was 12.1 years, mean 28-joint Disease Activity Score (DAS28)-C-reactive protein was 4.49, and 48.5% of patients were concomitantly treated with methotrexate (MTX). Overall retention rate of ABA was 77.1% at 52 weeks; 14.8% of patients discontinued because of inadequate response and 3.5% because of adverse events. The proportion of patients achieving DAS28-defined low disease activity (LDA) significantly increased from baseline to 52 weeks (7.3% to 43.8%, p < 0.01); 40.9% of patients who did not achieve LDA at 24 weeks had more than 1 categorical improvement in DAS28-defined disease activity at 52 weeks. Multivariate logistic regression revealed concomitant MTX use to be an independent predictor of the categorical improvement in DAS28-defined disease activity from 24 to 52 weeks (adjusted OR 3.124, p = 0.010). CONCLUSION: In routine clinical practice, ABA demonstrated satisfactory clinical efficacy and safety in patients with established RA for 52 weeks. The clinical efficacy of ABA increased with time even after 24 weeks, and this was strongly influenced by concomitant MTX use. Our study provides valuable real-world findings on the longterm management of RA with ABA.
25753581 The effectiveness of risk communication regarding drug safety information: a nationwide su 2015 Jun WHAT IS KNOWN AND OBJECTIVE: We evaluated the effectiveness of warning letters published by the pharmaceutical regulatory agency in Japan on communication of drug safety and risk by quantitative analysis of the national health insurance claims database (NHICD). We then explored what factors may have affected risk communication. METHODS: We measured the implementation rate of the hepatitis virus-monitoring test among methotrexate (MTX)-treated patients; a warning letter had been issued regarding the use of MTX, as it apparently activates the hepatitis virus. Data from the NHICD, which include 99·3% of Japanese residents, were used. A total of 4,933,481 patients with rheumatoid arthritis (RA) (January-June, 2010) were the focus of this study. RESULTS: The implementation rate of the hepatitis virus-monitoring test increased from 1·4% before to 1·8% after the warning letter announcement. Logistic regression analysis suggested that the installation of a drug information management room is one of the important factors affecting risk communication. Further analysis revealed that the hepatitis virus monitoring rates in hospitals without drug information management rooms increased from 2·3% to 4·1% due to the issue of the warning letter. WHAT IS NEW AND CONCLUSION: The warning letter from the regulatory agency plays an important role in risk communication in hospitals without drug information management rooms.
26020396 Abatacept improves whole-body insulin sensitivity in rheumatoid arthritis: an observationa 2015 May Rheumatoid arthritis (RA) is characterized by increased insulin resistance, a well-known risk factor for diabetes and cardiovascular diseases. The aim of the present study was to evaluate the effect of abatacept on insulin sensitivity in RA patients with moderate to severe disease despite treatment with methotrexate. Fifteen RA patients were recruited for the present study. Patients were evaluated at time 0 and after 6 months of the treatment with i.v. abatacept at the dosage recommended for weight range. Evaluation included oral glucose tolerance test (OGTT) at both time points. Insulin sensitivity was estimated with insulin sensitivity index (ISI) by Matsuda, a measure of whole-body insulin sensitivity. ISI significantly increased after the treatment with abatacept from 3.7 ± 2.6 to 5.0 ± 3.2 (P = 0.003) with a mean difference of 1.23. Analysis of glucose and insulin values during OGTT revealed a reduction of both glucose (303.9 ± 73.4 mg/dL min versus 269.2 ± 69.5 mg/dL min, P = 0.009) and insulin (208.4 ± 119.7 mg/dL min versus 158.0 ± 95.3 mg/dL min, P = 0.01) area under the curves (AUCs). Accordingly also glycated hemoglobin significantly improved (5.5 ± 0.4% versus 5.3 ± 0.3%, P = 0.04). No significant differences were found for measures of β-cell function insulinogenic index (1.11 ± 1.19 versus 1.32 ± 0.82, P = 0.77) and oral disposition index (2.0 ± 5.4 versus 6.0 ± 6.0, P = 0.25). Treatment with abatacept seems to be able to improve whole-body insulin sensitivity in RA patients without affecting β-cell function.
26063325 Comparison of two different folic acid doses with methotrexate--a randomized controlled tr 2015 Jun 11 INTRODUCTION: There is reasonable evidence that folic acid 5-10 mg per week leads to reduction in methotrexate (MTX) toxicity in rheumatoid arthritis (RA). However, this is based on studies conducted with lower MTX dosage than used currently. It is unclear whether higher doses of folic acid may be better in reducing toxicity. METHODS: This was a double-blind randomized controlled trial of 24 weeks duration. To be eligible, patients should have rheumatoid arthritis (1987 American College of Rheumatology criteria), be 18-75 years of age, not be on MTX and have active disease as defined by 'Modified Disease Activity Score using three variables' (DAS28(3)) > 3.2. MTX was started at 10 mg/week and escalated to 25 mg/week by 12 weeks. Folic acid was given at a dose of 10 mg (FA10) or 30 mg per week (FA30). Co-primary endpoints were incidence of toxicity (undesirable symptoms and laboratory abnormalities) and change in disease activity by 24 weeks. Intention-to-treat and per-protocol analyses were performed. RESULTS: Among 100 patients enrolled, 51 and 49 were randomized to FA10 and FA30 respectively. By 24 weeks, there were 6 patient withdrawals in either group and mean(±SD) dose of MTX was 22.8 ± 4.4 and 21.4 ± 4.6 mg per week (p = 0.1). Frequency of patients with undesirable symptoms was non-significantly lower by 7.4% (95% confidence interval -27.4 to 12.7%) in FA10 compared to FA30. There was also no difference in frequency of transaminitis (>Upper limit of normal (ULN)) (42.6, 45.7%, p = 0.7) or transminitis as per primary endpoint (>2xULN) (10.6, 8.7%, p = 1.0) or cytopenias (4.3, 4.3%, p = 0.9). There was no difference in the primary end-point of occurrence of any adverse effect (symptom or laboratory) in FA10 and FA30 (46.8, 54.3%, p = 0.5). At 24 weeks, DAS28(3) declined in both groups by a similar extent (-1.1 ± 1.0, -1.3 ± 1.0, p = 0.2) and 'European League Against Rheumatism' good or moderate response occurred in 56.9 and 67.4% (p = 0.3). CONCLUSIONS: Even with the high doses of MTX used in current practice, there was no additional benefit (or harm) of a higher dose of folic acid (30 mg/week) over a usual dose (10 mg/week). TRIAL REGISTRATION: Clinicaltrials.gov NCT01583959 Registered 15 March 2012.
27140438 Adalimumab, etanercept, infliximab, certolizumab pegol, golimumab, tocilizumab and abatace 2016 Apr OBJECTIVES: Rheumatoid arthritis (RA) is a chronic inflammatory disease associated with increasing disability, reduced quality of life and substantial costs (as a result of both intervention acquisition and hospitalisation). The objective was to assess the clinical effectiveness and cost-effectiveness of seven biologic disease-modifying antirheumatic drugs (bDMARDs) compared with each other and conventional disease-modifying antirheumatic drugs (cDMARDs). The decision problem was divided into those patients who were cDMARD naive and those who were cDMARD experienced; whether a patient had severe or moderate to severe disease; and whether or not an individual could tolerate methotrexate (MTX). DATA SOURCES: The following databases were searched: MEDLINE from 1948 to July 2013; EMBASE from 1980 to July 2013; Cochrane Database of Systematic Reviews from 1996 to May 2013; Cochrane Central Register of Controlled Trials from 1898 to May 2013; Health Technology Assessment Database from 1995 to May 2013; Database of Abstracts of Reviews of Effects from 1995 to May 2013; Cumulative Index to Nursing and Allied Health Literature from 1982 to April 2013; and TOXLINE from 1840 to July 2013. Studies were eligible for inclusion if they evaluated the impact of a bDMARD used within licensed indications on an outcome of interest compared against an appropriate comparator in one of the stated population subgroups within a randomised controlled trial (RCT). Outcomes of interest included American College of Rheumatology (ACR) scores and European League Against Rheumatism (EULAR) response. Interrogation of Early Rheumatoid Arthritis Study (ERAS) data was undertaken to assess the Health Assessment Questionnaire (HAQ) progression while on cDMARDs. METHODS: Network meta-analyses (NMAs) were undertaken for patients who were cDMARD naive and for those who were cDMARD experienced. These were undertaken separately for EULAR and ACR data. Sensitivity analyses were undertaken to explore the impact of including RCTs with a small proportion of bDMARD experienced patients and where MTX exposure was deemed insufficient. A mathematical model was constructed to simulate the experiences of hypothetical patients. The model was based on EULAR response as this is commonly used in clinical practice in England. Observational databases, published literature and NMA results were used to populate the model. The outcome measure was cost per quality-adjusted life-year (QALY) gained. RESULTS: Sixty RCTs met the review inclusion criteria for clinical effectiveness, 38 of these trials provided ACR and/or EULAR response data for the NMA. Fourteen additional trials contributed data to sensitivity analyses. There was uncertainty in the relative effectiveness of the interventions. It was not clear whether or not formal ranking of interventions would result in clinically meaningful differences. Results from the analysis of ERAS data indicated that historical assumptions regarding HAQ progression had been pessimistic. The typical incremental cost per QALY of bDMARDs compared with cDMARDs alone for those with severe RA is > £40,000. This increases for those who cannot tolerate MTX (£50,000) and is > £60,000 per QALY when bDMARDs were used prior to cDMARDs. Values for individuals with moderate to severe RA were higher than those with severe RA. Results produced using EULAR and ACR data were similar. The key parameter that affected the results is the assumed HAQ progression while on cDMARDs. When historic assumptions were used typical incremental cost per QALY values fell to £38,000 for those with severe disease who could tolerate MTX. CONCLUSIONS: bDMARDs appear to have cost per QALY values greater than the thresholds stated by the National Institute for Health and Care Excellence for interventions to be cost-effective. Future research priorities include: the evaluation of the long-term HAQ trajectory while on cDMARDs; the relationship between HAQ direct medical costs; and whether or not bDMARDs could be stopped once a patient has achieved a stated target (e.g. remission). STUDY REGISTRATION: This study is registered as PROSPERO CRD42012003386. FUNDING: The National Institute for Health Research Health Technology Assessment programme.
27197690 Tumour necrosis factor inhibition versus rituximab for patients with rheumatoid arthritis 2016 Jul 16 BACKGROUND: Tumour necrosis factor (TNF) inhibition and B-cell depletion are highly effective treatments for active rheumatoid arthritis, but so far no randomised controlled trials have directly compared their safety, efficacy, and cost-effectiveness. This study was done to test the hypothesis that using rituximab would be clinically non-inferior and cheaper compared with TNF inhibitor treatment in biological-treatment naive patients with rheumatoid arthritis. METHODS: This open-label, randomised controlled, non-inferiority trial enrolled patients with active, seropositive rheumatoid arthritis and an inadequate response to synthetic disease modifying anti-rheumatic drugs (DMARDs) from 35 rheumatology departments in the UK. Patients were randomly assigned 1:1 to the rituximab or TNF inhibitor groups with minimisation to account for methotrexate intolerance using a web-based randomisation system. Patients were given intravenous rituximab 1 g on days 1 and 15, and after 26 weeks if they responded to treatment but had persistent disease activity (28 joint count disease activity score [DAS28-ESR] >3.2; rituximab group) or a TNF inhibitor-adalimumab (40 mg subcutaneously every other week) or etanercept (50 mg per week subcutaneously) according to the patient's and rheumatologist's choice (TNF inhibitor group). Patients could switch treatment in the case of drug-related toxic effects or absence or loss of response. The primary outcome measure was the change in DAS28-ESR between 0 and 12 months in the per-protocol population of patients who were assigned to treatment and remained in follow-up to 1 year. We assessed safety in all patients who received at least one dose of study drug. We also assessed the cost-effectiveness of each strategy. The non-inferiority margin was specified as 0.6 DAS28-ESR units. This study is registered with ClinicalTrials.gov, number NCT01021735. FINDINGS: Between April 6, 2009, and Nov 11, 2013, 295 patients were randomly assigned and given either rituximab (n=144) or TNF inhibitor (n=151) treatment. After 12 months, the change in DAS28-ESR for patients assigned to rituximab was -2.6 (SD 1.4) and TNF inhibitor was -2.4 (SD 1.5), with a difference within the prespecified non-inferiority margin of -0.19 (95% CI -0.51 to 0.13; p=0.24). The health-related costs associated with the rituximab strategy were lower than the TNF inhibitor strategy (£9,405 vs £11,523 per patient, p<0.0001). 137 (95%) of 144 patients in the rituximab group and 143 (95%) of 151 patients in the TNF inhibitor group had adverse events. 37 serious adverse events occurred in patients receiving rituximab compared with 26 in patients receiving TNF inhibitors, of which 27 were deemed to be possibly, probably, or definitely related to the treatment (15 vs 12, p=0.5462). One patient in each group died during the study. INTERPRETATION: Initial treatment with rituximab is non-inferior to initial TNF inhibitor treatment in patients seropositive for rheumatoid arthritis and naive to treatment with biologicals, and is cost saving over 12 months. FUNDING: Arthritis Research UK, Roche.
27977768 Folic Acid Supplementation Is Suboptimal in a National Cohort of Older Veterans Receiving 2016 OBJECTIVES: Co-prescription of folic acid in patients receiving low dose oral methotrexate is recommended because it reduces adverse events and prolongs the use of methotrexate (MTX). However, little is known about how often new users of methotrexate are co-prescribed folic acid, and what factors are associated with its use. We aimed to determine the prevalence, predictors of, and persistence of folic acid use in a population-based cohort of MTX users with rheumatic diseases. METHODS: Using a national, administrative database of patients seen through the Veterans Health Administration (VHA) that included pharmacy and laboratory data, we performed an observational cohort study of veterans over 65 years old who were new users of MTX. We used log-binomial regression to identify independent predictors of folic acid use and Kaplan Meyer survival analysis to examine persistence of folic acid over time. RESULTS: We studied 2467 incident users of MTX. 27% of patients were not prescribed folic acid through the VHA pharmacy within 30 days of MTX initiation. Patients who did not see a rheumatologist were 23% less likely to receive folic acid compared to patients who did have a rheumatologist visit during the baseline period (RR (95% CI) 0.77 (0.72, 0.82). These results remained unchanged even after adjusting for demographic, clinical, and other factors (adjusted RR (95% CI) 0.78 (0.74, 0.85)). After 20 months, only 50% of patients continued to receive folic acid. CONCLUSIONS: In a nationwide VHA cohort of new users of oral MTX, many patients did not receive folic acid or discontinued it over time. Rheumatologists were more likely to prescribe folic acid than other providers. These data highlight the need to improve patient safety for users of methotrexate by standardizing workflows for folic acid supplementation.
25763999 Evaluation of humoral and cellular immune responses to a DNA vaccine encoding chicken type 2015 A major challenge in the development of effective therapies for rheumatoid arthritis (RA) is finding a method for the specific inhibition of the inflammatory disease processes without the induction of generalized immunosuppression. Of note, the development of therapeutic DNA vaccines and boosters that may restore immunological tolerance remains a high priority. pcDNA-CCOL2A1 is a therapeutic DNA vaccine encoding chicken type II collagen(CCII). This vaccine was developed by our laboratory and has been shown to exhibit efficacy comparable to that of the current "gold standard" treatment, methotrexate (MTX). Here, we used enzyme-linked immunosorbent assays with anti-CII IgG antibodies, quantified the expression levels of Th1, Th2, and Th3 cytokines, and performed flow cytometric analyses of different T-cell subsets, including Th1, Th2, Th17, Tc, Ts, Treg, and CD4(+)CD29(+)T cells to systemically evaluate humoral and cellular immune responses to pcDNA-CCOL2A1 vaccine in normal rats. Similar to our observations at maximum dosage of 3 mg/kg, vaccination of normal rats with 300 μg/kg pcDNA-CCOL2A1 vaccine did not induce the production of anti-CII IgG. Furthermore, no significant changes were observed in the expression levels of pro-inflammatory cytokines interleukin (IL)-1α, IL-5, IL-6, IL-12(IL-23p40), monocyte chemotactic protein (MCP)-1, macrophage inflammatory protein (MIP)-1α, regulated on activation in normal T-cell expressed and secreted (RANTES), receptor activator for nuclear factor-κB ligand (RANKL), and granulocyte colony-stimulating factor (G-CSF) or anti-inflammatory cytokines IL-4 and IL-10 in vaccinated normal rats relative to that in controls(P > 0.05). However, transforming growth factor (TGF)-β levels were significantly increased on days 10 and 14, while interferon (IFN)-γ and tumor necrosis factor (TNF)-α levels were significantly decreased on days 28 and 35 after vaccination(P < 0.05). Similarly, there were no significant differences in the percentages of Tc, Ts, Th1/Th2, and Th17 cells between the 2 groups(P > 0.05), with the exception of Treg cells, which were significantly reduced on days 14 and 21 after vaccination (P < 0.05), and CD4(+)CD29(+)T cells, which were significantly increased on days 7 and 14 after vaccination(P < 0.05).Taken together, these results suggested that pcDNA-CCOL2A1 vaccine did not markedly affect the balance of immune system components in vaccinated normal rats, indicating that this DNA vaccine may have clinical applications in the treatment of RA.
27057681 Preoperative Use of Methotrexate and the Risk of Early Postoperative Complications in Pati 2016 Aug BACKGROUND: Preoperative immunosuppressive use among patients with Crohn's disease or ulcerative colitis may lead to an increased risk of postoperative complications. There is limited information on the preoperative safety profile of methotrexate (MTX) in inflammatory bowel disease (IBD). METHODS: A retrospective study of patients who underwent abdominal surgery for IBD between 1993 and 2012 was performed and records abstracted, including preoperative use of MTX, azathioprine/6-mercaptopurine, antitumor necrosis factor, and corticosteroids. Early postoperative complications, including death, septic, and nonseptic complications were identified. A meta-analysis was also performed on the use of preoperative MTX in patients with IBD or rheumatoid arthritis. RESULTS: A total of 180 patients with IBD underwent abdominal surgery. A total of 15 patients received MTX either monotherapy or in combination therapy. Total early postoperative complications were identified in 71 (39%) patients, specifically 5 patients on oral MTX. A total of 51 cases (28%) of septic complications and 20 (11%) nonseptic. No significant association between the use of MTX and early postoperative complications was found. The odds ratio (OR) of complications versus no complications associated with MTX was 0.75 (95% CI, 0.25-2.29) and with azathioprine/6-mercaptopurine, OR 1.48 (95% CI, 0.77-2.84). The odds of a septic complication associated with MTX were 0.58 (95% CI, 0.09-3.73), and higher in azathioprine/6-mercaptopurine, OR 3.97 (95% CI, 1.03-15.3). Our meta-analysis also did not reveal an increased risk of postoperative complications in IBD or rheumatoid arthritis on preoperative MTX (OR 0.62, 95% CI, 0.34-1.15). CONCLUSIONS: Preoperative MTX use does not seem to be associated with early postoperative complications in IBD.
26474452 Efficacy and Safety of Subcutaneous Golimumab in Methotrexate-Naive Patients With Rheumato 2016 Jun OBJECTIVE: To evaluate the safety and efficacy of golimumab through 5 years in adults with active rheumatoid arthritis (RA) who had not previously received methotrexate (MTX). METHODS: In the GO-BEFORE study, 637 MTX-naive adult patients with active RA were randomized (1:1:1:1) to placebo + MTX (group 1), golimumab 100 mg + placebo (group 2), golimumab 50 mg + MTX (group 3), or golimumab 100 mg + MTX (group 4). Inadequate responders in groups 1, 2, and 3 entered early escape at week 28 to golimumab 50 mg + MTX, golimumab 100 mg + MTX, or golimumab 100 mg + MTX, respectively; remaining patients in group 1 could cross over to golimumab 50 mg + MTX at week 52. Assessments included the American College of Rheumatology 20%/50%/70% improvement criteria (ACR20/50/70) response, the Disease Activity Score in 28 joints (DAS28) using C-reactive protein (CRP) level, and the modified Sharp/van der Heijde score (SHS). Efficacy was analyzed using an intent-to-treat (ITT) analysis. Pharmacokinetics and immunogenicity were evaluated at selected visits. RESULTS: A total of 422 patients completed golimumab treatment through week 256. At week 256, 72.8%, 54.6%, and 38.0% of all patients in the full ITT population (n = 637) had an ACR20/50/70 response, respectively; 84.1% had a good or moderate DAS28-CRP response; and 72.7% had a clinically meaningful improvement in physical function. Radiographic progression was minimal in all treatment groups through week 256, and the overall mean change from baseline in SHS was 1.36. Serum trough golimumab concentrations were approximately dose proportional and maintained through week 256. Antibodies to golimumab occurred in 9.6% of patients through week 256. Infections were the most common type of adverse event (AE); 204 of 616 patients (33.1%) had ≥1 serious AE. CONCLUSION: Clinical efficacy with golimumab treatment was maintained through week 256 of the GO-BEFORE trial of MTX-naive RA patients. No unexpected AEs occurred; safety results through 5 years are consistent with earlier reports.
27704400 Certolizumab Pegol: A Review in Inflammatory Autoimmune Diseases. 2016 Dec Certolizumab pegol (Cimzia(®)) is a subcutaneously administered polyethylene glycolylated (PEGylated) antigen-binding fragment of a recombinant human monoclonal antibody that selectively neutralizes TNFα. The drug is indicated for a variety of inflammatory autoimmune diseases, including Crohn's disease (CD), rheumatoid arthritis (RA), psoriatic arthritis (PsA) and axial spondyloarthritis (axSpA), based on its benefit in these settings in well-designed clinical trials. In these studies, certolizumab pegol (as first- or subsequent-line therapy) reduced the severity of CD when used as an induction or maintenance therapy, and improved the signs/symptoms and slowed the radiographic progression of RA (with or without concomitant methotrexate), PsA and axSpA. Certolizumab pegol is generally well tolerated, with upper respiratory tract infections, rash and urinary tract infections being among the most frequent adverse reactions. Thus, certolizumab pegol is an effective option for the management of these autoimmune diseases.
25902789 Tofacitinib, an oral Janus kinase inhibitor: analysis of malignancies across the rheumatoi 2016 May OBJECTIVES: Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). To further assess the potential role of Janus kinase inhibition in the development of malignancies, we performed an integrated analysis of data from the tofacitinib RA clinical development programme. METHODS: Malignancy data (up to 10 April 2013) were pooled from six phase II, six Phase III and two long-term extension (LTE) studies involving tofacitinib. In the phase II and III studies, patients with moderate-to-severe RA were randomised to various tofacitinib doses as monotherapy or with background non-biological disease-modifying antirheumatic drugs (DMARDs), mainly methotrexate. The LTE studies (tofacitinib 5 or 10 mg twice daily) enrolled patients from qualifying prior phase I, II and III index studies. RESULTS: Of 5671 tofacitinib-treated patients, 107 developed malignancies (excluding non-melanoma skin cancer (NMSC)). The most common malignancy was lung cancer (n=24) followed by breast cancer (n=19), lymphoma (n=10) and gastric cancer (n=6). The rate of malignancies by 6-month intervals of tofacitinib exposure indicates rates remained stable over time. Standardised incidence ratios (comparison with Surveillance, Epidemiology and End Results) for all malignancies (excluding NMSC) and selected malignancies (lung, breast, lymphoma, NMSC) were within the expected range of patients with moderate-to-severe RA. CONCLUSIONS: The overall rates and types of malignancies observed in the tofacitinib clinical programme remained stable over time with increasing tofacitinib exposure.
27624791 A multicentre randomised controlled trial to compare the pharmacokinetics, efficacy and sa 2017 Mar OBJECTIVE: To demonstrate pharmacokinetic equivalence of CT-P10 and innovator rituximab (RTX) in patients with rheumatoid arthritis (RA) with inadequate responses or intolerances to antitumour necrosis factor agents. METHODS: In this randomised phase I trial, patients with active RA were randomly assigned (2:1) to receive 1000 mg CT-P10 or RTX at weeks 0 and 2 (alongside continued methotrexate therapy). Primary endpoints were area under the serum concentration-time curve from time zero to last quantifiable concentration (AUC(0-last)) and maximum serum concentration after second infusion (C(max)). Additional pharmacokinetic parameters, efficacy, pharmacodynamics, immunogenicity and safety were also assessed. Data are reported up to week 24. RESULTS: 103 patients were assigned to CT-P10 and 51 to RTX. The 90% CIs for the ratio of geometric means (CT-P10/RTX) for both primary endpoints were within the bioequivalence range of 80%-125% (AUC(0-last): 97.7% (90% CI 89.2% to 107.0%); C(max): 97.6% (90% CI 92.0% to 103.5%)). Pharmacodynamics and efficacy were comparable between groups. Antidrug antibodies were detected in 17.6% of patients in each group at week 24. CT-P10 and RTX displayed similar safety profiles. CONCLUSIONS: CT-P10 and RTX demonstrated equivalent pharmacokinetics and comparable efficacy, pharmacodynamics, immunogenicity and safety. TRIAL REGISTRATION NUMBER: NCT01534884.
25837853 Assessment of the Effect of Methotrexate Therapy on Bone Metabolism in Patients with Rheum 2015 Oct Proinflammatory cytokines and growth factors, which regulate mutual interactions between immune system cells and bone tissue cells, play a major role in the formation of bone changes in rheumatoid arthritis (RA). The aim of the work was to assess serum concentration of osteoprotegerin (OPG), RANKL, Dkk-1 and sclerostin in RA patients compared to a control group and to analyze changes of these concentrations during methotrexate (MTX) therapy. Patients enrolled in the study were 30 women of Caucasian origin aged 30-74 years with RA. Patients with active form of the disease were administered recommended doses of MTX for at least 6 months. The study group was divided into subgroup I-patients with improvement; and subgroup II-patients with no improvement. The control group consisted of 12 healthy women in the age of 41-73. Before MTX therapy, RA patients had higher levels of RANKL (644.97 ± 477.13 vs. 255.19 ± 130.26 pmol/l), lower values of OPG/RANKL (0.01 ± 0.0101 vs. 0.02 ± 0.0078) and higher levels of Dkk-1 protein (1821.32 ± 1060.28 vs. 548.52 ± 36.35 pg/ml) compared to the control group. In the analyzed group of patients (all patients receiving MTX regardless of responder non responder status) after 6 months of therapy, a statistically significant increase in the ratio of OPG/RANKL was found (0.0118 ± 0.0102 vs. 0.0141 ± 0.0118; p = 0.02). The index value of OPG/RANKL differed significantly depending on the resultant effect of treatment (0.01702 ± 0.01274 in the subgroup of improvement vs. 0.00675 ± 0.00289 in the subgroup without improvement). The difference in the mean concentrations of Dkk-1 before and after treatment with MTX between subgroups I and II was statistically significant (p = 0.002). In subgroup I, mean concentration of Dkk-1 decreased after 6 months of treatment with MTX (2054.72 ± 1004.74 vs. 1831.70 ± 851.70 pg/ml); while in subgroup II, the mean concentration of Dkk-1 increased (1214.48 ± 738.32 vs. 2275.01 ± 1385.23 pg/ml). There were no statistically significant changes in the mean concentrations of sclerostin before and after treatment with MTX (in whole group treatment with MTX, in subgroup I, and in subgroup II). The results confirm the presence of disorders of bone metabolism in patients with RA. Treatment with MTX affects the value of the ratio of OPG/RANKL and concentration of Dkk-1.
27311184 [DMARDs (Focusing on iguratimod)]. 2016 Jun Conventional synthetic disease modifying anti-rheumatic drugs (csDMARDs) other than methotrexate (MTX: anchor csDMARDs) are effective for single use, reinforcement of MTX, biologics and induction and maintenance of biologics-free condition. Newly developed iguratimod (IGU) does not suppress immunological reaction, therefore, it is useful for single use or combination with other csDMARDs in patients with complications. IGU can be used as a first csDMARDs before MTX use during the screening for MTX. IGU might be effective for reinforcement of MTX, biologics and induction and maintenance of biologics-free condition just like other csDMARDs. IGU can be used in wide variety of situation of the treatment of rheumatoid arthritis and it is desired that after the all-case surveillance condition for approval, IGU become a standard csDMARDs all over the world which was made in Japan.
26882094 Changes in Body Mass Related to the Initiation of Disease-Modifying Therapies in Rheumatoi 2016 Aug OBJECTIVE: Unintentional weight loss is important and can be predictive of long-term outcomes in patients with rheumatoid arthritis (RA). This study was undertaken to assess how primary therapies for RA may influence changes in body mass index (BMI) in RA patients from a large administrative database. METHODS: Unique dispensing episodes of methotrexate, prednisone, leflunomide, and tumor necrosis factor inhibitors (TNFi) administered to RA patients were identified from the US Department of Veterans Affairs pharmacy databases. Values for C-reactive protein (CRP) level and BMI closest to the time point within 30 days of the treatment course start date and at follow-up time points were linked. Missing laboratory values were imputed. Weight loss was defined as a decrease in BMI of >1 kg/m(2) . Regression models were used to evaluate changes in BMI during each drug treatment as compared to treatment with methotrexate. To assess the impact of confounding by indication, propensity scores for use of each drug were incorporated in analyses using matched-weighting techniques. RESULTS: In total, 52,662 treatment courses in 32,859 RA patients were identified. At 6 months from the date of prescription fill, weight gain was seen among patients taking methotrexate, those taking prednisone, and those taking TNFi. On average, compared to methotrexate-treated patients, prednisone-treated patients had significantly more weight gain, while leflunomide-treated patients demonstrated weight loss. In multivariable models, more weight loss (β = -0.41 kg/m(2) , 95% confidence interval [95% CI] -0.46, -0.36; P < 0.001) and a greater risk of weight loss (odds ratio 1.73, 95% CI 1.55, 1.79; P < 0.001) were evident among those receiving leflunomide compared to those receiving methotrexate. Treatment with prednisone was associated with greater weight gain (β = 0.072 kg/m(2) , 95% CI 0.042, 0.10; P < 0.001). These associations persisted in analyses adjusted for propensity scores and in sensitivity analyses. CONCLUSION: Leflunomide is associated with significantly more, but modest, weight loss, while prednisone is associated with greater weight gain compared to other therapies for RA.
24951881 Teaching methotrexate self-injection with a web-based video maintains patient care while r 2015 Jan The aim of the study was to compare standard nurse-led methotrexate self-injection patient education to a web-based methotrexate self-injection education video in conjunction with standard teaching on patient self-confidence for self-injection, as well as patient satisfaction, patient knowledge and teaching time. Consecutive rheumatology patients seen for methotrexate self-injection education were enrolled. Prior to education, patient self-confidence for self-injection, age, gender and education were recorded. Patients were randomized 1:1 to standard teaching or the intervention: a 12-min methotrexate self-injection education video followed by further in-person nurse education. Patients recorded their post-education confidence for self-injection, satisfaction with the teaching process and answered four specific questions testing knowledge on methotrexate self-injection. The time spent providing direct education to the patient was recorded. Twenty-nine patients participated in this study: 15 had standard (C) teaching and 14 were in the intervention group (I). Average age, gender and education level were similar in both groups. Both groups were satisfied with the quality of teaching. There was no difference in pre-confidence (C = 5.5/10 vs. I = 4.7/10, p = 0.44) or post-confidence (C = 8.8, I = 8.8, p = 0.93) between the groups. There was a trend toward improved patient knowledge in the video group versus the standard group (C = 4.7/6, I = 5.5/6, p = 0.15). Nurse teaching time was less in the video group (C = 60 min, I = 44 min, p = 0.012), with men requiring longer education time than women across all groups. An education video may be a good supplement to standard in-person nurse teaching for methotrexate self-injection. It equals the standard teaching practise with regard to patient satisfaction, confidence and knowledge while decreasing teaching time by 25 %.