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ID PMID Title PublicationDate abstract
23179005 Leflunomide in dialysis patients with rheumatoid arthritis--a pharmacokinetic study. 2013 Feb Pharmacokinetic data of disease modifying antirheumatic drugs during hemodialysis are limited to sulfasalazine, methotrexate, and cyclosporine. Only respective anecdotal data have been reported on leflunomide. We repeatedly measured teriflunomide (A77-1726), the active metabolite of leflunomide, during standard hemodialysis sessions and calculated teriflunomide clearances in five patients with rheumatoid arthritis (RA) and end-stage renal disease. The calculated teriflunomide clearances during a standardized dialysis session of 3-4.5 h at a blood flow rate of 160-300 ml/min were between 0 and 4.3 ml/min, the mean clearances of the total dialysis ranged between 1.1 and 3.4 ml/min. Total amount of teriflunomide removed was 5.8-8.8 μg per dialysis session. Dialytic removal of the active metabolite of leflunomide, teriflunomide (A77-1726), is negligible. Leflunomide can be used for RA patients on chronic dialysis without any dosage modification.
23161899 Oral administration of GLPG0259, an inhibitor of MAPKAPK5, a new target for the treatment 2013 May BACKGROUND: Mitogen-activated protein (MAP) kinases are key regulators of cytokine production, and are therefore potential targets for treatment of rheumatoid arthritis (RA). OBJECTIVE: This two-part phase II study investigated the efficacy and safety of a once-daily 50 mg GLPG0259 (an inhibitor of MAP kinase-activated protein kinase 5) dose vs placebo (part A). An interim analysis after part A would determine whether the dose-finding part (part B) would be performed. METHODS: In part A, eligible methotrexate (MTX)-refractory patients with RA were randomised to receive either a once-daily 50 mg dose of GLPG0259 or placebo, in addition to a stable dose of MTX, for 12 weeks. The primary efficacy end point was the percentage of patients achieving an American College of Rheumatology 20% improvement (ACR20) response after 12 weeks. RESULTS: The interim analysis showed no difference between the percentage of subjects achieving the primary efficacy variable of ACR20 or the secondary efficacy variables (ACR50, ACR70 and Disease Activity Score 28) at week 12 in the GLPG0259-treated (n=19) and placebo-treated (n=11) groups. Owing to lack of efficacy, the study was terminated, and part B was not initiated. CONCLUSIONS: This innovative study design quickly provided conclusive results on the lack of efficacy of GLPG0259 in patients with RA.
25112460 Therapeutic options after treatment failure in rheumatoid arthritis or spondyloarthritides 2014 Aug The prognosis for patients with rheumatoid arthritis or spondyloarthritides has improved dramatically due to earlier diagnosis, recognition of the need to treat early with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), alone or in combinations, the establishment of treatment targets, and the development of biological DMARDs (bDMARDs). Many patients are now able to achieve clinical remission or low disease activity with therapy, and reduce or eliminate systemic corticosteroid use. Guidelines recommend methotrexate as a first-line agent for the initial treatment of rheumatoid arthritis; however, a majority of patients will require a change of csDMARD or step up to combination therapy with the addition of another csDMARD or a bDMARD. However, treatment failure is common and switching to a different therapy may be required. The large number of available treatment options, combined with a lack of comparative data, makes the choice of a new therapy complex and often not evidence based. We summarize and discuss evidence to inform treatment decisions in patients who require a change in therapy, including baseline factors that may predict response to therapy.
24441151 The effect of tocilizumab on bone mineral density in patients with methotrexate-resistant 2014 May OBJECTIVE: The aim of this study was to analyse the effects of therapy with tocilizumab (TCZ), an anti-IL-6 receptor antibody, on BMD of the lumbar spine and femoral neck in patients with RA. METHODS: Eighty-six patients with active RA (indicated by a 28-joint DAS ESR >3.2) despite treatment with MTX 12 mg/week were included in this open-label prospective study and started on TCZ (8 mg/kg every 4 weeks). All patients used a stable dosage of MTX and were not allowed to use steroids or bisphosphonates during the study period. BMD of the lumbar spine and femoral neck was measured by dual-energy X-ray absorptiometry at baseline and 52 weeks after initiating TCZ. RESULTS: Seventy-eight patients completed this study. BMD of the lumbar spine and femoral neck remained stable after 1 year of TCZ treatment. In 33 patients who had osteopenia at baseline, there was a significant increase in BMD of the lumbar spine [mean 0.022 (s.d.) 0.042, P < 0.05] and femoral neck [0.024 (0.0245), P < 0.05]. CONCLUSION: TCZ affects BMD in patients who had active RA despite treatment with MTX. BMD of the lumbar spine and femoral neck in patients with normal BMD at baseline was stable. TCZ increased the BMD of patients who had osteopenia at baseline.
25050521 Effect of etanercept, infliximab and methotrexate in the treatment of arthritis. 2015 Feb BACKGROUND: Rheumatoid arthritis a chronic inflammatory autoimmune disease with inflammation of the joint, leading to damage of bone and surrounding cartilage. OBJECTIVES: Our study was designed to find the efficacy of etanercept, infliximab and methotrexate in effective therapeutic management against arthritis patients. METHODS: A total of 315 patients, including both the sexes in the age group of 45-70 years with active rheumatoid arthritis attending Hospital of Academy of Military Medical Sciences, Beijing, China during the period of December 2012 to November 2013 were included in the study. 100 patients with joint pains, but not with rheumatoid arthritis were taken as a control group. All the patients were treated with infliximab, methotrexate and etanercept. RESULTS: In our study, patients responded, 75% to infliximab and etanercept combinations than to methotrexate. The combination therapy also showed a radiological decrease in the joint damage. There is significant when combinations of these drugs were used for the therapy (P<0.001). CONCLUSION: In our study, use of infliximab and etanercept combinations lowered the joint damage and helped in the improvement of the patient's life.
24758075 [Treatment of rheumatoid arthritis by Yangxue Tongluo Recipe combined with immunosuppressi 2014 Mar OBJECTIVE: To observe the therapeutic effect of Yangxue Tongluo Recipe (YTR) combined with immunosuppressive agents in the treatment of rheumatoid arthritis (RA). METHODS: Totally 88 RA patients were randomly assigned to the treatment group [47 cases, YTR combined Methotrexate (MTX) + Leflunomide (LEF) treatment] and the control group (41 cases, MTX + LEF therapy). All patients received 12-week treatment. Clinical symptoms and signs, laboratory tests [erythrocyte sedimentation rate (ESR), rheumatoid factor (RF), and C reactive protein (CRP)], and adverse reactions were observed before and after treatment. RESULTS: The total effective rate was 91.5% (43/47 cases) in the treatment group, and the total effective rate was 75.6% (31/41 cases) in the control group. There was statistical difference between the two groups (P < 0.05). The morning stiffness, the rest pain, the number of tender joints, the number of swollen joints, tender joint index, swollen joint index, ESR, RF, and CRP were significantly improved in the two groups after treatment (P < 0.01). Besides, clinical symptoms and signs, ESR, RF, and CRP were more improved in the treatment group after treatment, when compared with those in the control group (P < 0.05). Gastrointestinal discomfort was the main adverse reaction in the two groups, but the occurrence was lower in the treatment group than in the control group (P > 0.05). CONCLUSIONS: The clinical efficacy of YTR combined MTX + LEF in the treatment of RA was better than using Western medicine alone. It was more safe with less adverse reactions.
24375965 Generalization and extrapolation of treatment effects from clinical studies in rheumatoid 2014 Jul OBJECTIVE: Pragmatic clinical trials have been proposed as a solution for nongeneralizability of randomized clinical trial (RCT) results. We investigated whether treatment effects of pragmatic clinical trials are indeed generalizable to clinical practice and how efficacy estimates from published RCTs can be translated to daily practice populations. METHODS: Data from pragmatic clinical trials of the Utrecht Rheumatoid Arthritis Cohort and the observational Nijmegen Early Rheumatoid Arthritis inception cohort were used. The treatment effects of methotrexate and hydroxychloroquine as opposed to the pyramid approach were compared between the trials and observational study using a modified comprehensive cohort design analysis. The changes from baseline in disease activity (Disease Activity Score in 28 joints [DAS28]) and functional disability (Health Assessment Questionnaire [HAQ]) and European League Against Rheumatism (EULAR) response at 6 months were studied. The influence of population and treatment characteristics on the American College of Rheumatology 50% improvement criteria response compared with control therapy also at 6 months from RCTs was assessed using the relative risk (RR) and risk difference (RD). RESULTS: The DAS28 and HAQ generally improved more in patients in the pragmatic trials than in daily practice. However, using EULAR response as outcome, the treatment effect was not found to be different. In published RCT data, higher glucocorticoid use, disease duration, and cotreatment with disease-modifying antirheumatic drugs increased the RR. Use of glucocorticoids increased the RD, and higher values of baseline DAS28 and HAQ decreased the RR and RD. CONCLUSION: Pragmatic clinical trials might be directly generalizable only regarding relative treatment response. In extrapolating published RCT results to daily practice, population characteristics associated with disease severity, disease duration, and treatment history or cotreatment need to be taken into account.
25243145 Modifications in lipid levels are independent of serum TNF-α in rheumatoid arthritis: res 2014 OBJECTIVE: To compare the modifications in lipids between patients with rheumatoid arthritis (RA) receiving etanercept plus methotrexate (ETA + MTX) versus methotrexate (MTX) and their relationship with serum levels of tumor necrosis factor-alpha (TNF-α). METHODS: In an observational cohort study, we compared changes in lipid levels in patients receiving ETA + MTX versus MTX in RA. These groups were assessed at baseline and at 4 and 24 weeks, measuring clinical outcomes, total cholesterol, triglycerides, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol, and TNF-α. RESULTS: Baseline values for lipid levels were similar in both groups. HDL-C levels increased significantly only in the ETA + MTX group (from 45.5 to 50.0 mg/dL at 4 weeks, a 10.2% increase, P < 0.001, and to 56.0 mg/dL at 24 weeks, a 25.1% increase, P < 0.001), while other lipids underwent no significant changes. ETA + MTX also exhibited a significant increase in TNF-α (44.8 pg/mL at baseline versus 281.4 pg/mL at 24 weeks, P < 0.001). The MTX group had no significant changes in lipids or TNF-α. Significant differences in HDL-C between groups were observed at 24 weeks (P = 0.04) and also in TNF-α  (P = 0.01). CONCLUSION: HDL-C levels increased significantly following treatment with ETA + MTX, without a relationship with decrease of TNF-α.
23678153 Golimumab in patients with active rheumatoid arthritis despite methotrexate therapy: resul 2013 Jul OBJECTIVE: To assess the longterm efficacy and safety of golimumab in patients with active rheumatoid arthritis (RA) despite methotrexate (MTX) therapy. METHODS: We randomized 444 RA patients with inadequate response to MTX (3:3:2:2) to placebo + MTX (Group 1), golimumab 100 mg + placebo (Group 2), golimumab 50 mg + MTX (Group 3), or golimumab 100 mg + MTX (Group 4). Subcutaneous golimumab/placebo was injected every 4 weeks. Patients could escape early (Group 1 added golimumab 50 mg, Group 2 added MTX, Group 3 increased golimumab to 100 mg, Group 4 continued 100 mg) based on Week 16 swollen and tender joint counts. From Week 24, Group 1 patients received golimumab 50 mg + MTX. After the Week 52 database lock, patients in the longterm extension received golimumab 50-100 mg ± MTX. Coprimary endpoints [Week 14 American College of Rheumatology (ACR)20, Week 24 Health Assessment Questionnaire Disability Index (HAQ-DI)] and Week 52 findings have been published; 2-year findings (observed data by randomized group, no imputation) are presented. RESULTS: Of 444 randomized patients, 392 continued from Week 52 (Group 1: n = 116, Group 2: n = 116, Group 3: n = 84, Group 4: n = 76). Clinical improvement was maintained through Week 104; ~75% and 72% of patients randomized to golimumab 50 mg + MTX and 100 mg + MTX achieved ACR20 response, respectively. The majority [88% (105/120)] of golimumab + MTX-treated patients with Week 24 HAQ-DI improvement ≥ 0.25 maintained improved physical function through Week 104. Group 1 patients with delayed golimumab treatment exhibited more Week 104 radiographic progression (mean change score = 1.15) than golimumab + MTX-randomized patients (0.52). Incidences of serious infections were 2.24, 4.77, 5.78/100 patient-years of followup for golimumab 50 mg + MTX, 100 mg + placebo, and 100 mg + MTX, respectively. CONCLUSION: Clinical improvement was maintained and no new safety signals were identified with 2 years of golimumab + MTX. Golimumab efficacy and safety, including serious infections, will continue to be monitored through 5 years (Clinical Trial No. NCT00264550).
23161901 Methotrexate polyglutamation in relation to infliximab pharmacokinetics in rheumatoid arth 2013 Jun OBJECTIVE: The combination of methotrexate (MTX) with infliximab can modify infliximab pharmacokinetics and lower the incidence of antibodies against infliximab (ATIs). We hypothesised that the pharmacokinetic interaction between MTX and infliximab is related to activation of MTX to immunosuppressive MTX polyglutamates (MTXPGs). METHODS: Adult patients with rheumatoid arthritis receiving weekly MTX with infliximab for more than 3 months were enrolled in a cross-sectional study. Blood was collected at trough before the infusion of infliximab. Red blood cell (RBC) MTXPGs were measured using liquid chromatography, and circulating levels of infliximab were measured using a cell-based assay. ATIs were measured using enzyme immunoassays. Statistical analyses consisted of multiple regression and Wilcoxon tests. RESULTS: In the 61 patients enrolled in the study, ATIs were detected in 11 (18%). Regression analyses revealed that lower infliximab levels (median 3.3 µg/ml) were associated with the presence of ATIs and lower RBC MTXPG levels (median 28 nmol/l) (p<0.05). Logistic regression revealed that RBC MTXPG levels above 25 nmol/l were associated with a 4.7-fold lower likelihood of having ATIs (OR=4.7; 95% CI 1.1 to 20.8; p=0.02). None of the 12 patients with RBC MTXPG levels above 50 nmol/l tested positive for ATIs. CONCLUSIONS: These hypothesis-generating data indicate that MTXPGs are associated with infliximab pharmacokinetics and ATI formation.
24692301 Effect of methotrexate use and erythrocyte methotrexate polyglutamate on glycosylated hemo 2014 Aug OBJECTIVE: To investigate whether methotrexate (MTX) use, as compared to other therapies, and erythrocyte methotrexate polyglutamate (MTXGlu) concentrations are associated with changes in glycosylated hemoglobin (HbA1c ) levels in rheumatoid arthritis (RA) patients. METHODS: The derivation cohort consisted of patients selected from the Treatment in the Rotterdam Early Arthritis Cohort who fulfilled the 2010 American College of Rheumatology/European League Against Rheumatism classification criteria for RA. Patients were randomized to 6 treatment arms: triple disease-modifying antirheumatic drug (DMARD) therapy (consisting of MTX, sulfasalazine, and hydroxychloroquine [HCQ]) + intramuscular (IM) glucocorticoids, triple DMARD therapy + oral glucocorticoids, MTX + oral glucocorticoid therapy, MTX therapy, oral glucocorticoid therapy, and HCQ therapy. HbA1c levels were determined at baseline and at 3 months. Concentrations of erythrocyte MTXGlu1-5 were measured after 3 months of treatment. Within treatment arms, changes in the level of HbA1c were compared by paired t-test. Associations of MTXGlu concentrations with changes in the level of HbA1c were tested using multiple linear regression analysis, adjusted for age, sex, body mass index, and comedication. Significant associations were validated using data on RA patients taking MTX who were enrolled in the Methotrexate in Rotterdam cohort. RESULTS: In the derivation cohort, the mean change in HbA1c level after 3 months of treatment was -1.9 mmoles/mole (-0.18%) (P = 0.001). Levels of HbA1c decreased in 4 of the individual treatment groups, as follows: for the triple DMARD therapy + IM glucocorticoids treatment arm, -5.5 mmoles/mole (-0.50%) (P < 0.001), for the triple DMARD therapy + oral glucocorticoids treatment arm, -3.7 mmoles/mole (-0.34%) (P < 0.001), for the MTX treatment arm, -0.8 mmoles/mole (-0.08%) (P = 0.018), and for the HCQ treatment arm, -2.0 mmoles/mole (-0.19%) (P = 0.175). Increased levels of MTXGlu2 (β = -0.20, P = 0.005), MTXGlu3 (β = -0.31, P < 0.001), MTXGlu4 (β = -0.33, P < 0.001) after treatment, MTXGlu5 (β = -0.39, P < 0.001), and total MTXGlu (β = -0.29, P < 0.001) were associated with decreased levels of HBA1c . In the validation cohort, levels of HbA1c were decreased by 2.6 mmoles/mole (0.23%) (P < 0.001) after treatment, and MTXGlu3 was associated with decreased levels of HbA1c (β = -0.26, P = 0.018). CONCLUSION: MTX use and higher concentrations of erythrocyte MTXGlu are associated with decreased levels of HbA1c in RA patients. Triple DMARD therapy and HCQ treatment resulted in reduced HbA1c levels, and glucocorticoid treatment resulted in increased levels of HbA1c .
23953497 Improving treatment with methotrexate in rheumatoid arthritis-development of a multimedia 2014 Feb OBJECTIVES: To develop and test an evidence-based, multimedia patient education program (MPEP) about methotrexate (MTX) treatment for rheumatoid arthritis (RA) and a new measure of patient knowledge [Methotrexate in Rheumatoid Arthritis Knowledge test (MiRAK)]. METHODS: The content of the MPEP and MiRAK was guided by concept-mapping workshops with patients (N = 24), literature review, health professional, and expert linguistic input. The MPEP and MiRAK underwent multiple stages of testing and revision with patients and health professionals. The MiRAK was administered to RA patients (N = 169) and its properties examined using the Rasch analyses. A subset of respondents (N = 131) repeated the MiRAK to determine test-retest reliability. A before-after pilot study with patients who had recently started MTX (N = 31) tested responsiveness of the MiRAK and feasibility and acceptability of the MPEP. RESULTS: A DVD of 24-minutes duration was produced that presents detailed, evidence-based information about MTX. The Rasch analyses of the 60 MiRAK items revealed that these could be summated into a single score. The MiRAK had good model fit, supporting internal construct validity, good internal consistency (person separation index; 0.84), test-retest reliability (ICC; 0.89), and ability to detect change (ES; 2.38). The before-after study suggested that patients could self-administer the MPEP, with the majority finding it informative and easy to use. CONCLUSIONS: We developed a MPEP about MTX treatment for RA, which was found to be user-friendly and easily implementable. The MiRAK is a new scale, testing a broad spectrum of MTX knowledge. Analyses revealed strong evidence for its validity and reliability.
24845391 Systemic inflammation and cardiovascular risk factors predict rapid progression of atheros 2015 Jun OBJECTIVE: To estimate atherosclerosis progression and identify influencing factors in rheumatoid arthritis (RA). METHODS: We used carotid ultrasound to measure intima-media thickness (IMT) in RA patients, and ascertained cardiovascular (CV) risk factors, inflammation markers and medications. A second ultrasound was performed approximately 3 years later. We calculated the progression rate by subtracting the baseline from the follow-up IMT, divided by the time between the two scans. We used logistic regression to identify baseline factors predictive of rapid progression. We tested for interactions of erythrocyte sedimentation rate (ESR) with CV risk factors and medication use. RESULTS: Results were available for 487 RA patients. The mean (SD) common carotid IMT at baseline was 0.571 mm (0.151). After a mean of 2.8 years, the IMT increased by 0.050 mm (0.055), p≤0.001, a progression rate of 0.018 mm/year (95% CI 0.016 to 0.020). Baseline factors associated with rapid progression included the number of CV risk factors (OR 1.27 per risk factor, 95% CI 1.01 to 1.61), and the ESR (OR 1.12 per 10 mm/h, 95% CI 1.02 to 1.23). The ESR×CV risk factor and ESR×medication product terms were significant, suggesting these variables modify the association between the ESR and IMT progression. CONCLUSIONS: Systemic inflammation and CV risk factors were associated with rapid IMT progression. CV risk factors may modify the role of systemic inflammation in determining IMT progression over time. Methotrexate and antitumour necrosis factor agents may influence IMT progression by reducing the effect of the systemic inflammation on the IMT.
24898259 Retrospective evaluation of continuation rates following a switch to subcutaneous methotre 2014 OBJECTIVES: To retrospectively evaluate continuation rates in patients with rheumatoid arthritis (RA) who failed to respond to or tolerate oral methotrexate (MTX) and were subsequently switched to subcutaneous MTX (SC MTX) in routine clinical practice. METHOD: We conducted a retrospective review of all patients with RA who had been prescribed SC MTX following oral MTX at the Norfolk and Norwich University Hospital and had been captured on the hospital pharmacy database of MTX use between 17 May 2011 and 20 March 2012. Only patients for whom complete records were available before and for at least 6 months after the switch were included. RESULTS: A total of 196 patients were included in the analysis (75.5% women; mean age at diagnosis 47.4 years; mean duration of oral MTX therapy 6.6 years). Patients were changed from oral to SC MTX because of lack of efficacy (50.5%), adverse events (43.9%), or other/unknown reasons (5.6%). High continuation rates were seen, with 83.0% of patients analysed still on SC MTX at 1 year, 75.2% at 2 years, and 47.0% at 5 years. Following the switch to SC MTX, < 10% of patients were prescribed additional biologic therapy during the first and second year because of an insufficient response. CONCLUSIONS: Treatment with SC MTX results in high continuation rates in patients who fail to respond to or tolerate oral MTX. Consequently, management guidelines should be adapted to include advice that SC MTX should be used before biologic therapy and that MTX failure is defined as failure only when use of SC MTX has failed.
23599435 A phase 2 dose-ranging study of subcutaneous tabalumab for the treatment of patients with 2013 Sep 1 OBJECTIVES: To assess the dose-response relationship, efficacy and safety of tabalumab, a human monoclonal antibody that neutralises membrane-bound and soluble B-cell activating factor (BAFF), in patients with rheumatoid arthritis (RA) with inadequate response to methotrexate (MTX). METHODS: In this phase 2, 24-week, double-blind, placebo-controlled, dose-ranging study, patients with RA (N=158) on stable  MTX were randomised by Bayesian-adaptive method to receive 1, 3, 10, 30, 60, or 120 mg tabalumab or placebo subcutaneously every 4 weeks for 24 weeks. The primary objective was to test for a significant dose-response relationship using a statistical model of the proportion of patients having ≥50% improvement in American College of Rheumatology (ACR) criteria (ACR50) at week 24 (prespecified α=0.10). RESULTS: At week 24, a significant dose-response relationship was observed using ACR50 (p=0.059) and ACR20 (p=0.044) response rates. Using model-estimated data, only 120 mg had significantly higher ACR50 and ACR20 response rates versus placebo (p<0.05). Observed response rates were significantly higher for 120 mg versus placebo as measured by ACR50 at weeks 12 (p=0.039) and 20 (p=0.018), but not week 24, and by ACR20 at weeks 12 (p=0.011) and 24 (p=0.039). Mean DAS28 C-reactive protein  improved with 120 mg at week 24 (p=0.048). Frequency of TEAEs was similar across groups (range 50-69%, p=0.884). Ten (8.2%) tabalumab and 5 (13.9%) placebo patients reported a serious adverse event (SAE). Infections occurred more frequently in patients exposed to tabalumab (30.3% vs 19.4%). Serious infections were reported in 3 (2.5%) tabalumab-treated patients only. CONCLUSIONS: A dose-response relationship was detected with monthly subcutaneous tabalumab. A significant effect was detected with the 120 mg dose with no unexpected safety signals. CLINICAL TRIAL #: NCT00785928.
24529746 Hepatitis A vaccine for immunosuppressed patients with rheumatoid arthritis: a prospective 2014 Mar BACKGROUND: Hepatitis A vaccine is the most frequently used travel vaccine, yet data are scarce about its ability to induce protection in patients with concurrent immunosuppressive treatment. We assessed the immunogenicity of this vaccine in rheumatoid arthritis (RA) patients treated with tumour necrosis factor-inhibitors (TNFi) and/or methotrexate (MTX). METHODS: Hepatitis A vaccine was administered to non-immune RA patients at 0 and 6 months. Hepatitis A virus (HAV) antibodies were assessed at 0, 1, 6, 7, 12, and 24 months with a quantitative Chemiluminescent Microparticle Immuno Assay (CMIA) for HAV-IgG. Samples from month 1, 6, and 7 were, in addition, analysed with a microparticle EIA (MEIA) for anti-HAV IgM + IgG. RESULTS: The final study population consisted of 53 patients treated with TNFi (n = 15), TNFi + MTX (n = 21) or MTX (n = 17). One and six months after the first dose, 10% and 33% of the patients had attained seroprotection. One and six months after the second dose 83% and 72% were seroprotected. At month 24, 86% of the vaccinees showed protective levels. CONCLUSIONS: Two doses of hepatitis A vaccine at a 6-month interval provided protection for most immunosuppressed RA patients. A single dose does not seem to afford sufficient protection to this group of patients.
24286335 Safety, tolerability, pharmacokinetics and pharmacodynamics of an anti- oncostatin M monoc 2013 Sep 24 INTRODUCTION: Oncostatin M (OSM) has been implicated in the pathophysiology of rheumatoid arthritis (RA) through its effect on inflammation and joint damage. GSK315234 is a humanised anti-OSM Immunoglobulin G1 (IgG1) monoclonal antibody (mAb). This 3-part study examines the safety, tolerability and efficacy of GSK315234 in patients with active RA. METHOD: This was a 3-part (Parts A, B and C), multicenter study. Part A and Part B were randomised, double-blind, placebo-controlled, Bayesian adaptive dose finding studies to investigate the safety, tolerability, efficacy, pharmacokinetics and pharmacodynamics of single (Part A) and 3 repeat (Part B) intravenous infusions of GSK315234 in patients with active RA on a background of methotrexate (MTX). Part C was a single dose, randomised, single-blind, placebo-controlled study to assess subcutaneously administered GSK315234 to patients with active RA on a background of MTX. RESULT: The primary endpoint of the study was mean change in DAS28 at Day 28 in Part A and Day 56 in Part B and C. All patients receiving at least one dose of GSK315234 were included in safety analysis. In Part A, there were statistically significant differences in DAS28 between 3 mg/kg and placebo at Day 56, 84 and 91. There was also a statistically significant difference in DAS28 between 0.3 mg/kg, 3 mg/kg and 10 mg/kg, as compared to placebo, at Day 84. Although these changes were small and occurred late, they supported progression to Part B and C to determine the therapeutic potential of GSK315234. For Part B, no significant difference was observed between 6 mg/kg and placebo. For Part C, a statistically significant difference in DAS28 was observed at Day 40, Day 84 and Day 100 between the 500 mg subcutaneous group, as compared to placebo. No significant findings were observed at any of the time points for EULAR response criteria, ACR20, ACR50 or ACR70. An exploratory analysis of clinical, pharmacokinetic and pharmacodynamics data suggests the lack of efficacy may be due to moderate binding affinity and rapid off-rate of GSK315234 as compared to the higher affinity OSM receptor causing a protein carrier effect prolonging the half life of OSM due to accumulation of the OSM/antibody complex in the serum and synovial fluid. CONCLUSION: Our data highlighted the importance of binding affinity and off-rate effect of a mAb to fully neutralize the target and how this may influence its efficacy and potentially worsen disease activity. Using an anti-OSM mAb with high affinity should test this hypothesis and examine the potential of OSM as a therapeutic target in RA. TRIAL REGISTRATION: ClinicalTrials.gov no: NCT00674635.
23377198 A biologic pharmacosurveillance program for rheumatoid arthritis: a single-center experien 2013 Jun We have reviewed the experience in a single center of a biologic register for rheumatoid arthritis patients. Over the past decade, the entry demographics show that we are treating patients at an earlier stage and with slightly less severe disease. Our outcomes measured by the percentage in DAS28 remission are comparable with national databases. We were surprised by the small number who were switched from their first biologic to a second (27 %), but this might reflect the lack of a firm "treat to target" approach. Our use of concomitant methotrexate/leflunomide is less than we would have liked and thought, but our use of concomitant corticosteroids is much less than normally seen. A single-center registry can provide useful monitoring and quality assurance data and stimulate change.
24187096 Correlation of radiographic progression with the cumulative activity of synovitis estimate 2013 Dec OBJECTIVE: Our prospective study aimed to demonstrate that the cumulative synovial power Doppler (PD) ultrasound scores correlate with radiographic progression better than conventional measures in patients with rheumatoid arthritis (RA). We also investigated the difference between antirheumatic agents. METHODS: Sixty-nine patients with RA who had recently received either methotrexate (MTX; n = 23), tumor necrosis factor (TNF) antagonists (n = 28), or tocilizumab (TCZ; n = 18) were enrolled. Patients underwent clinical, laboratory, and ultrasonographic assessment at baseline, 12 weeks, and 24 weeks. Radiographic damage was evaluated using van der Heijde modified total Sharp score (TSS) at baseline and 24 weeks. RESULTS: Fifty-seven patients continued the same treatment regimen for 24 weeks and completed the study, and 21 patients (36.8%) showed radiographic progression during the study period. In all patients, ΔTSS significantly correlated both with cumulative 28-joint Disease Activity Score-C-reactive protein (DAS28-CRP; ρ = 0.342, p = 0.009) and cumulative total PD scores (ρ = 0.357, p = 0.006). In MTX-treated patients, cumulative total PD scores significantly correlated with ΔTSS (ρ = 0.679, p = 0.004), whereas cumulative DAS28-CRP did not (ρ = 0.487, p = 0.056). However, cumulative total PD scores did not correlate with ΔTSS in TNF antagonist-treated or TCZ-treated patients. CONCLUSION: Our data confirm the evidence that synovial PD activity more accurately reflects active synovial inflammation (which actually causes joint destruction) than do conventional measures in patients treated with MTX. Our data also indicate that TNF antagonists can inhibit short-term radiographic progression in the presence of active synovitis.
24241487 Longterm effect of delaying combination therapy with tumor necrosis factor inhibitor in pa 2014 Jan OBJECTIVE: To evaluate the longterm safety of adalimumab administered with or without methotrexate (MTX) and compare the efficacy of combination therapy initialization to adalimumab or MTX monotherapy initialization during the open-label extension (OLE) of the PREMIER trial (ClinicalTrials.gov Identifier:NCT00195663). METHODS: Patients with early rheumatoid arthritis (RA) were randomized to receive blinded adalimumab + MTX, adalimumab alone, or MTX alone for 2 years. Following the double-blinded period, patients enrolling in the OLE were given adalimumab for up to 8 additional years, beginning as monotherapy; investigators could add MTX at their discretion. Results for clinical, functional, and radiographic progression were collected for up to 10 years of treatment. RESULTS: During the PREMIER OLE, 250/497 patients (50.3%) completed the trial without new safety signals arising. Similar proportions of patients discontinued the trial early, although lack of efficacy was reported less often for patients initially randomized to the adalimumab + MTX arm (9.3%; 21.2%, and 23.7% for adalimumab and MTX monotherapies, respectively). Clinical and functional disease control was maintained throughout the trial. Patients initially randomized to adalimumab + MTX displayed better outcomes, particularly in prevention of radiographic progression (modified total Sharp score change = 4.0, 8.8, 11.0 at Year 10 for the initial adalimumab + MTX, adalimumab, and MTX arms, respectively). CONCLUSION: Intensive therapy with adalimumab + MTX combination in patients with early RA has longterm benefits compared to patients initiating with 2-year adalimumab or MTX monotherapy that persists up to 10 years following adalimumab OLE. No new safety findings were observed following longterm adalimumab treatment.