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ID PMID Title PublicationDate abstract
24971392 Methotrexate-associated nonalcoholic fatty liver disease with transaminitis in rheumatoid 2014 BACKGROUND: The aim of this study was to determine the risk factors of MTX-associated nonalcoholic fatty liver disease (NAFLD) with transaminitis in a cohort of rheumatoid arthritis (RA) patients from Singapore. METHODS: Patients who developed ultrasound proven NAFLD with transaminitis while on MTX therapy were identified. The demographic and clinical characteristics of the above patients (cases) were compiled and compared with age- and gender-matched controls who were RA patients on long standing MTX therapy without any episode of transaminitis. RESULTS: Among the 978 patients who had received MTX, the prevalence of MTX-associated NAFLD was 4.7% (46 patients). Compared to the controls, the cases had significantly higher mean cumulative dose of MTX (4.03 ± 2.25 g versus 10.04 ± 9.94 g, P ≤ 0.05), weekly dose of MTX (11.3 ± 4.8 mg versus 13.1 ± 4.4 mg weekly, P = 0.033), and fasting blood glucose (P = 0.029). Following multivariate regression analysis, only cumulative dose of MTX remained significant (P = 0.015). Among the cases, the cumulative dose of MTX was found to have a significant positive correlation with the alanine transaminase (ALT) level (P < 0.05, standardised beta coefficient 0.512). CONCLUSION: The cumulative dose of MTX was the only independent predictor of MTX-associated NAFLD with transaminitis.
24559216 Factors influencing the prescription of intensive combination treatment strategies for ear 2014 OBJECTIVES: Despite the availability and demonstrated effectiveness of intensive combination treatment strategies (ICTS) for early rheumatoid arthritis (RA), a discrepancy seems to exist between theoretical evidence and actual prescription in daily practice. The purpose of this study was to explore and identify the factors influencing the prescription of ICTS. METHOD: This study involved rheumatologists and nurses participating in the Care for Rheumatoid Arthritis (CareRA) trial, a multicentre randomized controlled trial (RCT) comparing different ICTS for early RA with conventional disease-modifying anti-rheumatic drugs (DMARDs) plus step-down glucocorticoids (GCs). A qualitative study was carried out using individual semi-structured interviews. Each interview was recorded, transcribed literally, and analysed thematically. In addition, observations at outpatient clinics were used to clarify the interpretation of the results. RESULTS: We interviewed 26 rheumatologists and six nurses and observed five outpatient visits. Identified facilitators included available scientific evidence, personal faith in treatment strategy, staff support, and low treatment costs. Rheumatologists had no doubts about the value of methotrexate (MTX) but some questioned the value of combination strategy, others the effectiveness and/or the dosage of individual compounds. Additional barriers for prescribing ICTS included need for patient education, fear for patients' preconceptions, concerns about applicability to the individual patient, difficulties with breaking routine, interference with organizational structures and processes, time constraints, and lack of financial support. CONCLUSIONS: A heterogeneous set of factors highlights the complexity of prescribing ICTS for early RA in daily clinical practice. Future improvement strategies should stimulate the facilitators while at the same time addressing the barriers. The generalizability of these findings to other health care systems needs further examination.
23099471 Monitoring C-reactive protein levels to predict favourable clinical outcomes from tocilizu 2013 Sep OBJECTIVES: The inflammatory cytokine interleukin-6 (IL-6) directly stimulates C-reactive protein (CRP) expression. The present study aimed to examine how clinical treatment outcomes of rheumatoid arthritis (RA) with tocilizumab (TCZ), a humanised monoclonal anti-IL-6 receptor antibody, are related to CRP levels monitored for 52 weeks. METHODS: One hundred and twenty-two RA patients who underwent TCZ treatment between May 2008 and September 2009 were registered in the Tsurumai Biologics Communication Registry. Data were collected at initiation of treatment (baseline) and over 52 weeks for Disease Activity Score 28-ESR (DAS28-ESR), Boolean core measurements, serum CRP levels and matrix metalloproteinase-3 levels. To compare clinical results, patients were divided into three groups based on treatment time required to achieve normal CRP levels. RESULTS: Multivariate analysis using the Cox proportional-hazards regression model found that higher CRP levels at baseline was a significant and independent factor in predicting normal CRP levels over 52 weeks (hazard ratio 0.86 per 1 mg/dL). In contrast, disease duration, concomitant methotrexate use and previous tumour necrosis factor inhibitor failure were not significant factors. Patients with normal CRP levels at 12 weeks of TCZ treatment achieved better clinical outcomes, including remission based on DAS28-ESR criteria, compared to patients with elevated CRP levels at 12 weeks. CONCLUSIONS: Adequate suppression of pathological IL-6 signalling during TCZ treatment improves clinical outcomes and can be monitored with serum CRP levels, a readily available biomarker in clinical practice.
22572888 A retrospective study of serum KL-6 levels during treatment with biological disease-modify 2013 Mar OBJECTIVE: We investigated associations between treatment with methotrexate (MTX) or biological disease-modifying antirheumatic drugs (DMARDs) and elevation of serum Krebs von den Lungen-6 (KL-6) levels in Japanese patients with rheumatoid arthritis (RA). METHODS: Using a standardized form, data were collected retrospectively from medical records and analyzed descriptively. RESULTS: Of a total of 198 RA patients with KL-6 serum levels measured at initiation of treatment (month 0) and two or more times by month 12, 27 (17.9 %) of 151 RA patients treated with biological DMARDs, including infliximab, etanercept, adalimumab, and tocilizumab (the biological DMARDs group), and 5 (10.6 %) of 47 patients treated without biological DMARDs but with MTX (MTX group), met criterion B (max. KL-6 ≥500 U/ml and >1.5-fold from baseline) by 12 months. The majority of patients (n = 28) meeting criterion B had no apparent interstitial lung disease or malignancy. Of these 28 patients, 21 had serum KL-6 levels available after reaching their maximum level, and 13 (61.9 %) of the 21 then met criterion R [decrease to less than 500 U/ml or to less than (baseline + 0.5 × (maximum - baseline))] by month 12. CONCLUSION: Serum KL-6 levels may increase during treatment with MTX or these biological DMARDs without significant clinical events.
23545897 Genetic variants associated with methotrexate efficacy and toxicity in early rheumatoid ar 2014 Feb Methotrexate (MTX) has emerged as first-line therapy for early moderate-to-severe rheumatoid arthritis (RA), but individual variation in treatment response remains unexplained. We tested the associations between 863 known pharmacogenetic variants and MTX response in 471 Treatment of Early Aggressive Rheumatoid Arthritis Trial participants with early RA. Efficacy and toxicity were modeled using multiple regression, adjusted for demographic and clinical covariates. Penalized regression models were used to test joint associations of markers and/or covariates with the outcomes. The strongest genetic associations with efficacy were in CHST11 (five markers with P<0.003), encoding carbohydrate (chondroitin 4) sulfotransferase 11. Top markers associated with MTX toxicity were in the cytochrome p450 genes CYP20A1 and CYP39A1, solute carrier genes SLC22A2 and SLC7A7, and the mitochondrial aldehyde dehydrogenase gene ALDH2. The selected markers explained a consistently higher proportion of variation in toxicity than efficacy. These findings could inform future development of personalized therapeutic approaches.
24412895 A treat-to-target strategy with methotrexate and intra-articular triamcinolone with or wit 2015 May OBJECTIVES: To investigate whether a treat-to-target strategy with methotrexate and intra-articular glucocorticosteroid injections suppresses MRI inflammation and halts structural damage progression in patients with early rheumatoid arthritis (ERA), and whether adalimumab provides an additional effect. METHODS: In a double-blind, placebo-controlled trial, 85 disease-modifying antirheumatic drug-naïve patients with ERA were randomised to receive methotrexate, intra-articular glucocorticosteroid injections and placebo/adalimumab (43/42). Contrast-enhanced MRI of the right hand was performed at months 0, 6 and 12. Synovitis, osteitis, tenosynovitis, MRI bone erosion and joint space narrowing (JSN) were scored with validated methods. Dynamic contrast-enhanced MRI (DCE-MRI) was carried out in 14 patients. RESULTS: Synovitis, osteitis and tenosynovitis scores decreased highly significantly (p<0.0001) during the 12-months' follow-up, with mean change scores of -3.7 (median -3.0), -2.2 (-1) and -5.3 (-4.0), respectively. No overall change in MRI bone erosion and JSN scores was seen, with change scores of 0.1 (0) and 0.2 (0). The tenosynovitis score at month 6 was significantly lower in the adalimumab group, 1.3 (0), than in the placebo group, 3.9 (2), Mann-Whitney: p<0.035. Furthermore, the osteitis score decreased significantly during the 12-months' follow-up in the adalimumab group, but not in the placebo group, Wilcoxon: p=0.001-0.002 and p=0.062-0.146. DCE-MRI parameters correlated closely with conventional MRI inflammatory parameters. Clinical measures decreased highly significantly during follow-up. CONCLUSIONS: A treat-to-target strategy with methotrexate and intra-articular glucocorticosteroid in patients with ERA effectively decreased synovitis, osteitis and tenosynovitis and halted structural damage progression as judged by MRI. The findings suggest that addition of adalimumab is associated with further suppression of osteitis and tenosynovitis.
24665571 Cost-effectiveness analysis of tocilizumab in combination with methotrexate for rheumatoid 2014 Feb BACKGROUND/AIM: Recent studies have shown that biological treatments for rheumatoid arthritis can change the course of rheumatoid arthritis and improve functional ability of patients with rheumatoid arthritis. In spite of this fact, use of biological therapy is still limited by high prices of these medicines, especially in countries in socioeconomic transition. The aim of our study was to compare cost-effectiveness of a combination of tocilizumab and methotrexate with methotrexate alone for rheumatoid arthritis in Serbia, a country in socioeconomic transition. METHODS: For the purpose of our study we designed a Markov model using data on therapy efficacy from the available literature, and data on the costs of health states calculated from records of actual patients treated in the Clinical Center Kragujevac, Serbia. The duration of one cycle in our model was set at one month, and the time horizon was 480 months (40 years). The study was done from the social perspective, and all the costs and outcomes were discounted for 3% per year. RESULTS: Treating rheumatoid arthritis with disease-modifying antirheumatic drugs (DMARDs) alone was more cost-effective in comparison with a combination of biologic treatment with tocilizumab and DMARDs. The total costs for treating a patient with DMARDs for one year were on average 261,945.42 RSD, or 2,497.70 Euro and the total costs for treatment with tocilizimab plus DMARDs were on average 1,959,217.44 RSD, or 18,659.20 Euro. However, these results are susceptible to changes in costs and treatment effects of tocilizumab in patients with more severe forms of rheumatoid arthritis. CONCLUSION: Our results show that the use of tocilizumab for rheumatoid arthrits in economic environment of Serbia is not cost-effective. Use of tocilizumab for treating rheumatoid arthritis can become affordable, if costs of its use become lower. In order to start using expensive biologic medicines in patients in transitional countries, special strategy and pricing policy of international pharmaceutical companies are necessary, which would include calculation of prices of biologic medicines on the basis of local pharmacoeconomic studies.
25546788 7th International Immunoglobulin Conference: Immunomodulation. 2014 Dec Rheumatoid arthritis (RA) is a debilitating autoimmune disease that is usually treated aggressively to slow the rate of joint destruction. The therapeutic strategy used at the French centre, described here, is to use the non-biological disease-modifying drug, methotrexate, as first-line therapy and to add biological agents as second-line treatment. The two other autoimmune diseases discussed in this session were immunobullous skin diseases, and secondary recurrent miscarriage (RM). In the former conditions, low levels of pathogenic autoantibodies can be achieved with adjuvant intravenous immunoglobulin (IVIg) therapy, usually in combination with an immunosuppressant. Secondary RM has an autoimmune basis, as shown by high tumour necrosis factor (TNF)-α levels and specific human leucocyte antigen (HLA) polymorphisms. Although the mechanism is not yet known, IVIg may also be an effective treatment, despite the generally low doses used in published studies.
23146660 Infliximab reduces CD147, MMP-3, and MMP-9 expression in peripheral blood monocytes in pat 2013 Jan 5 Recent studies have reported elevated expression levels in active rheumatoid arthritis patients of the cluster of differentiation (CD) 147 on CD14(+) peripheral blood monocytes and as a result, CD147 may be a target for the development of a novel rheumatoid arthritis therapy. This report describes the inhibitory effects of infliximab on CD147 and metalloproteinases (MMP)-3 and MMP-9 overexpression in peripheral blood monocytes obtained from patients with active rheumatoid arthritis. Thirty patients with active rheumatoid arthritis that were refractory to methotrexate therapy were randomized at a 4:1 ratio into groups A and B, respectively. Group A received three to four infusions of infliximab (3mg/kg) and group B participants received four infusions of placebo. Both groups were also treated with a stable background dose of methotrexate. The CD147 expression levels on CD14(+) peripheral blood monocytes of rheumatoid arthritis patients was detected by flow cytometry. The expression of CD147, MMP-3, and, MMP-9 mRNA in peripheral blood mononuclear cells was assayed by real-time quantitative PCR, and the expression of MMP-3 and MMP-9 in serum was measured by a multiplexed microsphere-based flow assay. Results showed that the expression of CD147 and MMP-9 mRNA in group A decreased compared to group B. Expression of CD147 on CD14(+) monocytes was reduced (P<0.05), and serum MMP-3 and -9 levels in group A were decreased by week 18. These data suggested that infliximab could inhibit CD147 expression on CD14(+) monocytes as well as reduce the levels of MMP-3 and MMP-9 in peripheral blood monocytes.
25181946 Comparison of the efficacy and safety of two starting dosages of prednisolone in early act 2014 Sep 2 BACKGROUND: Although glucocorticoids are widely used in the treatment of patients with early rheumatoid arthritis, the best dosage of glucocorticoids with regards to efficacy and safety is not known.The aim of the study 'Comparison of the efficacy and safety of two starting dosages of prednisolone in early active rheumatoid arthritis' (CORRA) is to compare two standard glucocorticoid starting dosages and the non-use of glucocorticoids in the treatment of patients with early active rheumatoid arthritis on the background of the established 'anchor' therapy with methotrexate. METHODS/DESIGN: CORRA is an investigator-initiated, randomized, multicenter, double-blind, placebo-controlled trial with two treatment arms, starting with 60 mg or 10 mg prednisolone per day, tapered down to 5 mg prednisolone within eight weeks, and one placebo arm, each arm comprising 150 patients. The duration of the intervention is 12 weeks. In parallel, all patients will be treated with methotrexate (usual dosage 15 mg/week). The primary efficacy endpoint is the progression of radiographic joint damage after one year compared to baseline. Important secondary endpoints are the percentage of patients in remission, patient global assessment of disease activity, and changes of functional capacity. Safety monitoring is performed.The statistical analysis is performed in three hierarchical steps. The first step is an analysis of covariance (α = 0.05) to compare the group with the initial prednisolone dosage of 60 mg and the placebo group. In case of a statistically significant result, the comparison of the group starting with 10 mg prednisolone with the placebo group will be performed as a second step (α = 0.05). In case of superiority of the 10 mg prednisolone group versus the placebo group, the third step will be a non-inferiority test for the 10 mg prednisolone group versus the 60 mg prednisolone group (α = 0.025). DISCUSSION: The CORRA trial will yield information concerning the optimal glucocorticoid dosage schedule in the treatment of patients with early rheumatoid arthritis. TRIAL REGISTRATION: This trial was registered on 19 November 2013 at ClinicalTrials.gov. REGISTRATION NUMBER: NCT02000336.
24221190 Patients with the most advanced rheumatoid arthritis remain with Th1 systemic defects afte 2014 Feb Systemic immune defects might reflect severely dysregulated control of chronic inflammation related to disease progression. Th17/Treg cell imbalance has been demonstrated to be involved in rheumatoid arthritis (RA) pathogenesis. Despite controversial results, a growing anti-inflammatory role in this process has been recently attributed to Th1 responses. The aim of the study was to estimate the extent of Th1/Th17/Treg imbalance in peripheral blood (PB) of patients with short- and long-term RA in relation to cytokine milieu and its reversal after therapy with methotrexate and/or TNF inhibitors, respectively. Patients with different duration of RA (median 6 vs. 120 months) in the active phase of RA were enrolled in this study. We performed flow cytometric analysis of PB Th1, Th17, and Treg populations together with estimation of serum cytokine concentrations using cytometric bead array. Disease activity was calculated on the basis of clinical and biochemical indices of inflammation (DAS28, ESR, CRP). All parameters were measured and correlated with each other before and after 6 months therapy. Elevated levels of circulating Th17 cells and IL-6 were found in all active patients, of which Th17 cells were down-regulated by the treatment. Significantly reduced Th1 and functional CTLA-4+ Treg cell frequencies as well as Th1 cytokines observed only in progressive RA seemed to be irreversible. Although therapy induced clinical improvement in almost all patients, those with advanced RA remained with signs of inflammation. Our report demonstrates that both the extent of systemic immune abnormalities and their restoration are dependent on duration of the active RA.
24081439 Fish oil in recent onset rheumatoid arthritis: a randomised, double-blind controlled trial 2015 Jan BACKGROUND: The effects of fish oil (FO) in rheumatoid arthritis (RA) have not been examined in the context of contemporary treatment of early RA. This study examined the effects of high versus low dose FO in early RA employing a 'treat-to-target' protocol of combination disease-modifying anti-rheumatic drugs (DMARDs). METHODS: Patients with RA <12 months' duration and who were DMARD-naïve were enrolled and randomised 2:1 to FO at a high dose or low dose (for masking). These groups, designated FO and control, were given 5.5 or 0.4 g/day, respectively, of the omega-3 fats, eicosapentaenoic acid + docosahexaenoic acid. All patients received methotrexate (MTX), sulphasalazine and hydroxychloroquine, and DMARD doses were adjusted according to an algorithm taking disease activity and toxicity into account. DAS28-erythrocyte sedimentation rate, modified Health Assessment Questionnaire (mHAQ) and remission were assessed three monthly. The primary outcome measure was failure of triple DMARD therapy. RESULTS: In the FO group, failure of triple DMARD therapy was lower (HR=0.28 (95% CI 0.12 to 0.63; p=0.002) unadjusted and 0.24 (95% CI 0.10 to 0.54; p=0.0006) following adjustment for smoking history, shared epitope and baseline anti-cyclic citrullinated peptide. The rate of first American College of Rheumatology (ACR) remission was significantly greater in the FO compared with the control group (HRs=2.17 (95% CI 1.07 to 4.42; p=0.03) unadjusted and 2.09 (95% CI 1.02 to 4.30; p=0.04) adjusted). There were no differences between groups in MTX dose, DAS28 or mHAQ scores, or adverse events. CONCLUSIONS: FO was associated with benefits additional to those achieved by combination 'treat-to-target' DMARDs with similar MTX use. These included reduced triple DMARD failure and a higher rate of ACR remission.
24429167 Safety of etanercept and methotrexate in patients with rheumatoid arthritis and hepatitis 2014 Feb OBJECTIVE: To evaluate the safety and efficacy of therapy with etanercept and methotrexate (MTX) in patients with active rheumatoid arthritis (RA) and mild hepatitis C virus (HCV) infection. METHODS: In this prospective open study, 29 patients with active RA were randomly assigned to receive therapy with MTX alone, etanercept alone, or a combination of MTX and etanercept, and monitored up to 54 weeks. The primary endpoint was safety; secondary aims were efficacy as defined by the 44-joint Disease Activity Score (DAS44) and health assessment questionnaire (HAQ). Serum liver enzymes and HCV viral load were serially measured. RESULTS: In the whole cohort, aspartate aminotransferase (AST) serum levels were (mean ± SD) 35 ± 3 at entry, 39 ± 5, 41 ± 7, and 38 ± 4 at 14, 30, and 54 weeks, respectively; alanine aminotransferase (ALT) serum levels were 43 ± 5 at entry, 47 ± 5, 53 ± 9, and 50 ± 6 at 14, 30, and 54 weeks, respectively. HCV viral load was 5.6 ± 0.5 at entry, 5.9 ± 0.6, 5.7 ± 0.3, and 5.6 ± 0.6 at 14, 30, and 54 weeks, respectively. AST and ALT did not significantly change in all 3 arms of treatment, nor did HCV viral load. A significant reduction of DAS44 (p < 0.01) and HAQ (p < 0.04) was detected at 54 weeks compared to baseline. No patient discontinued the therapy because of worsening of liver disease. CONCLUSION: This study showed that patients with RA and chronic HCV and mild hepatitis may be successfully treated with etanercept and MTX without increasing the risk of hepatotoxicity and HCV replication. ClinicalTrials.gov Identifier NCT01543594.
24583629 Genome-wide analysis of methotrexate pharmacogenomics in rheumatoid arthritis shows multip 2014 Apr OBJECTIVE: Methotrexate (MTX) is the drug of first choice for the treatment of rheumatoid arthritis (RA), but is effective only in around 60% of the patients. Identification of genetic markers to predict response is essential for effective treatment within a critical window period of 6 months after diagnosis, but have been hitherto elusive. In this study, we used genome-wide genotype data to identify the potential risk variants associated with MTX (poor)response in a north Indian RA cohort. MATERIALS AND METHODS: Genome-wide genotyping data for a total of 457 RA patients [297 good (DAS28-3≤3.2) and 160 poor (DAS28-3≥5.1) responders] on MTX monotherapy were tested for association using an additive model. Support vector machine and genome-wide pathway analysis were used to identify additional risk variants and pathways. All risk loci were imputed to fine-map the association signals and identify causal variant(s) of therapeutic/diagnostic relevance. RESULTS: Seven novel suggestive loci from genome-wide (P≤5×10(-5)) and three from support vector machine analysis were associated with MTX (poor)response. The associations of published candidate genes namely DHFR (P=0.014), FPGS (P=0.035), and TYMS (P=0.005) and purine and nucleotide metabolism pathways were reconfirmed. Imputation, followed by bioinformatic analysis indicated possible interaction between two reversely oriented overlapping genes namely ENOSF1 and TYMS at the post-transcriptional level. CONCLUSION: In this first ever genome-wide analysis on MTX treatment response in RA patients, 10 new risk loci were identified. These preliminary findings warrant replication in independent studies. Further, TYMS expression at the post-transcriptional level seems to be probably regulated through an antisense-RNA involving the 6-bp ins/del marker in the overlapping segment at 3'UTR of TYMS-ENOSF1, a finding with impending pharmacogenetic applications.
24332807 The comparison of effects of biologic agents on rheumatoid arthritis damage progression is 2014 Jun OBJECTIVES: To indirectly compare the 12-month effects of available biologic agents in slowing RA radiographic progression. METHODS: A systematic review of literature of randomised, double-blind, controlled trials (RCTs) evaluating RA radiographic progression as end point was conducted using a PubMed searching of MEDLINE from January 1995 to May 2012. For each trial, the mean change from baseline of the standardised annual radiographic progression score (weighted for estimated annual progression rate) was estimated, and the effect size was calculated as the difference between biologic and non-biologic-treated groups. In order to optimise data homogeneity and improve RCTs comparison, a mixed-effect model was applied including previous responsiveness to methotrexate (MTX-experienced or MTX-naïve populations) and period of study enrollment as moderators. RESULTS: The PubMed search resulted in 183 references, and 14 were eligible for the meta-analysis. The analysis of study distribution in forest plots showed a high correlation between the study period of enrollment and the impact of biological therapy in both MTX-naïve and MTX-experienced subgroups. In particular, effect size was the highest for older trials and progressively decreased in the most recent ones, suggesting a highest propensity to radiographic progression in populations enrolled in older trials. Some statistically significant differences among RCTs were found in both subgroups but were significantly biased by the different propensity to radiographic progression due to period of enrollment. CONCLUSIONS: Our meta-analysis demonstrated that period of enrollment deeply influence study population propensity to radiographic progression in each trial. This finding does not allow the indirect comparison of various biologic agents, despite our mixed-model significantly reducing heterogeneity among RCTs.
25131223 Tartrate-resistant acid phosphatase 5b is a potential biomarker for rheumatoid arthritis: 2014 BACKGROUND: Bone damage around the joints is one of the major pathophysiological mechanisms that leads to rheumatoid arthritis (RA) chronic disability. Serum tartrate-resistant acid phosphatase 5b (TRACP-5b) is secreted by osteoclasts, its activity can be used as a clinically relevant bone resorption marker. The aim of this study was to test whether the measurement of serum levels of TRACP-5b in patients with RA would correlate with measures of disease activity and with responses to therapy. METHODS: Fifty-six patients were randomly assigned to receive recombinant human cytotoxic tlymphocyte-associated antigen-4 immunoglobulin (RhCTLA4-Ig), infliximab or methotrexate (MTX). The clinical and serologic indicators of RA activity were evaluated at baseline and at 24 weeks. Serum TRACP-5b was measured by Enzyme-linked Immunosorbent Assay (ELISA) at 0, 12 and 24 weeks. Hand X-rays were obtained at baseline. RESULTS: At baseline, the levels of TRACP-5b correlated with the severity of X-ray damage, disease duration (r = 0.332, P = 0.012), and tender joint count (r = 0.408, P = 0.002). The 24 weeks values of TRACP-5b for RhCTLA4-Ig group and infliximab group differed significantly from the baseline values in each group (P < 0.05; P < 0.05), whereas only the value for RhCTLA4-Ig group differed significantly from the 24 weeks value for the MTX group (P < 0.01). Considering the two biologics-treated groups together, the TRACP-5b levels at 24 weeks differed significantly from the baseline values only in those patients who reached an ACR70 level (P < 0.05). CONCLUSIONS: Measurement of serum TRACP-5b in RA patients reflects clinical and radiological measures of disease activity, treatment with certain biologics, and degree of response to therapy. TRACP-5b should be investigated further as a potential biomarker to predict response to therapy, including slowing of radiographic progression.
24032521 Continuation of TNF blockade in patients with inflammatory rheumatic disease. An observati 2013 Oct BACKGROUND: Increased infection risk in inflammatory rheumatic diseases may be due to inflammation or immunosuppressive treatment. The influence of tumor necrosis factor (TNF) inhibitors on the risk of developing surgical site infections (SSIs) is not fully known. We compared the incidence of SSI after elective orthopedic surgery or hand surgery in patients with a rheumatic disease when TNF inhibitors were continued or discontinued perioperatively. PATIENTS AND METHODS: We included 1,551 patients admitted for elective orthopedic surgery or hand surgery between January 1, 2003 and September 30, 2009. Patient demographic data, previous and current treatment, and factors related to disease severity were collected. Surgical procedures were grouped as hand surgery, foot surgery, implant-related surgery, and other surgery. Infections were recorded and defined according to the 1992 Centers for Disease Control definitions for SSI. In 2003-2005, TNF inhibitors were discontinued perioperatively (group A) but not during 2006-2009 (group B). RESULTS: In group A, there were 28 cases of infection in 870 procedures (3.2%) and in group B, there were 35 infections in 681 procedures (5.1%) (p = < 0.05). Only foot surgery had significantly more SSIs in group B, with very low rates in group A. In multivariable analysis with groups A and B merged, only age was predictive of SSI in a statistically significant manner. INTERPRETATION: Overall, the SSI rates were higher after abolishing the discontinuation of anti-TNF perioperatively, possibly due to unusually low rates in the comparator group. None of the medical treatments analyzed, e.g. methotrexate or TNF inhibitors, were significant risk factors for SSI. Continuation of TNF blockade perioperatively remains a routine at our center.
23345600 Pneumococcal polysaccharide vaccination in rheumatoid arthritis patients receiving tociliz 2013 Aug OBJECTIVES: We assessed the impact of tocilizumab (TCZ), a humanised monoclonal anti-interleukin-6 receptor antibody, on antibody response following administration of the 23-valent pneumococcal polysaccharide vaccine (PPV23). METHODS: A total of 190 patients with rheumatoid arthritis (RA) received PPV23. Patients were classified into TCZ (n=50), TCZ + methotrexate (MTX) (n=54), MTX (n=62) and RA control (n=24) groups. We measured serotype-specific IgG concentrations of pneumococcal serotypes 6B and 23F using ELISA and functional antibody activity using a multiplexed opsonophagocytic killing assay, reported as the opsonisation indices (OIs), before and 4-6 weeks after vaccination. Positive antibody response was defined as a 2-fold or more increase in the IgG concentration or as a ≥10-fold or more increase in the OI. RESULTS: IgG concentrations and OIs were significantly increased in all treatment groups in response to vaccination. The TCZ group antibody response rates were comparable with those of the RA control group for each serotype. MTX had a negative impact on vaccine efficacy. Multivariate logistic analysis confirmed that TCZ is not associated with an inadequate antibody response to either serotype. No severe adverse effect was observed in any treatment group. CONCLUSIONS: TCZ does not impair PPV23 immunogenicity in RA patients, whereas antibody responses may be reduced when TCZ is used as a combination therapy with MTX.
24907147 Short-term efficacy of etanercept plus methotrexate vs combinations of disease-modifying a 2014 Nov OBJECTIVES: The aims of this study were to investigate the short-term benefit of etanercept (ETN) + MTX vs conventional synthetic DMARDs (csDMARDs; HCQ, LEF or SSZ) + MTX in subjects with established RA. The effect of disease duration (≤2 years vs >2 years) and severity (moderate vs severe) on treatment outcomes was also assessed. Methods. Data from Asian and Latin American subjects with inadequate response to MTX were pooled from the APPEAL (ETN 25 mg biweekly + MTX or csDMARD + MTX; NCT00422227) and Latin RA (ETN 50 mg/week + MTX or csDMARD + MTX; NCT00848354) studies. Endpoints included the 28-joint DAS with ESR (DAS28-ESR) low disease activity (LDA; ≤3.2), DAS28 remission (<2.6) and HAQ score ≤0.5. RESULTS: Four hundred seventy-eight subjects received ETN + MTX, 245 subjects received csDMARD + MTX [HCQ + MTX (n = 81), LEF + MTX (n = 69), SSZ + MTX (n = 95)]. At week 16, significantly more subjects receiving ETN + MTX vs subjects on csDMARDs + MTX achieved DAS28-ESR LDA (39% vs 18%, P < 0.001), remission (18% vs 7%, P < 0.001) and HAQ ≤0.5 (48% vs 34%, P < 0.001). For both treatment arms, these endpoints were achieved by a greater proportion of subjects with ≤2 years vs >2 years disease duration and with moderate vs severe disease activity. CONCLUSION: Overall, ETN + MTX was more effective in treating subjects with established RA than csDMARDs + MTX at 16 weeks. More subjects with shorter disease duration and moderate disease activity achieved optimal response regardless of treatment regimen. TRIAL REGISTRATION: clinicaltrials.gov, NCT00422227 and NCT00848354.
23515142 Tocilizumab monotherapy versus adalimumab monotherapy for treatment of rheumatoid arthriti 2013 May 4 BACKGROUND: Roughly a third of patients with rheumatoid arthritis treated with biological treatments receive them as monotherapy. Tocilizumab--an inhibitor of interleukin 6 receptor signalling--has been studied as monotherapy in several clinical trials. We assessed the efficacy and safety of tocilizumab monotherapy compared with adalimumab monotherapy for patients with rheumatoid arthritis. METHODS: We did this randomised, double-blind, parallel-group, phase 4 superiority study in 76 centres in 15 countries in North and South America, Australasia, and Europe. We enrolled patients who were aged at least 18 years, had severe rheumatoid arthritis for 6 months or more, and were intolerant to methotrexate or were inappropriate for continued methotrexate treatment. Patients were randomly assigned (1:1; block size of four) to receive tocilizumab 8 mg per kg bodyweight intravenously every 4 weeks plus placebo subcutaneously every 2 weeks or adalimumab 40 mg subcutaneously every 2 weeks plus placebo intravenously every 4 weeks for 24 weeks. Investigators, patients, and sponsor personnel were masked to assignment. The primary endpoint was change in disease activity score using 28 joints (DAS28) from baseline to week 24. This trial is registered with ClinicalTrials.gov, number NCT01119859. FINDINGS: We screened 452 patients and enrolled 326 patients. The intention-to-treat population contained 325 patients (163 assigned to tocilizumab, 162 assigned to adalimumab). Week 24 mean change from baseline in DAS28 was significantly greater in the tocilizumab group (-3·3) than in the adalimumab group (-1·8) patients (difference -1·5, 95% CI -1·8 to -1·1; p<0·0001). 16 of 162 (10%) patients in the adalimumab group versus 19 of 162 (12%) in the tocilizumab group had serious adverse events. More patients in the tocilizumab group than in the adalimumab group had increased LDL-cholesterol, increased alanine aminotransferase concentrations, and reduced platelet and neutrophil counts. INTERPRETATION: Tocilizumab monotherapy was superior to adalimumab monotherapy for reduction of signs and symptoms of rheumatoid arthritis in patients for whom methotrexate was deemed inappropriate. The adverse event profiles of tocilizumab and adalimumab were consistent with previous findings. FUNDING: F Hoffmann-La Roche.