Search for: rheumatoid arthritis    methotrexate    autoimmune disease    biomarker    gene expression    GWAS    HLA genes    non-HLA genes   

ID PMID Title PublicationDate abstract
21406270 Isolation of functional autologous collagen-II specific IL-10 producing Tr1 cell clones fr 2011 Aug IL-10 producing regulatory type 1 (Tr1) cells represents a subpopulation of CD4+ regulatory cells able to prevent in vitro bystander T-cell proliferation and to inhibit a wide range of inflammatory diseases in mice. Our aim was to evaluate the frequency and function of joint specific Tr1 cells in the peripheral blood of severe Rheumatoid Arthritis (RA) patients. The collagen II protein was chosen to isolate Tr1 cells specific for a joint antigen. We successfully isolated Tr1 clones from 9 out of 11 RA patients. We showed that cells from patients display the same phenotype and surface marker regulation as previously shown for human Tr1 cells, characterized by expression of markers of regulation (FoxP3, CD25) at the activated but not at the resting state. Importantly, cells from patients showed Tr1 cytokine secretion (IL-10 and IFN-γ) and immunosuppressive action on bystander T cell proliferation. Based on these results, we demonstrated that collagen II specific Tr1 cells can be isolated from the blood of severe refractory patients and that these cells are not altered in their phenotype and function.
21373746 Pectenotoxin-2 induces G1 arrest of the cell cycle in synovial fibroblasts of patients wit 2011 Jun Rheumatoid arthritis (RA), a chronic inflammatory disease, is characterized by hyperplasia of the synovial fibroblasts, due in part to increased cell growth. This study investigated the mechanisms underlying the anti-proliferative action of pectenotoxin-2 (PTX-2), isolated from marine sponges, in synovial fibroblasts obtained from RA patients. PTX-2 concentration-dependently inhibited the growth of synovial fibroblasts, arresting them in the G1 phase of their cell cycle. The G1 arrest was correlated with down-regulation of cyclin D1 and cyclin-dependent kinase (Cdk) 6, with a concomitant up-regulation of the tumor suppressor, p53, and the Cdk inhibitor, p21 (WAF1/CIP1). Following PTX-2 treatment of synovial fibroblasts, an increased binding of p21 with Cdk2 and Cdk6 was paralleled by a significant decrease in retinoblastoma protein (pRB) phosphorylation and in the protein levels of E2F transcription factors. Thus, PTX-2 might help identify new therapeutic agents against RA-mediated hyperplasia of synovial fibroblasts.
22325083 Overexpression of decoy receptor 3 in synovial tissues of inflammatory arthritis. 2012 Mar OBJECTIVES: Decoy receptor 3 (DCR3) was a newly identified soluble receptor which was reported to modulate the function of T cells, dendritic cells and macrophages. The aim of this study was to investigate DCR3 expression on the synovial tissue in different types of arthritis. METHODS: We obtained synovial tissues from 17 rheumatoid arthritis (RA), 17 ankylosing spondylitis (AS) and 17 osteoarthritis (OA) patients. Synovial specimens were stained with hematoxylin and eosin. The amount of lymphocytes and mononuclear cells infiltration and vascularity during light microscopic examination was scored from 0-4. The expression of CD3, CD4, CD8, CD68 and DCR3 in lining layer (LL) and sublining layer (SL) cells was stained using the immunohistochemical method and analysed by microscopic examination (score from 0-4, 0=absent, 1=slight, 2=moderate, 3=large, 4=extreme). RESULTS: OA patients were older than the RA and AS patients (65.9±10.3 years for OA, 58.4±17.7 for RA, and 43.2±16.4 for AS). Synovial tissues in RA patients had significantly increased mononuclear cells infiltration when compared to AS and OA patients (2.3±0.6, 1.9±0.5, 1.6±0.5, respectively, p<0.05). There was no striking difference in DCR3 expression in the synovial LL between RA, AS, and OA patients. CD4+ T cells and CD68+ monocytes/macrophages in the SL were more prominent in RA and AS than in OA (p<0.05). Similarly, DCR3 in the SL was more overexpressed in RA and AS than in OA (1.83±0.21, 1.71±0.36, 1.39±0.31, respectively, p<0.01). CONCLUSIONS: The increased synovial inflammatory cells infiltration in RA and AS was associated with the elevated DCR3 expression.
22339947 Anti-citrullinated fibronectin antibodies in rheumatoid arthritis are associated with huma 2012 Feb 17 INTRODUCTION: Fibronectin is one of the most abundant proteins present in the inflamed joint. Here, we characterized the citrullination of fibronectin in the joints of rheumatoid arthritis (RA) patients and studied the prevalence, epitope specificity and human leukocyte antigen (HLA) association of autoantibodies against citrullinated fibronectin in RA. METHODS: Citrullinated residues in fibronectin isolated from RA patient synovial fluid were identified by mass spectrometry. The corresponding citrullinated and non-citrullinated peptides were synthesized and used to analyze the presence of autoantibodies to these peptides in RA sera and sera from other diseases and healthy controls by ELISA. The data were compared with risk factors like shared epitope HLA alleles and smoking, and with clinical features. RESULTS: Five citrullinated residues were identified in fibronectin from RA synovial fluid. RA sera reacted in a citrulline-dependent manner with two out of four citrullinated fibronectin peptides, one of which contains two adjacent citrulline residues, in contrast to non-RA sera, which were not reactive. The most frequently recognized peptide (FN-Cit1035,1036, LTVGLTXXGQPRQY, in which × represents citrulline) was primarily targeted by anti-CCP (cyclic citrullinated peptide) 2-positive RA patients. Anti-FN-Cit1035,1036 autoantibodies were detected in 50% of established anti-CCP2-positive RA patients and in 45% of such patients from a early arthritis clinic. These antibodies appeared to be predominantly of the immunoglobulin G (IgG) isotype and to be associated with HLA shared epitope alleles (odds ratio = 2.11). CONCLUSIONS: Fibronectin in the inflamed synovia of RA patients can be citrullinated at least at five positions. Together with the flanking amino acids, three of these citrullinated residues comprise two epitopes recognized by RA autoantibodies. Anti-citrullinated fibronectin peptide antibodies are associated with HLA shared epitope alleles.
22393128 Low-dose prednisone inclusion in a methotrexate-based, tight control strategy for early rh 2012 Mar 6 BACKGROUND: Treatment strategies for tight control of early rheumatoid arthritis (RA) are highly effective but can be improved. OBJECTIVE: To investigate whether adding prednisone, 10 mg/d, at the start of a methotrexate (MTX)-based treatment strategy for tight control in early RA increases its effectiveness. DESIGN: A 2-year, prospective, randomized, placebo-controlled, double-blind, multicenter trial (CAMERA-II [Computer Assisted Management in Early Rheumatoid Arthritis trial-II]). (International Standard Randomised Controlled Trial Number: ISRCTN 70365169) SETTING: 7 hospitals in the Netherlands. PATIENTS: 236 patients with early RA (duration <1 year). INTERVENTION: Patients were randomly assigned to an MTX-based, tight control strategy starting with either MTX and prednisone or MTX and placebo. Methotrexate treatment was tailored to the individual patient at monthly visits on the basis of predefined response criteria aiming for remission. MEASUREMENTS: The primary outcome was radiographic erosive joint damage after 2 years. Secondary outcomes included response criteria, remission, and the need to add cyclosporine or a biologic agent to the treatment. RESULTS: Erosive joint damage after 2 years was limited and less in the group receiving MTX and prednisone (n = 117) than in the group receiving MTX and placebo (n = 119). The MTX and prednisone strategy was also more effective in reducing disease activity and physical disability, achieving sustained remission, and avoiding the addition of cyclosporine or biologic treatment. Adverse events were similar in both groups, but some occurred less in the MTX and prednisone group. LIMITATION: A tight control strategy for RA implies monthly visits to an outpatient clinic, which is not always feasible. CONCLUSION: Inclusion of low-dose prednisone in an MTX-based treatment strategy for tight control in early RA improves patient outcomes. PRIMARY FUNDING SOURCE: Catharijne Foundation.
22364134 The effects of tumor necrosis factor inhibitors on cardiovascular risk in rheumatoid arthr 2012 There is abundant evidence that rheumatoid arthritis (RA), a chronic inflammatory disorder, is associated with an increased risk for cardiovascular (CV) disease. While there may be several mechanisms contributing to a higher CV risk in RA patients, inflammation is considered to be the main cause explaining the excess CV burden. Inflammatory processes appear pivotal to the atherothrombotic process and are linked to endothelial dysfunction, fatty streak initiation and progression, deterioration of fatty streaks into (unstable) plaques, and plaque rupture. Moreover, systemic inflammation, through tumor necrosis factor (TNF) or related cytokines, appears to accelerate atherothrombosis either directly or via effects on conventional and novel CV risk factors, such as lipids and lipoproteins, blood pressure, haemostatic factors, and insulin resistance. New and highly specific therapeutic agents (TNF inhibitors) may significantly lower CV risk in RA. This review summarizes the evidence base supporting the notion that TNF inhibitors confer benefit CV disease risk in RA.
23011957 A bivariate Bayesian dose-finding procedure applied to a seamless phase I/II trial in rheu 2012 Nov We describe a dose escalation procedure for a combined phase I/II clinical trial. The procedure is based on a Bayesian model for the joint distribution of the occurrence of a dose limiting event and of some indicator of efficacy (both considered binary variables), making no assumptions other than monotonicity. Thus, the chances of each outcome are assumed to be non-decreasing in dose level. We applied the procedure to the design of a placebo-controlled, sequential trial in rheumatoid arthritis, in each stage of which patients were randomized between placebo and all dose levels that currently appeared safe and non-futile. On the basis of data from a pilot study, we constructed five different scenarios for the dose-response relationships under which we simulated the trial and assessed the performance of the procedure. The new design appears to have satisfactory operating characteristics and can be adapted to the requirements of a range of trial situations.
22137924 Anti-TNF therapy. 2011 Aug There are now five anti-tumour necrosis factor (TNF) drugs licenced for use in rheumatoid arthritis. This chapter examines the similarities and differences between the drugs and looks for clues with regard to their rational prescribing. The major difference is between the monoclonal antibody-based drugs and the soluble receptor etanercept. Etanercept exhibits the best drug survival and is also associated with a lower risk of opportunistic infections, particularly tuberculosis. Immunogenicity should explain some of the differences between the different drugs but the lack of standardised assays has hindered this area of research. The optimal approach to the patient who has failed their first anti-TNF remains unclear and awaits appropriate clinical trials. The safety profile of anti-TNFs has become clearer, largely through registry data. There is a small increase in serious and opportunistic infections but there does not appear to be a heightened cancer risk, and cardiovascular risk is probably reduced.
22762068 Rosehip - an evidence based herbal medicine for inflammation and arthritis. 2012 Jul BACKGROUND: Rosehips - which contain a particular type of galactolipid - have a specific antiinflammatory action. A standardised rosehip powder has been developed to maximise the retention of phytochemicals. This powder has demonstrated antioxidant and anti-inflammatory activity as well as clinical benefits in conditions such as osteoarthritis, rheumatoid arthritis and inflammatory bowel disease. OBJECTIVE: To examine the evidence suggesting that standardised rosehip powder may be a viable replacement or supplement for conventional therapies used in inflammatory diseases such as arthritis. DISCUSSION: A meta-analysis of three randomised controlled trials involving 287 patients with a median treatment period of 3 months reported that treatment with standardised rosehip powder consistently reduced pain scores and that patients allocated to rosehip powder were twice as likely to respond to rosehip compared to placebo. In contrast to nonsteroidal anti-inflammatory drugs and aspirin, rosehip has antiinflammatory actions that do not have ulcerogenic effects and do not inhibit platelets nor influence the coagulation cascade or fibrinolysis.
21898060 Repeat etanercept administration restores clinical response of patients with rheumatoid ar 2012 Nov We determined whether repeated treatment with the tumor necrosis factor-α (TNF-α) antagonist etanercept can be effective after an initial clinical response to this drug is lost. We describe three female patients with active, refractory rheumatoid arthritis who were administered with a second course of etanercept after eventually becoming refractory to a first course. Disease activity was high in all three patients before initial etanercept therapy, and each of them had clinically responded by 24 weeks. However, the initial clinical effect was lost between 1.5 and 3.5 years thereafter, and tocilizumab was administered, but the effect was lost again between 3 and 18 months later. Two patients did not respond to subsequent treatment with adalimumab and infliximab. Etanercept administered once again reduced disease activity in all three patients, none of whom developed any acute side effects. Etanercept re-administration significantly improved clinical disease activity and inflammatory parameters in three patients with RA who were refractory to biological anti-TNF agents.
23178792 Reduced apoptosis correlates with enhanced autophagy in synovial tissues of rheumatoid art 2013 Feb OBJECTIVE: Defective apoptosis contributes to the massive synovial hyperplasia in rheumatoid arthritis (RA), but the mechanism is largely unknown. To investigate the reasons for the reduced apoptosis in RA synovium, we analyzed autophagy and its relationship to apoptosis in synovial tissues from RA and osteoarthritis (OA) patients. METHODS: Synovial tissues were obtained from seven RA and 12 OA patients undergoing knee replacement surgery. Apoptosis was detected by the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay and staining for p85 fragment of PolyADP-ribose polymerase (PARP). Autophagy was determined by immunoblotting for the autophagic markers Beclin-1 and LC3. MicroRNA-30a (miR-30a), which targets Beclin-1, was measured by real-time RT-PCR. The interplay between autophagy and apoptosis was determined via Spearman's correlation analysis. RESULTS: In comparison with OA, the synovial tissues from RA displayed decreased TUNEL-positive nuclei (P < 0.01). In contrast, Beclin-1 and LC3 were overexpressed in the synovial lining layers of RA, which was correlated with decreased levels of miR-30a. Moreover, there was a significant reverse relationship between apoptosis and autophagy in RA synovial tissues (P < 0.01 and r = -0.8937). CONCLUSION: The impaired apoptosis in RA synovium might result from increased autophagy, which in turn could be due to the deregulation of miRNA-30a.
21972241 Early menopause is an independent predictor of rheumatoid arthritis. 2012 Mar BACKGROUND: As rheumatoid arthritis (RA) occurs more often in women than in men, it has been suggested that reproductive hormones may play an important role in the pathogenesis. METHODS: Between 1991 and 1996, 30 447 subjects (18 326 women) were included in a community-based health survey. Information on female hormonal changes and stress-related factors was obtained using a self-administered questionnaire. This population was linked to four different local and national RA registers. The medical records for patients with a diagnosis of RA were subjected to a structured review and all women with incident RA according to the 1987 American College of Rheumatology criteria after inclusion in the health survey were included in a nested case-control study. Matched controls (1:4) were selected from the health survey population. RESULTS: Early age at menopause (≤45 years) was associated with the subsequent development of RA (OR 2.42, 95% CI 1.32 to 4.45). The effect of early menopause remained significant after adjusting for smoking, level of education and length of breastfeeding (OR 1.92, 95% CI 1.02 to 3.64) CONCLUSION: RA was predicted by an early age at menopause. This implicates an influence of hormonal changes during the fertile period on the development of RA in postmenopausal women.
21586414 Gluten-free diet in nonceliac disease. 2011 Jun A gluten-free diet (GFD) is commonly recognized as the treatment for celiac disease. It also has been investigated as a treatment option for other medical conditions, including dermatitis herpetiformis, irritable bowel syndrome, neurologic disorders, rheumatoid arthritis, diabetes mellitus, and HIV-associated enteropathy. The strength of the evidence for the use of a GFD in these nonceliac diseases varies, and future research may better define the benefits of a GFD for those conditions with weak existing evidence.
22999909 Improving agreement in assessment of synovitis in rheumatoid arthritis. 2013 Mar OBJECTIVE: Synovitis assessment through evaluation of swollen joints is integral in steering treatment decisions in rheumatoid arthritis (RA). However, there is high inter-observer variation. The objective was to assess if a short collegiate consensus would improve swollen joint agreement between rheumatologists and whether this was affected by experience. METHODS: Eighteen rheumatologists from French university rheumatology units participated in three 30 minutes rounds over a half day meeting evaluating joint counts of RA patients in small groups, followed by short consensus discussions. Agreement was evaluated at the end of each round as follows: (i) global agreement of swollen joints (ii) swollen joint agreement according to level of experience of the rheumatologist (iii) swollen joint count and (iv) agreement of disease activity state according to the Disease Activity Score (DAS28). Agreement was calculated using percentage agreement and kappa. RESULTS: Global agreement of swollen joints failed to improve (kappa 0.50 to 0.52) at the joint level. Agreement between seniors did not improve but agreement between newly qualified rheumatologists and their senior peer, which was initially poor (kappa 0.28), improved significantly (to 0.54) at the end of the consensus exercises. Concordance of DAS28 activity states improved from 71% to 87%. CONCLUSION: Consensus exercises for swollen joint assessment is worthwhile and may potentially improve agreement between clinicians in clinical synovitis and disease activity state, benefit was mostly observed in newly qualified rheumatologists.
21946458 Methotrexate pneumonitis in rheumatoid arthritis: increased prevalence with increasing lat 2011 Oct BACKGROUND: There is an association between increasing prevalence and increasing latitude for some autoimmune diseases, including rheumatoid arthritis (RA). Furthermore, in RA patients, a geographical variation in methotrexate pneumonitis has been suggested at a regional level in New Zealand. OBJECTIVE: The objective of the study was to determine if there is an increased incidence of methotrexate pneumonitis with increasing latitude in New Zealand. METHODS: A search was conducted using the NZ Ministry of Health's National Minimum Data Set for patients with discharge codes for RA (M05, M06) or history of RA and drug-induced lung disease (J702, J703, J704) or other (J189, J680, J90, J984) and methotrexate (Y431), for the period July 1, 1999, to June 30, 2008. Anonymous data were provided by the Ministry of Health for the 43 patients fulfilling these coding criteria and also the latitude and population of each domicile code. A Poisson regression analysis was undertaken with latitude as a continuous variable, adjusting for the total population at different latitudes. RESULTS: The incidence rate ratio for methotrexate pneumonitis shows a 16% increase per 1 degree of latitude (95% confidence interval, 7%-27%; P = 0.02). CONCLUSIONS: There was a latitudinal gradient seen in the rate of patient discharges for methotrexate pneumonitis, in the defined period. This supports the hypothesis that there is a latitude-dependent risk factor for this disorder and raises questions regarding possible environmental cofactors. It also supports the growing pool of evidence that certain immune-mediated conditions are more common at higher latitudes.
22833070 Differential diagnosis of rheumatoid and psoriatic arthritis at an early stage in the smal 2012 Jun The 2 major and clinically most important primary inflammatory rheumatic diseases which affect small hand and feet joints are rheumatoid arthritis (RA) and psoriatic arthritis (PsA). The most important initial histopathological feature of RA is synovitis followed by chronic proliferative granulomatous pannus-tissue, which is associated with cartilage and bone destruction. Early inflammatory changes in RA also develop synchronously within the subchondral bone marrow. Enthesitis is the hallmark of SNSA, and is often seen as one of the first radiological manifestations of the diseases. As a rule inflammation within the synovial joints, histologically similar to RA, is not so pronounced. Consequently destructive changes within the synovial joints are much less with the exception of PsA in which pronounced bone destruction may develop (arthritis mutilans). Considerable overlapping in clinical and morphological manifestation of RA and PsA may be present. For evaluation of hand and feet joints and surrounding soft tissue structures in RA and PsA different imaging modalities are used, which include projection radiography, ultrasonography (US), radionuclide techniques and magnetic resonance imaging (MRI). MRI has become the imaging modality of choice for evaluation of arthritis, when conventional radiography is not conclusive.
23244196 Stages of change, barriers, benefits, and preferences for exercise in RA patients: a cross 2013 OBJECTIVES: To determine the distribution of exercise stages of change in a rheumatoid arthritis (RA) cohort, and to examine patients' perceptions of exercise benefits, barriers, and their preferences for exercise. METHODS: One hundred and twenty RA patients who attended the Rheumatology Unit of a University Hospital were asked to participate in the study. Those who agreed were administered a questionnaire to determine their exercise stage of change, their perceived benefits and barriers to exercise, and their preferences for various features of exercise. RESULTS: Eighty-nine (74%) patients were finally included in the analyses. Their mean age was 58.4 years, mean RA duration 10.1 years, and mean disease activity score 2.8. The distribution of exercise stages of change was as follows: precontemplation (n = 30, 34%), contemplation (n = 11, 13%), preparation (n = 5, 6%), action (n = 2, 2%), and maintenance (n = 39, 45%). Compared to patients in the maintenance stage of change, precontemplators exhibited different demographic and functional characteristics and reported less exercise benefits and more barriers to exercise. Most participants preferred exercising alone (40%), at home (29%), at a moderate intensity (64%), with advice provided by a rheumatologist (34%) or a specialist in exercise and RA (34%). Walking was by far the preferred type of exercise, in both the summer (86%) and the winter (51%). CONCLUSIONS: Our cohort of patients with RA was essentially distributed across the precontemplation and maintenance exercise stages of change. These subgroups of patients exhibit psychological and functional differences that make their needs different in terms of exercise counselling.
23104976 Relative importance of doctor-reported outcomes vs patient-reported outcomes in DMARD inte 2013 Feb OBJECTIVE: For optimal RA management, the current recommendation is to adapt DMARD therapy to the level of inflammation and not only of patient complaints. We designed the DUO (epidemiological study of treatment decison in RA: DROs and PROs) study to assess the relative weight of patient-reported outcomes (PROs) and doctor-reported outcomes (DROs) in DMARD intensification in RA patients. METHODS: This French, observational, multicentre, cross-sectional study was conducted in 2009 on RA patients included by rheumatologists. The percentage of patients with DMARD intensification was evaluated with regard to the concomitant DAS28-ESR and Patient Acceptable Symptom State (PASS) questionnaire assessments. Logistic regression was used to find significant criteria of DMARD intensification. The relative weight of subjective/objective criteria was assessed using attributable risk fractions. RESULTS: A total of 1107 patients were analysed (76% women; median disease duration 6 years); DMARD intensification was proposed to 15% of patients (24% of patients with DAS >3.2 and 33% of patients with non-acceptable PASS). DMARD intensification determinants comprised both DROs (high tender and swollen joint counts) and PROs (high patient global assessment of disease activity), but also short disease duration and rheumatologist characteristics (young, hospital based). Respectively, 61% and 42% of DMARD intensification were attributable to PROs and DROs. CONCLUSION: The DUO study showed DMARD intensification was predominantly based on PROs compared with DROs and influenced by disease duration and type of rheumatology practice. Most RA patients with DAS28 >3.2 had no DMARD intensification.
22640174 Cost utility of tumour necrosis factor-α inhibitors for rheumatoid arthritis: an applicat 2012 Jul 1 BACKGROUND: Rheumatoid arthritis (RA) is a chronic autoimmune disease that affects approximately 1.5 million people in the US. Tumour necrosis factor (TNF)-α inhibitors have been shown to effectively treat and maintain remission in patients with moderately to severely active RA compared with conventional agents. The high acquisition cost of TNF-α inhibitors prohibits access, which mandates economic investigations into their affordability. The lack of head-to-head comparisons between these agents makes it difficult to determine which agent is the most cost effective. OBJECTIVE: This study aimed to determine which TNF-α inhibitor was the most cost-effective agent for the treatment of moderately to severely active RA from the US healthcare payer's perspective. METHODS: A Markov model was constructed to analyse the cost utility of five TNF-α inhibitors (in combination with methotrexate [+MTX]) versus MTX monotherapy using Bayesian methods for evidence synthesis. The model had a cycle length of 3 months and an overall time horizon of 5 years. Transition probabilities and utility scores were based on published studies. Total direct costs were adjusted to year 2009 $US using the medical component of the Consumer Price Index. All costs and QALYs were discounted at a rate of 3% per year. Patient response to the different strategies was determined by the American College of Rheumatology (ACR)50 criteria. One-way and probabilistic sensitivity analyses (PSAs) were performed to test the robustness of the base-case scenario. The base-case scenario was changed to ACR20 criteria (scenario 1) and ACR70 criteria (scenario 2) to determine the model's robustness. Cost-effectiveness acceptability curves and cost-effectiveness frontiers were used to estimate the cost-effectiveness probability of each treatment strategy. A willingness-to-pay (WTP) threshold was defined as three times the US GDP per capita ($US139,143 per additional QALY gained). Primary results were presented as incremental cost-effective ratios (ICERs). RESULTS: Etanercept+MTX was the most cost-effective treatment strategy in the base-case scenario up to a WTP threshold of $US2 185,497 per QALY gained. At a WTP threshold of greater than $US2 185,497 per QALY gained, certolizumab+MTX was the most cost-effective treatment strategy. One-way analyses showed that the base-case scenario was sensitive to the probability of achieving ACR50 criteria for MTX and each TNF-α inhibitor, and changes in the utility score for patients who achieved the ACR50 criteria. With the exception of infliximab, all of the TNF-α inhibitors were sensitive to drug cost per cycle. In the scenario analyses, certolizumab+MTX was a dominant treatment strategy using ACR20 criteria, but etanercept+MTX was a dominant treatment strategy using ACR70 criteria. CONCLUSIONS: Etanercept+MTX was a cost-effective treatment strategy in the base-case scenario; however, the model was sensitive to parameter uncertainties and ACR response criteria. Although Bayesian methods were used to determine transition probabilities, future studies will need to focus on head-to-head comparisons of multiple TNF-α inhibitors to provide valid comparisons.
21444302 Pharmacological induction of interferon type I activity following treatment with rituximab 2011 Jun OBJECTIVE: Despite the fact that rituximab depletes B cells in all treated patients with RA, not all patients show a favourable clinical response. The goal of this study was to provide insight into pharmacological changes in peripheral blood that are associated with clinical response to rituximab. METHODS: Gene expression profiling was performed on peripheral blood RNA of 13 patients with RA (test group) using Illumina HumanHT beadchip microarrays. An independent group of nine patients was used for validation using TaqMan quantitative PCR. Clinical responder status was determined after 6 months using change in 28-joint Disease Activity Score (ΔDAS28) and European League Against Rheumatism (EULAR) response criteria. Significance analysis of microarrays and ontology analysis were used for data analysis and interpretation. RESULTS: Pharmacogenomic analyses demonstrated marked interindividual differences in the pharmacological responses at 3 and 6 months after start of treatment with rituximab. Interestingly, only differences in the regulation of type I interferon (IFN)-response genes after 3 months correlated with the ΔDAS28 response. Good responders (DAS>1.2; n=7) exhibited a selective increase in the expression of type I IFN-response genes, whereas this activity was unchanged or hardly changed in non-responders (DAS<1.2; n=6) (p=0.0040 at a cut-off of 1.1-fold induction). Similar results were obtained using EULAR response criteria. These results were validated in an independent cohort of nine patients (five non-responders and four responders, p=0.0317). CONCLUSIONS: A good clinical response to rituximab in RA is associated with a selective drug-induced increase in type I IFN-response activity in patients with RA. This finding may provide insight in the biological mechanism underlying the therapeutic response to rituximab.