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ID PMID Title PublicationDate abstract
21044434 Drug combinations with methotrexate to treat rheumatoid arthritis. 2010 Sep MTX is still considered the anchor drug among the disease-modifying antirheumatic agents, and it is widely accepted as first line treatment in the management of rheumatoid arthritis (RA). The ultimate therapeutic goal in treatment of RA is remission or at least low disease activity and this goal may not always be achieved with MTX monotherapy. Over the last two decades drug combinations based on MTX have been used increasingly to treat patients with RA. Combination DMARD therapy may be used initially or in a step-up strategy after MTX monotherapy in patients with persistently active disease on monotherapy. Many different MTX based combination regimens have been studied. Frequently used combinations on an MTX background include leflunomide, cyclosporine, azathioprine, sulfasalazine, gold and hydroxychloroquine. In conclusion, the use of MTX in combination with other DMARDs may still represent a valuable therapeutic option in patients who fail to DMARD monotherapy or in whom combination therapy is considered initially. However, in patients at risk for rapid radiographic progression, the early use of biologics has to be considered.
20480201 Clinical evaluation of tocilizumab for patients with active rheumatoid arthritis refractor 2010 Aug We retrospectively observed the clinical efficacy and safety of tocilizumab (TCZ) in 74 patients with rheumatoid arthritis (RA) at 13 hospitals, without any restrictions on disease duration or stage, treatment history, and other influencing factors. TCZ was infused by the approved method, and disease activity was evaluated every 4 weeks until week 24 using a joint disease activity score (DAS28). Remission and treatment response were categorised using European League Against Rheumatism (EULAR) definitions. We also analysed the impact of previous treatment with other biologics and of concomitant methotrexate (MTX) therapy on the efficacy of TCZ. At week 24, the DAS28 had improved from 5.5 to 2.7 and the EULAR remission rate was 55.2%. Good and moderate responses according to the EULAR criteria were obtained in 61 and 36% of the patients, respectively. The biologic-naïve group had a significantly better DAS28 (2.1 vs. 2.8) and a significantly higher "good" response rate (86% vs. 54%) than the biologic-exposed group. Although the TCZ + MTX treatment group and the TCZ monotherapy group had a good response rate of 71 and 48%, respectively, the difference was not significant. Based on these results, we conclude that TCZ is able to significantly alleviate disease symptoms in a wide range of patients with RA in a normal clinical context.
20187135 Two-year clinical and radiographic results with combination etanercept-methotrexate therap 2010 Mar OBJECTIVE: To evaluate how continuation of and alterations to initial year 1 combination etanercept-methotrexate (MTX) therapy and MTX monotherapy regimens affect long-term remission and radiographic progression in early, active rheumatoid arthritis. METHODS: Subjects were randomized at baseline for the entire 2-year period; those who completed 1 year of treatment with combination or MTX monotherapy entered year 2. The original combination group either continued combination therapy (the EM/EM group; n = 111) or received etanercept monotherapy (the EM/E group; n = 111) in year 2; the original MTX monotherapy group either received combination therapy (the M/EM group; n = 90) or continued monotherapy (the M/M group; n = 99) in year 2. Efficacy end points included remission (a Disease Activity Score in 28 joints [DAS28] <2.6) and radiographic nonprogression (change in the modified Sharp/van der Heijde score < or = 0.5) at year 2. A last observation carried forward analysis from the modified intention-to-treat population (n = 398) and a post hoc nonresponder imputation (NRI) analysis (n = 528) were performed for remission. RESULTS: At year 2, DAS28 remission was achieved by 62/108, 54/108, 51/88, and 33/94 subjects in the EM/EM, EM/E, M/EM, and M/M groups, respectively (P < 0.01 for the EM/EM and M/EM groups versus the M/M group). This effect was corroborated by a more conservative post hoc 2-year NRI analysis, with remission observed in 59/131, 50/134, 48/133, and 29/130 of the same respective groups (P < 0.05 for each of the EM/EM, EM/E, and M/EM groups versus the M/M group). The proportions of subjects achieving radiographic nonprogression (n = 360) were 89/99, 74/99, 59/79, and 56/83 in the EM/EM (P < 0.01 versus each of the other groups), EM/E, M/EM, and M/M groups, respectively. No new safety signals or between-group differences in serious adverse events were seen. CONCLUSION: Early sustained combination etanercept-MTX therapy was consistently superior to MTX monotherapy. Combination therapy resulted in important clinical and radiographic benefits over 2 study years, without significant additional safety risk.
19357113 Efficacy and safety of pamapimod in patients with active rheumatoid arthritis receiving st 2010 Feb OBJECTIVE: To determine the efficacy and safety of pamapimod in adult patients with active rheumatoid arthritis (RA) who had an inadequate clinical response to methotrexate (MTX). METHODS: Patients receiving stable doses of MTX were randomised to one of six dose groups and received 12 weeks of double-blind pamapimod (up to 300 mg once daily) or matching placebo. The primary efficacy measure was the proportion of patients with > or =20% improvement in RA based on the American College of Rheumatology criteria (ACR20) at 12 weeks. Secondary measures were ACR50, Disease Activity Score (DAS)/European League Against Rheumatism (EULAR) responses and the individual ACR core set of parameters. Safety measures included adverse events (AEs), laboratory testing and immunology assessments. RESULTS: On a background of MTX, the percentage of patients with an ACR20 response at week 12 in the pamapimod groups (31% to 43%) was not significantly different from placebo (34%). Secondary efficacy end points showed a similar pattern. AEs were typically mild and included infections, gastrointestinal disturbances, dizziness and rashes; AEs resulting in discontinuation of study drug were primarily attributed to infections. CONCLUSION: In patients with active RA receiving stable doses of MTX, pamapimod showed non-significant improvement in efficacy outcomes compared to placebo.
19644853 Determinants of red blood cell methotrexate polyglutamate concentrations in rheumatoid art 2009 Aug OBJECTIVE: Methotrexate (MTX) is the most commonly used disease-modifying antirheumatic drug (DMARD) in the management of rheumatoid arthritis (RA). MTX is transported into cells, where additional glutamate moieties are added and it is retained as MTX polyglutamates (MTXGlu [referred to as a group as MTXGlun]). There is large interpatient variability in MTXGlun concentrations. This study was undertaken to determine nongenetic factors that influence red blood cell (RBC) MTXGlun concentrations in patients receiving long-term stable low-dose oral MTX. METHODS: One hundred ninety-two patients receiving long-term oral MTX for the treatment of RA were recruited. Trough MTXGlun concentrations were measured by high-performance liquid chromatography. Univariate analysis was performed to determine variables influencing MTXGlun concentrations. Backward stepwise multivariate regression analysis was done to determine variables that affect individual MTXGlun concentrations; variables with P values of <0.1 in the univariate analysis for any MTXGlun were included. RESULTS: Univariate analysis revealed that increased age, lower estimated glomerular filtration rate (GFR), higher MTX dosage, longer duration of MTX treatment, and use of prednisone were associated with significantly higher MTXGlun concentrations. Smokers had significantly lower concentrations of MTXGlu3, MTXGlu3-5, and MTXGlu1-5. Sex, rheumatoid factor and anti-cyclic citrullinated peptide status, RBC folate level, and body mass index had no significant effect on MTXGlun levels. Concomitant use of other DMARDs was associated with lower MTXGlu2 levels, and treatment with nonsteroidal antiinflammatory drugs was associated with lower MTXGlu3 and MTXGlu1-5 concentrations. Multivariate regression analysis revealed that age, MTX dosage, and estimated GFR were the major determinants of MTXGlun concentrations. CONCLUSION: Large interpatient variability in MTXGlun concentrations can be explained, at least in part, by a combination of factors, particularly age, MTX dosage, and renal function. There are complex interactions between smoking, RBC folate levels, and concentrations of MTXGlun.
19862529 Recurrent pneumothorax associated with pulmonary nodules after leflunomide therapy in rheu 2011 Jul Rheumatoid arthritis (RA) is a multisystem inflammatory disease characterized by destructive synovitis and systemic extraarticular involvement. One of the most common pulmonary manifestations of RA is rheumatoid nodule. Spontaneous pneumothorax also very rare pulmonary finding and could be associated with pulmonary nodules. Antirheumatic drugs, methotrexate, leflunomide (LEF), infliximab and etanercept, were known as risk factors for developing rheumatoid nodule. However, there was no case report of rheumatoid nodule-associated pneumothorax with the use of LEF. We report, first, herein a case of 46-year-old woman with RA who suffered recurrent spontaneous pneumothorax associated with multiple bilateral subpleural cavitary nodules during treatment with LEF. We reviewed the cases of LEF-related pulmonary nodules developed in patients with RA. Thus, we suggested that pneumothorax can be a rare respiratory fatal complication in patients with RA with pulmonary nodules and LEF can be a rare cause of these manifestations.
19695086 Improving healthcare consumer effectiveness: an Animated, Self-serve, Web-based Research T 2009 Aug 20 BACKGROUND: People with rheumatoid arthritis (RA) should use DMARDs (disease-modifying anti-rheumatic drugs) within the first three months of symptoms in order to prevent irreversible joint damage. However, recent studies report the delay in DMARD use ranges from 6.5 months to 11.5 months in Canada. While most health service delivery interventions are designed to improve the family physician's ability to refer to a rheumatologist and prescribe treatments, relatively little has been done to improve the delivery of credible, relevant, and user-friendly information for individuals to make treatment decisions. To address this care gap, the Animated, Self-serve, Web-based Research Tool (ANSWER) will be developed and evaluated to assist people in making decisions about the use of methotrexate, a type of DMARD. The objectives of this project are: 1) to develop ANSWER for people with early RA; and 2) to assess the extent to which ANSWER reduces people's decisional conflict about the use of methotrexate, improves their knowledge about RA, and improves their skills of being 'effective healthcare consumers'. METHODS/DESIGN: Consistent with the International Patient Decision Aid Standards, the development process of ANSWER will involve: 1.) creating a storyline and scripts based on the best evidence on the use of methotrexate and other management options in RA, and the contextual factors that affect a patient's decision to use a treatment as found in ERAHSE; 2.) using an interactive design methodology to create, test, analyze and refine the ANSWER prototype; 3.) testing the content and user interface with health professionals and patients; and 4.) conducting a pilot study with 51 patients, who are diagnosed with RA in the past 12 months, to assess the extent to which ANSWER improves the quality of their decisions, knowledge and skills in being effective consumers. DISCUSSION: We envision that the ANSWER will help accelerate the dissemination of knowledge and skills necessary for people with early RA to make informed choices about treatment and to manage their health. The latest in animation and online technology will ensure ANSWER fills a knowledge translation gap, focusing on the next generation of people living with RA.
19765281 Suppressive effect of secretory phospholipase A2 inhibitory peptide on interleukin-1beta-i 2009 INTRODUCTION: Secretory phospholipase A2 (sPLA2) and matrix metalloproteinase (MMP) inhibitors are potent modulators of inflammation with therapeutic potential, but have limited efficacy in rheumatoid arthritis (RA). The objective of this study was to understand the inhibitory mechanism of phospholipase inhibitor from python (PIP)-18 peptide in cultured synovial fibroblasts (SF), and to evaluate its therapeutic potential in a human tumor necrosis factor (hTNF)-driven transgenic mouse (Tg197) model of arthritis. METHODS: Gene and protein expression of sPLA2-IIA, MMP-1, MMP-2, MMP-3, MMP-9, tissue inhibitor of metalloproteinase (TIMP)-1, and TIMP-2 were analyzed by real time PCR and ELISA respectively, in interleukin (IL)-1beta stimulated rheumatoid arthritis (RA) and osteoarthritis (OA) synovial fibroblasts cells treated with or without inhibitors of sPLA2 (PIP-18, LY315920) or MMPs (MMP Inhibitor II). Phosphorylation status of mitogen-activated protein kinase (MAPK) proteins was examined by cell-based ELISA. The effect of PIP-18 was compared with that of celecoxib, methotrexate, infliximab and antiflamin-2 in Tg197 mice after ip administration (thrice weekly for 5 weeks) at two doses (10, 30 mg/kg), and histologic analysis of ankle joints. Serum sPLA2 and cytokines (tumor necrosis factor (TNF)alpha, IL-6) were measured by Escherichia coli (E coli) assay and ELISA, respectively. RESULTS: PIP-18 inhibited sPLA2-IIA production and enzymatic activity, and suppressed production of MMPs in IL-1beta-induced RA and OA SF cells. Treatment with PIP-18 blocked IL-1beta-induced p38 MAPK phosphorylation and resulted in attenuation of sPLA2-IIA and MMP mRNA transcription in RA SF cells. The disease modifying effect of PIP-18 was evidenced by significant abrogation of synovitis, cartilage degradation and bone erosion in hTNF Tg197 mice. CONCLUSIONS: Our results demonstrate the benefit that can be gained from using sPLA2 inhibitory peptide for RA treatment, and validate PIP-18 as a potential therapeutic in a clinically relevant animal model of human arthritis.
20024555 Serum chemokines in patients with rheumatoid arthritis treated with etanercept. 2011 Apr Chemokines promote leucocyte traffic into the synovium, leading to the initiation and progression of the rheumatoid arthritis (RA). The aim of the study was to determine the effects of etanercept, a soluble tumour necrosis factor receptor (sTNFr), on the serum chemokines levels in patients with active RA. Patients were treated with 50 mg of subcutaneous injection of etanercept per week and methotrexate (10-25 mg/week). Serum levels of interleukin-8 (IL-8), RANTES (regulated upon activation, normal T cell expressed and secreted) and monocyte chemoattractant protein-1 (MCP-1) were assessed by ELISA at months 0, 3, 6, 9 and 12, prior to injection. 3-month treatment with etanercept diminished serum concentrations of IL-8, RANTES and MCP-1 (P < 0.05, P < 0.01 and P < 0.001, respectively). Subsequent etanercept administrations prolonged decrease in serum chemokines levels and in the case of IL-8 even intensified the reduction of its concentration in serum. These changes were accompanied by significant decrease of disease activity score (DAS28) (in all cases P < 0.001). Prior to the first etanercept administration, serum concentrations of studied chemokines correlated with markers of RA activity such as the erythrocyte sedimentation rate (ESR) and DAS28. Following next drug injection such associations were less or not significant. Therapy with etanercept and MTX not only caused a clinical improvement but also diminished serum chemokines levels in RA patients. Further treatment with etanercept sustained chemokines suppression.
19248091 Involvement of breast cancer resistance protein expression on rheumatoid arthritis synovia 2009 Mar OBJECTIVE: To determine whether multidrug-resistance efflux transporters are expressed on immune effector cells in synovial tissue from patients with rheumatoid arthritis (RA) and compromise the efficacy of methotrexate (MTX) and leflunomide (LEF). METHODS: Synovial tissue biopsy samples obtained from RA patients before treatment and 4 months after starting treatment with MTX (n = 17) or LEF (n = 13) were examined by immunohistochemical staining and digital image analysis for the expression of the drug efflux transporters P-glycoprotein, multidrug resistance-associated protein 1 (MRP-1) through MRP-5, MRP-8, MRP-9, and breast cancer resistance protein (BCRP), and the relationship to clinical efficacy of MTX and LEF was assessed. RESULTS: BCRP expression was observed in all RA synovial biopsy samples, both pretreatment and posttreatment, but not in control noninflammatory synovial tissue samples from orthopedic patients. BCRP expression was found both in the intimal lining layer and on macrophages and endothelial cells in the synovial sublining. Total numbers of macrophages in RA patients decreased upon treatment; in biopsy samples with persistently high macrophage counts, 2-fold higher BCRP expression was observed. Furthermore, median BCRP expression was significantly increased (3-fold) in nonresponders to disease-modifying antirheumatic drugs (DMARDs) compared with responders to DMARDs (P = 0.048). Low expression of MRP-1 was found on synovial macrophages, along with moderate expression in T cell areas of synovial biopsy specimens from one-third of the RA patients. CONCLUSION: These findings show that the drug resistance-related proteins BCRP and MRP-1 are expressed on inflammatory cells in RA synovial tissue. Since MTX is a substrate for both BCRP and MRP-1, and LEF is a high-affinity substrate for BCRP, these transporters may contribute to reduced therapeutic efficacy of these DMARDs.
20574650 Elevated level of serum cystatin-C concentration is a useful predictor for myelosuppressio 2010 Dec Methotrexate (MTX) is indispensable for the treatment of rheumatoid arthritis (RA). However, a small number of patients treated with MTX occasionally encounter some life-threatening events, including myelosuppression. Renal insufficiency, one of risk factors for these events, is difficult to assess because the serum creatinine concentration level and estimated glomerular filtration rate are sometimes inaccurately determined in aged RA patients. As a better indicator to evaluate this pathology, we measured the serum cystatin-C (Cys-C) level in 78 RA patients ≥ 50 years who were treated with MTX and observed for a year. The measurement achieved successful screening of two patients with leukocytopenia, one with interstitial lung disease (ILD), and two with liver dysfunction. An additional four referral inpatients with MTX-induced adverse events (three with pancytopenia, one with ILD) were enrolled for analysis, amounting to 82 patients. The logistic regression analysis showed that a correlation was observed between myelotoxicity and serum Cys-C level (elevation per 0.1 mg/dl; odds ratio 2.34, 95% confidence interval 1.08-5.09, p = 0.03). In conclusion, elderly RA patients potentially have subclinical renal insufficiency detected by the serum Cys-C concentration level. The elevated level of serum Cys-C is a more sensitive indicator to predict MTX-induced myelotoxicity than that of serum creatinine.
20007620 A new design for registration trials in rheumatoid arthritis allowing secondary head-to-he 2010 Jan Current drug development programs produce high quality data on the efficacy of new drugs, substantial data on safety, but little data on actual applicability of the new product compared to standard of care. After successful registration and launch, such data require years to accumulate and often remain incomplete. This viewpoint proposes a new trial design for phase 2 and 3 drug trials in rheumatoid arthritis. In this design the trial starts conventionally: patients that are inadequate responders to standard treatment (usually methotrexate) are randomised to receive the experimental drug or placebo on the background of continued (methotrexate) treatment. However, after 3 months all patients in the placebo group are additionally treated with one and the same standard of care treatment (usually an inhibitor of tumour necrosis factor) and all patients in the experimental group are additionally treated with a placebo corresponding to the chosen standard of care treatment. This design allows primary assessment of efficacy and safety of the experimental drug compared with placebo at the ethically acceptable limit of 3 months, followed by secondary assessments of efficacy (including durability) and safety compared to standard of care. The secondary assessments are observational and thus more prone to bias, but it is argued that the potential for bias is limited in this setting. Widespread adoption of the design will greatly help to determine the place of a new product in the spectrum of treatment possibilities of rheumatoid arthritis.
19000788 Differential influences of bucillamine and methotrexate on the generation of fibroblast-li 2009 Jan We have recently demonstrated that bone marrow CD34+ cells from rheumatoid arthritis (RA) patients displayed abnormal capacities to respond to TNF-alpha and to differentiate into fibroblast-like cells producing MMP-1 (type B synoviocyte -like cells). The current study examined the effects of representative potent disease-modifying antirheumatic drugs, including bucillamine (BUC) and methotrexate (MTX) on the in vitro generation of fibroblast-like cells from RA bone marrow CD34+ cells. CD34+ cells purified from bone marrow specimens of 8 patients with active RA were cultured in the presence or absence of pharmacologically attainable concentrations of intramolecular disulfide form of bucillamine (BUC-ID, 3 microM), a major metabolite of BUC or MTX (20 nM). After incubation for 28 days, the generation of fibroblast-like cells was assessed under phase-contrast light microscopy and the concentrations of MMP-1 and VEGF in the culture supernatants were measured by ELISA. BUC-ID, but not MTX, significantly suppressed the generation of fibroblast-like cells from RA bone marrow CD34+ cells stimulated with SCF, GM-CSF and TNF-alpha (p=0.024 as determined by Wilcoxon signed rank test). Accordingly, BUC-ID, but not MTX, significantly suppressed the production of MMP-1 (p=0.017) and VEGF (p=0.017) by RA bone marrow CD34+ cells, without inhibition of beta2-microglobulin production. These results demonstrate that BUC-ID, but not MTX, is a potent inhibitor of differentiation of fibroblast-like cells from RA bone marrow CD34+ cells. Since MTX, but not BUC, has been previously shown to influence on type A synoviocytes, the data provide rationale of combination of BUC and MTX in the treatment of RA.
21085018 The safety and effectiveness of a chloroform/methanol extract of Tripterygium wilfordii Ho 2010 Dec OBJECTIVES: The objective of the study was to assess the safety and effectiveness of the chloroform/methanol extract of Tripterygium wilfordii Hook F (T2) plus methotrexate (MTX) in treating patients with rheumatoid arthritis (RA). METHODS: One hundred sixty-six patients with RA, who started the combination therapy of T2 (20 mg b.i.d. or t.i.d.) and MTX (10-12.5 mg/wk), were enrolled, and these patients were followed up for at least 1 year. Demographics, disease severity, markers of disease activity before and after the combination therapy, and incidence of adverse events were evaluated. RESULTS: The patients were predominantly female (n = 134, 81%) with a mean age of 58.0 (SD, 7.9) years (range, 39-79 years) and a mean disease duration of 55.0 (SD, 72.2) months (range, 0-456 months). A total of 161, 161, 146, and 85 patients had received at least 1, 3, 12, and 24 months of the combination of T2 and MTX, with a total of 4162 patient-months' exposure to the combination therapy. The combination therapy reduced tender and swollen joint counts, morning stiffness, inflammatory indices such as ESR and CRP, and improved disease activity as measured by the DAS28 significantly by 3 months as well as 12 months (P < 0.05). Most of the adverse events noted during this study were mild. Menstrual irregularity occurred in 72.7% (16/22) of premenopausal female. Only 10 (6.0%) and 8 (4.8%) subjects withdrew because of adverse events or lack of efficacy, respectively. Severe infections were very rare. CONCLUSION: T2 plus MTX is an effective and relatively safe treatment for RA patients.
19043773 Developing of granulomatous thyroiditis during etanercept therapy. 2009 Jun We describe a 32-year-old man who developed granulomatous thyroiditis (GT) during etanercept therapy for rheumatoid arthritis (RA). Fever and thyroid pain developed 8 months after administration of etanercept. Noncaseating epithelioid cell granulomas consistent with GT were detected in a thyroid biopsy. Tissue staining and cultures for bacteria, mycobacterium, and fungus were all negative. Etanercept therapy was withdrawn and steroids regime was indicated with clinical and laboratory improvement. A month after, the patient developed hypothyroidism and recurrence of RA. A year after, the patient is asymptomatic with rituximab, methotrexate, and levothyroxine therapy. We report a case of GT probably in an etanercept-induced granulomatous reaction context.
20711095 Central diabetes insipidus induced by tuberculosis in a rheumatoid arthritis patient. 2010 Apr Tuberculosis, a polymorphic disease, is a diagnostic challenge, particularly when arises concomitantly to an autoimmune disease such as rheumatoid arthritis (RA). Herein, the authors describe a 33-year-old woman with nodular RA who was being treated with methotrexate, sulfasalazine and corticosteroids and presented with subcutaneous nodules simultaneously with aseptic meningitis. Mycobacterium tuberculosis was identified in cultures from a biopsy of an axillary nodule. The patient also developed polyuria and polydipsia with normal glycemia; antidiuretic hormone (ADH) treatment before and after a 3% saline infusion test was performed and diabetes insipidus was diagnosed. An encephalic MRI showed sellar and suprasellar masses, suggesting central diabetes insipidus (CDI). The patient received standard tuberculosis (TB) treatment for 6 months and also DDAVP (desmopressin acetate) during this period. Control of CDI was observed. A pre-surgical magnetic resonance imaging (MRI) showed no pituitary mass. It is known that intrasellar tuberculoma occurs in only 1% of TB patients. TB should be considered in the differential diagnosis of CDI, especially in immunosupressed patients and in countries where this infection is a serious public health problem.
20447954 Current evidence for the management of rheumatoid arthritis with synthetic disease-modifyi 2010 Jun OBJECTIVES: To assess the efficacy and safety of synthetic disease-modifying antirheumatic drugs (DMARDs) in adults with rheumatoid arthritis (RA)-a first step in a European League Against Rheumatism (EULAR) initiative to produce recommendations for the management of RA. METHODS: A systematic review of the literature using PubMed, Embase and the Cochrane library was performed up to January 2009. All randomised controlled trials (RCTs) reporting the efficacy of synthetic DMARDs (vs placebo or other synthetic DMARDs) on signs and symptoms, disability and/or radiographic structural damage in patients with RA were selected. Studies of biological agents or glucocorticoids were excluded. A pooled effect size (ES) was calculated by meta-analysis. Safety and the occurrence of infections and neoplasia was also assessed. RESULTS: 97 RCTs (14 159 patients) were analysed for efficacy. The pooled analysis indicated that methotrexate (MTX) was more efficacious in reducing signs and symptoms, disability and radiographic structural damage than other synthetic DMARDs pooled: ES for swollen joint count (SJC) versus pooled DMARDs=1.42 (95% CI 0.65 to 2.18). Leflunomide appeared to be as effective as MTX. Sulfasalazine and injectable gold were efficacious in reducing signs and symptoms and structural damage. Ciclosporin, minocycline, tacrolimus and hydroxychloroquine showed some efficacy in reducing SJC. Auranofin and D-penicillamine showed no significant superiority over placebo. The risks of cancer and of infection were increased with cyclophosphamide and azathioprine. CONCLUSIONS: MTX was well-tolerated and effective in reducing signs and symptoms, disability and structural damage. A comparison with other synthetic DMARDs was in favour of MTX, though at the tested doses MTX and leflunomide were equally effective.
20032971 CD11c as a transcriptional biomarker to predict response to anti-TNF monotherapy with adal 2010 Mar We performed transcription profiling using monocytes to identify predictive markers of response to anti-tumor necrosis factor (anti-TNF) therapy in patients with rheumatoid arthritis (RA). Several potential predictors of response were identified, including CD11c. Validation in samples from independent cohorts (total of n = 27 patients) using reverse transcription-PCR confirmed increased expression of CD11c in responders to adalimumab (100% sensitivity; 91.7% specificity, power 99.6%; alpha = 0.01). Pretherapy CD11c levels significantly correlated with the response criteria as defined by the American College of Rheumatology (ACR) (r = 0.656, P < 0.0001). However, CD11c was neither predictive of response to methotrexate (MTX) alone (n = 34) nor to MTX in combination with adalimumab (n = 16). Clinical responders revealed a reset to a normal expression pattern of resident/inflammatory monocyte markers, which was absent in nonresponders. Therefore, an analysis of key cell types identifies potentially predictive biomarkers that may help to restrict the use of adalimumab to therapy responders. Larger studies, including studies of monotherapy with other drugs, are now needed to confirm and validate the specificity of CD11c for anti-TNF biologics.
19124524 Clinical efficacy and safety of abatacept in methotrexate-naive patients with early rheuma 2009 Dec OBJECTIVES: To assess the efficacy and safety of abatacept in methotrexate-naive patients with early rheumatoid arthritis (RA) and poor prognostic factors. METHODS: In this double-blind, phase IIIb study, patients with RA for 2 years or less were randomly assigned 1 : 1 to receive abatacept (approximately 10 mg/kg) plus methotrexate, or placebo plus methotrexate. Patients were methotrexate-naive and seropositive for rheumatoid factor (RF), anti-cyclic citrullinated protein (CCP) type 2 or both and had radiographic evidence of joint erosions. The co-primary endpoints were the proportion of patients achieving disease activity score in 28 joints (DAS28)-defined remission (C-reactive protein) and joint damage progression (Genant-modified Sharp total score; TS) at year 1. Safety was monitored throughout. RESULTS: At baseline, patients had a mean DAS28 of 6.3, a mean TS of 7.1 and mean disease duration of 6.5 months; 96.5% and 89.0% of patients were RF or anti-CCP2 seropositive, respectively. At year 1, a significantly greater proportion of abatacept plus methotrexate-treated patients achieved remission (41.4% vs 23.3%; p<0.001) and there was significantly less radiographic progression (mean change in TS 0.63 vs 1.06; p = 0.040) versus methotrexate alone. Over 1 year, the frequency of adverse events (84.8% vs 83.4%), serious adverse events (7.8% vs 7.9%), serious infections (2.0% vs 2.0%), autoimmune disorders (2.3% vs 2.0%) and malignancies (0.4% vs 0%) was comparable for abatacept plus methotrexate versus methotrexate alone. CONCLUSIONS: In a methotrexate-naive population with early RA and poor prognostic factors, the combination of abatacept and methotrexate provided significantly better clinical and radiographic efficacy compared with methotrexate alone and had a comparable, favourable safety profile.
19811562 Lack of association between elevated mean red cell volume and haematological toxicity in p 2010 Aug AIMS: It has been suggested that elevated mean red cell volume (MCV) may be a predictor of haematological toxicity in rheumatoid arthritis (RA) patients receiving methotrexate (MTX). We wished to identify whether there was an association between MCV, red cell folate and haematological toxicity in patients on MTX monotherapy for the long-term management of RA. METHODS: Evidence of haematological toxicity was sought by note review of patients recruited in a cross-sectional study of MTX monotherapy in RA. Retrospective data included MCVs from before MTX initiation and after 3 and 6 months of treatment. Data were collected prospectively every 6 months for up to 2 years after enrolment. Any record of cytopenia or the development of haematological malignancy was recorded from commencement of MTX until the present day. Red cell folate concentrations were tested on enrolment to the study. RESULTS: A total of 165 patients was included, 74.5% female, median disease duration 7 years (range 3 months-57 years). The median duration of MTX treatment was 74.9 months (range 10-241 months) giving 1030.2 patient-years of MTX exposure. Twenty-four patients (14.5%) had a MCV > 98 fL on study entry. Evidence of haematological abnormality was found in six patients (3.6%); chronic lymphocytic leukaemia (1), persistent lymphocytosis (1), persistent monocytosis (1) and neutropenia (3). There was no association between red cell folate or MCV and haematological toxicity. CONCLUSION: Neutropenia and pancytopenia are rare side-effects of MTX therapy in this cohort. Elevated MCV or low mean red cell folate does not appear to be associated with haematological malignancy or toxicity in this cohort of patients on long-term MTX therapy.