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ID PMID Title PublicationDate abstract
18438841 Association between the level of circulating bioactive tumor necrosis factor alpha and the 2008 May OBJECTIVE: The tumor necrosis factor alpha (TNFalpha) -308A polymorphism has been associated with high production of TNFalpha and poor response to anti-TNFalpha therapy, but these associations remain controversial. The aim of this study was to explore the association between circulating TNFalpha bioactivity, the TNFalpha -308 polymorphism, and the clinical response to infliximab in patients with rheumatoid arthritis (RA). METHODS: One hundred ninety-eight patients with RA were treated with infliximab and methotrexate. Responses at 6 months according to the American College of Rheumatology (ACR) preliminary criteria for improvement in RA were recorded. Genotyping for the TNFalpha -308 polymorphism was performed by enzyme-linked oligosorbent assay. Circulating TNFalpha bioactivity was evaluated in 50 patients with RA by assessing the production of interleukin-6 (IL-6) in synoviocytes induced by a small amount of TNFalpha plus plasma. IL-6 production in 48-hour supernatants and the levels of TNFalpha protein and IL-6 were measured by enzyme-linked immunosorbent assay. RESULTS: The TNFalpha -308 polymorphism was not associated with the ACR response to infliximab. The level of circulating TNFalpha bioactivity was higher in patients with the TNFalpha -308 A/A or A/G genotype than that in patients with the G/G genotype (median 50.0 ng/ml [interquartile range (IQR) 31.5-62.0] versus 33.0 ng/ml [IQR 16.5-47.5]; P < 0.02). However, no difference was observed for the TNFalpha protein level according to genotype (median 0.62 pg/ml [IQR 0.00-8.85] for G/G versus 3.35 pg/ml [IQR 1.55-4.63] for A/A or A/G; P not significant). The level of circulating TNFalpha bioactivity was higher in good responders (> or =50% improvement) than in poor responders (< or =20% improvement) (median 45.0 ng/ml [IQR 21.0-59.0] versus 28.0 ng/ml [IQR 14.0-39.0]; P = 0.05). However, the level of TNFalpha protein was similar in both groups. CONCLUSION: The level of functional circulating TNFalpha is partially genetically determined and is predictive of the clinical response to infliximab. Nonresponders to anti-TNFalpha therapy are likely to have a disease that is not primarily driven by TNFalpha.
18238787 Kidney disease in RA patients: prevalence and implication on RA-related drugs management: 2008 Mar OBJECTIVES: The prevalence of kidney disease (KD) indicators together with the profile of RA drugs prescribed in RA patients was investigated in the MATRIX study (MeThotreXate And Renal Insufficiency). METHODS: Renal function (RF) was assessed using Cockcroft-Gault (CG) and abbreviated Modification of Diet in Renal Disease (aMDRD) study formulae. RESULTS: Serum creatinine (SCr) was normal in 81.4% of the 129 patients included. According to the National Kidney Foundation (NKF) classification, the distribution by stage of KD was, using the aMDRD and CG formulae, as follows: stage 1: 11.3% and 11.4%; stage 2: 20.0% and 20.3%; stage 3: 15.0% and 24.1%; stage 4: 0% and 1.3%; stage 5: 0%. Proteinuria, haematuria and leucocyturia were observed in 16%, 17% and 20% of the patients, respectively. Using the aMDRD and CG formulae, 36% and 38% of the prescriptions made in patients with glomerular filtration rate (GFR) <60 ml/min required a dosage adjustment. Among the patients with GFR <60 ml/min, 83-90% received at least one drug that required a dosage adjustment and 67-70% received at least one drug that was potentially nephrotoxic, according to aMDRD or CG formulae, respectively. Five (50%) and 8 (47%) patients did not have appropriate MTX dosage adjustment according to their stage of KD with aMDRD or CG formulae, respectively. CONCLUSION: Systematic estimation of RF with CG or aMDRD formulae and urine dipstick are necessary in RA patients. In patients with KD at high risk for drug toxicity, dosage should be adapted to RF.
18979150 Study of active controlled tocilizumab monotherapy for rheumatoid arthritis patients with 2009 We investigated the clinical efficacy and safety of tocilizumab (a humanized anti-IL-6 receptor antibody) monotherapy in active rheumatoid arthritis (RA) patients with an inadequate response to low dose methotrexate (MTX). In a multicenter, double-blind, randomized, controlled trial, 125 patients were allocated to receive either tocilizumab 8 mg/kg every 4 weeks plus MTX placebo (tocilizumab group) or tocilizumab placebo plus MTX 8 mg/week (control group) for 24 weeks. The clinical responses were measured using the American College of Rheumatology (ACR) criteria and the Disease Activity Score in 28 joints. Serum vascular endothelial growth factor (VEGF) levels were also monitored. At week 24, 25.0% in the control group and 80.3% in the tocilizumab group achieved ACR20 response. The tocilizumab group showed superior ACR response criteria over control at all time points. Additionally, serum VEGF levels were significantly decreased by tocilizumab treatment. The overall incidences of adverse events (AEs) were 72 and 92% (serious AEs: 4.7 and 6.6%; serious infections: 1.6 and 3.3%) in the control and the tocilizumab groups, respectively. All serious adverse events improved by adequate treatment. Tocilizumab monotherapy was well tolerated and provided an excellent clinical benefit in active RA patients with an inadequate response to low dose MTX.
16639489 [Case report: RAEB in a patient with rheumatoid arthritis treated with methotrexate and in 2006 Jan Anti TNF-alpha drugs seem to be the new frontier of Rheumatoid Arthritis (RA) therapy. The association infliximab methotrexate has been approved for the treatment of RA not responding to the classic therapy, but the short clinical experience in using antiTNF-alpha molecules brings to segnalation of new risks or adverse events. We describe a case of a patient, treated for many years with classic RA therapy, which developed a refractory anemia after treatment with association infliximab-methotrexate.
19074177 Evaluation of different methods used to assess disease activity in rheumatoid arthritis: a 2009 Apr OBJECTIVES: To evaluate different methods of reporting response to treatment or disease status for their ability to discriminate between active therapy and placebo, or to reflect structural progression or patient satisfaction with treatment using an exploratory analysis of the Abatacept in Inadequate Responders to Methotrexate (AIM) trial. METHODS: 424 active (abatacept approximately 10 mg/kg) and 214 placebo-treated patients with rheumatoid arthritis (RA) were evaluated. METHOD: of reporting included: (1) response (American College of Rheumatology (ACR) criteria) versus state (disease activity score in 28 joints (DAS28) criteria); (2) stringency (ACR20 vs 50 vs 70; moderate disease activity state (MDAS; DAS28 <5.1) vs low disease activity state (LDAS; DAS28 or=2). More stringent criteria (at least ACR50/LDAS), faster onset (3 visits) of ACR50/LDAS best reflected patient satisfaction (positive LR >10). CONCLUSIONS: The optimal method for reporting a measure of disease activity may differ depending on the outcome of interest. Time to onset and sustainability can be important factors when evaluating treatment response and disease status in patients with RA.
18257347 [Observation on therapeutic effect of heat needle combined with herb iontophoresis and wes 2007 Oct OBJECTIVE: To search for a therapeutic program for increasing the therapeutic effect of western medicine on rheumatoid arthritis (RA). METHODS: Ninety-six cases of RA were randomly assigned to a treatment group and a control group, 48 cases in each group. The treatment group were treated with heat electroacupuncture instrument with Chinese herb iontophoresis, combined with Meloxicam, Salazosulfamide, and Methotrexate. The control group with simple the western medicine. After treatment of a month, changes of the morning stiff duration, grasp strength, number of tenderness joints, tenderness index, joint rest pain, number of swelling joints, swelling index, assessment of the patient and doctor, and blood rheumatism factor (RF), C-response protein (CRP), erythrocyte sedimentation rate (ESR), the white blood cell (WBC) and platelet counts (PLT) were investigated. RESULTS: The effective rate was 79.2% in the treatment group and 52.1% in the control group, the treatment group being significantly better than the control group (P < 0.01). After treatment of one month, morning stiff duration, average grasp strength of the both hands, tenderness of joint and swelling of joints significantly improved (P < 0.01), with the treatment group being superior to the control group (P < 0.01). After treatment, blood RF, CRP, ESR, WBC and PLT decreased in the two groups (P < 0.01), and the decreases of blood CRP, ESR, PLT in the treatment group were more significantly as compared with the control group (P < 0.01). CONCLUSION: The therapeutic effect of heat needle combined with herb iontophoresis and western medicine is superior to simple medicine for treatment of rheumatoid arthritis.
18677056 [Daily practice using the guidelines for prevention and treatment of osteoporosis. The eff 2008 Aug Patients diagnosed as RA should be started with disease modifying anti-rheumatic drugs (DMARDs) as early as possible. Among the DMARDs, methotrexate (MTX) is considered the anchor drug and should be used first in patients as risk of developing persistent disease. The main goal of DMARDs treatment is to achieve remission and monitoring of disease activity and adverse events should guide decisions on choice and changes in treatment strategies. However, treatment of RA with DMARDs including MTX often fails to control disease activity and prevent structural damage in a some population of patients. Therefore, more effective treatment strategies are needed. Tumor necrosis factor-alpha (TNF-alpha) , a representative pro-inflammatory cytokine, plays a pivotal role in the pathological process of RA by mediating initiation to autoimmunity, lymphocyte accumulation and angiogenesis in the inflamed synovium, and joint destruction. Treatment of RA patients with TNF inhibitors have been efficacious for a) a prolonged improvement in disease activity and an induction to remission, b) inhibition of radiographic progression, when they are used in combination with MTX. Thus, the combined use of the TNF-inhibitor and MTX has brought about a paradigm shift in the treatment goal of RA. However, their small but definite risks of serious infections are also clear and their occurrence mandates that TNF-inhibitors should be supervised by physicians with experience in their use.
18173926 Fatal hepatic failure associated with hepatitis B virus reactivation in a hepatitis B surf 2007 Nov A 66-year-old female patient with rheumatoid arthritis, who had been HBsAg-negative and anti-HBs-positive, developed hepatic dysfunction following low-dose methotrexate therapy. Serologic testing for HBsAg, HBeAg, IgM HBc and HBV DNA were positive. Despite antiviral therapy with lamivudine, the hepatic condition gradually deteriorated until the patient died. Since HBV replication persists in the liver even in individuals with resolved HBV infection (i.e., HBsAg-negative, anti-HBs-positive), HBV reactivation may occur in these patients with immunosuppression. Therefore, especially in endemic areas, all patients being considered for immunosuppressive therapy should be closely monitored with liver function tests and evaluated for HBV reappearance even when HBsAg-negative.
18687711 Ascendancy of weekly low-dose methotrexate in usual care of rheumatoid arthritis from 1980 2008 Oct OBJECTIVES: To analyse consecutive patients with RA in usual rheumatology care between 1980 and 2004 at two settings for the proportion of patients taking MTX, interval from patient presentation to MTX prescription and radiographic and functional status outcomes. METHODS: Longitudinal study of all patients seen in usual care between 1980 and 2004, 1982 consecutive patients in Jyväskylä, Finland and 738 consecutive patients in Nashville, TN, USA. Clinical status was assessed as Larsen radiographic scores in Jyväskylä and modified health assessment questionnaire (MHAQ) in Nashville. RESULTS: The probability of initiating MTX within 5 yrs after presentation increased from <5% in Jyväskylä before 1989 to >90% in 2000-04, and from 25% in Nashville in 1980-84 to >90% since 1995. The median interval from presentation to MTX initiation in Jyväskylä was 14 yrs in 1980-84 vs 8.6 in 1985-89, 4.5 in 1990-94, 1.8 in 1995-99 and <1 yr in 2000-05; in Nashville, median intervals were 8.6 yrs in 1980-84, 4.4 years in 1985-89, and <2 months in 1990-95, 1995-2000 and 2000-05. Patient outcomes were substantially improved in both settings: in Jyväskylä, mean 5-yr Larsen radiographic scores (0-100) were 15.7 in 1980-84 vs 4.0 in 1995-99; in Nashville, mean MHAQ scores (0-3) for physical function were 1.13 in 1980-84 vs 0.57 in 2000-04. CONCLUSION: Early MTX in usual clinical care of RA increased from <5% in 1980 to >90% in 2004. Over this period, substantially improved outcomes were seen, most of which antedated biological agents.
17907159 Biomarkers predict radiographic progression in early rheumatoid arthritis and perform well 2007 Oct OBJECTIVE: To evaluate the performance of biochemical and traditional markers in predicting radiographic progression in rheumatoid arthritis (RA). METHODS: One hundred thirty-two patients with early RA were treated with nonbiologic therapies for 2 years and studied longitudinally. Genomic DNA was analyzed for presence of the shared epitope. Levels of matrix metalloproteinases (matrix metalloproteinase 1 [MMP-1], MMP-13, and MMP-3), tissue inhibitor of metalloproteinases 1 (TIMP-1), and cartilage oligomeric matrix protein (COMP) were assessed in serially obtained serum samples. The presence of pyridinoline (Pyr), deoxypyridinoline, glycosylated Pyr (Glc-Gal-Pyr), and C-telopeptide of type II collagen (CTX-II) was assessed in urine samples. Radiographs obtained at entry and at 2 years were evaluated using the modified Larsen score. RESULTS: Baseline and 2-year radiographs were available from 118 patients. Larsen scores worsened during the 2 years in 50 patients, while 68 patients had no radiographic progression. Levels of a variety of biochemical markers, i.e., MMP-3, CTX-II, COMP, TIMP-1, Pyr, and Glc-Gal-Pyr, correlated significantly with radiographic progression at entry and longitudinally as assessed by area under the curve (AUC). By multivariate analysis, a model including MMP-3 and CTX-II was identified as providing the best prediction of radiographic progression at entry (predictive accuracy by receiver operating characteristic [ROC] AUC = 0.76 [95% confidence interval 0.66-0.85]), while a combination of MMP-3, CTX-II, and swollen joint count formed the best longitudinal AUC model (predictive accuracy by ROC AUC = 0.81 [95% confidence interval 0.73-0.89]). Patient-reported measures (Health Assessment Questionnaire, pain scores) were of limited use. In a subset of 50 patients who were treated with methotrexate (MTX) during the followup period, median serum MMP-3 levels decreased after the initiation of MTX therapy (P = 0.0003). CONCLUSION: These results indicate that biochemical markers are useful predictors of radiographic progression in RA and that serum MMP-3 levels decrease significantly with MTX therapy. Multivariate models that include MMP-3 and CTX-II perform better than existing traditional markers in predicting radiographic outcome in RA.
18470473 Leflunomide (Arava) is a useful DMARD in Indian (Asian) patients: a clinic-based observati 2008 Aug Several drug trials, predominantly of Caucasian patients, have demonstrated the therapeutic role of leflunomide (LEF) in the treatment of rheumatoid arthritis (RA). We report an Indian (Asian) experience from a prospective observational study. Two hundred thirty affording patients with moderately severe active RA (naïve for LEF), mostly failing methotrexate (MTX), were begun LEF (Aravatrade mark; 20 mg daily, post loading 100 mg od x 3 days) in a clinic setting and followed regularly in an open cohort as per standard of care practice guidelines. A priori, LEF was to be preferably used as a single-agent disease-modifying anti-rheumatic drug (DMARD). One hundred forty-three patients and 87 patients were clinically assigned to the LEF monotherapy and LEF + MTX combination, respectively; less than one third received prednisolone. We focus on 146 patients (64%) completing 1 year treatment. Patients improved significantly (p < 0.05, analysis of variance) in several measures (including Health Assessment Questionnaire). Though unintended (non-randomized), the treatment subgroups matched at baseline. Of patients, 42% and 24% in LEF monotherapy and LEF + MTX, respectively showed American College of Rheumatology 50% Response Criteria (ACR 50) improvement. LEF monotherapy showed a better 'time to first ACR 20 improvement' outcome over 1 year (survival function curve, Cox Hazard Ratio = 0.71, 95% confidence interval 0.52, 0.96). Ten percent to 30% patients reported diarrhea, hair loss, skin rash, and dyspepsia; <3% reported abnormal liver functions. Eighty-four patients (36.5%) withdrew (8.7% adverse events and 18.7% non-affordability). LEF is an effective and safe DMARD in our ethnic patient population and may suffice as a single agent (to treat moderately severe RA) during the initial 1 year.
17642244 [Selection of one of the TNF blockers; infliximab and etanercept]. 2007 Jul Infliximab and etanercept, both of which inhibit tumor necrosis factor (TNF), show almost an equal efficacy in reducing disease activity of rheumatoid arthritis and suppressing joints and bone destruction in the disease. Requiring a concomitant usage of methotrexate (MTX), infliximab, a chimeric antibody against TNF-alpha, blocks TNF-alpha and kills TNF-alpha -producing cells. Etanercept, on the other hands, is a soluble TNF receptor which blocks TNF-alpha as well as TNF-beta but does not affect cells producing TNF-alpha. MTX is not required on the etanercept administration because no neutralizing antibodies against etanercept are theoretically generated. The strategy selecting one of them for a patient should be based on the understanding differences and characteristics of the reagents.
17412737 Open-label, pilot protocol of patients with rheumatoid arthritis who switch to infliximab 2007 Jul OBJECTIVE: To incorporate a new trial design to examine clinical response, cytokine expression and joint imaging in patients with rheumatoid arthritis (RA) switching from etanercept to infliximab treatment. METHODS: A randomised, open-label, clinical trial of 28 patients with an inadequate response to etanercept was conducted. Eligible patients received background methotrexate and were randomised 1:1 to discontinue etanercept and receive infliximab 3 mg/kg at weeks 0, 2, 6, 14 and 22, or to continue etanercept 25 mg twice weekly. Data were analysed for clinical response, serum biomarker levels, radiographic progression, MRI and adverse events. RESULTS: At week 16, 62% of infliximab-treated patients achieved American College of Rheumatology 20% criteria for improvement in RA (ACR20) responses compared with 29% of etanercept-treated patients. A 30.8% decrease from baseline in Disease Activity Score 28 was observed in patients receiving infliximab, compared with a 16.0% decrease in patients receiving etanercept. ACR20 and American College of Rheumatology 50% criteria for improvement in RA responses correlated at least minimally with intracellular adhesion molecule-1 and interleukin 8 in patients receiving infliximab. 38% of patients who were switched to infliximab showed reductions in Health Assessment Questionnaire scores (>0.4), compared with 0% of patients receiving etanercept. MRI analyses were inconclusive. Both drugs were well tolerated; 54% of infliximab-treated patients and 50% of etanercept-treated patients reported adverse events. CONCLUSIONS: In this exploratory, open-label trial (with single-blind evaluator), patients were randomised to continue with etanercept or switch to infliximab. The small sample size of this hypothesis-generating study was underpowered to show statistical differences between groups. There was a numerical trend favouring patients who switched to infliximab, therefore warranting further study with a more rigorous design.
18593759 Radiographic changes in rheumatoid arthritis patients attaining different disease activity 2009 Jun OBJECTIVE: To examine the association of radiographic progression and disease activity states in patients with rheumatoid arthritis (RA) treated with methotrexate with or without infliximab. METHODS: Patients (n = 1049) with active RA for 3 years or less and no previous methotrexate treatment were randomly assigned (4 : 5 : 5) to receive methotrexate plus placebo or methotrexate plus infliximab 3 or 6 mg/kg at weeks 0, 2 and 6, and every 8 weeks thereafter to week 46. Disease activity was classified by the simplified disease activity index as remission (< or =3.3), low (>3.3 to < or =11), moderate (>11 to < or =26), high (>26). Radiographic progression was measured as a change from baseline to week 54 in total Sharp score. RESULTS: At weeks 14 and 54, more patients receiving methotrexate plus infliximab than methotrexate plus placebo were in remission (10.7% versus 2.8% week 14; 21.3% versus 12.3% week 54; p<0.001 for both). Methotrexate plus placebo halted radiographic progression only if patients achieved remission within 3 months, whereas methotrexate plus infliximab also halted or minimised progression in patients with low or moderate activity, respectively. Patients with persistently high disease activity levels had much less progression of joint damage if treated with methotrexate plus infliximab versus methotrexate monotherapy. Even with infliximab plus methotrexate there was a direct relationship between disease activity and radiographic changes, although the slope was deflected when compared with methotrexate monotherapy. CONCLUSION: With methotrexate, joint damage progresses even at low and moderate disease activity levels, whereas methotrexate plus infliximab inhibits radiographic progression across all disease activity states.
16984661 Disease-modifying antirheumatic drugs are associated with a reduced risk for cardiovascula 2006 Rheumatoid arthritis (RA) is characterized by inflammation and an increased risk for cardiovascular disease (CVD). This study investigates possible associations between CVD and the use of conventional disease-modifying antirheumatic drugs (DMARDs) in RA. Using a case control design, 613 RA patients (5,649 patient-years) were studied, 72 with CVD and 541 without CVD. Data on RA, CVD and drug treatment were evaluated from time of RA diagnosis up to the first cardiovascular event or the end of the follow-up period. The dataset was categorized according to DMARD use: sulfasalazine (SSZ), hydroxychloroquine (HCQ) or methotrexate (MTX). Odds ratios (ORs) for CVD, corrected for age, gender, smoking and RA duration, were calculated per DMARD group. Patients who never used SSZ, HCQ or MTX were used as a reference group. MTX treatment was associated with a significant CVD risk reduction, with ORs (95% CI): 'MTX only', 0.16 (0.04 to 0.66); 'MTX and SSZ ever', 0.20 (0.08 to 0.51); and 'MTX, SSZ and HCQ ever', 0.20 (0.08 to 0.54). The risk reductions remained significant after additional correction for the presence of rheumatoid factor and erosions. After correction for hypertension, diabetes and hypercholesterolemia, 'MTX or SSZ ever' and 'MTX, SSZ and HCQ ever' showed significant CVD risk reduction. Rheumatoid factor positivity and erosions both increased CVD risk, with ORs of 2.04 (1.02 to 4.07) and 2.36 (0.92 to 6.08), respectively. MTX and, to a lesser extent, SSZ were associated with significantly lower CVD risk compared to RA patients who never used SSZ, HCQ or MTX. We hypothesize that DMARD use, in particular MTX use, results in powerful suppression of inflammation, thereby reducing the development of atherosclerosis and subsequently clinically overt CVD.
16508926 Predictors of joint damage in patients with early rheumatoid arthritis treated with high-d 2006 Mar OBJECTIVE: To identify disease characteristics leading to progression of joint damage in patients with early rheumatoid arthritis (RA) treated with methotrexate (MTX) versus those treated with infliximab plus MTX. METHODS: Patients who had not previously been treated with MTX with active RA were randomly assigned to receive escalating doses of MTX up to 20 mg/week plus placebo or infliximab at weeks 0, 2, and 6, and every 8 weeks thereafter through week 46. Radiographic joint damage was assessed using the modified Sharp/van der Heijde score (SHS). The relationship between disease activity measures at baseline and week 14, as well as those averaged over time, were examined in relation to the change in SHS from baseline through week 54. RESULTS: C-reactive protein (CRP) levels, erythrocyte sedimentation rate (ESR), and swollen joint count were associated with greater joint damage progression in the MTX-only group, while none of these parameters was associated with progression in the infliximab plus MTX group. Mean changes in SHS among patients in the highest CRP (> or = 3 mg/dl) and ESR (> or = 52 mm/hour) tertiles in the MTX-only group were 5.62 and 5.89, respectively, compared with 0.73 and 1.12 in the infliximab plus MTX group (P < 0.001). Patients with greater joint damage at baseline (SHS > or = 10.5) showed less progression with infliximab plus MTX compared with MTX alone (-0.39 versus 4.11; P < 0.001). Patients receiving MTX alone who had persistently active disease at week 14 showed greater radiographic progression of joint damage than those taking MTX plus infliximab. CONCLUSION: High CRP level, high ESR, or persistent disease activity was associated with greater radiographic progression in the group taking MTX alone, while little radiographic progression was seen in patients receiving both MTX and infliximab, regardless of the abnormal levels of these traditional predictors.
16308339 Methotrexate modulates the kinetics of adenosine in humans in vivo. 2006 Apr BACKGROUND: Animal studies suggest that the anti-inflammatory effect of methotrexate (MTX) is mediated by increased adenosine concentrations. OBJECTIVE: To assess the effect of MTX on the vasodilator effects of adenosine and the nucleoside uptake inhibitor, dipyridamole, in humans in vivo as a marker for changes in adenosine kinetics. METHODS: Ten patients with active arthritis were treated with MTX (15 mg/week). Measurements were performed before and after 12 weeks of treatment. At these time points, the activity of adenosine deaminase was measured in isolated lymphocytes, and forearm blood flow (FBF) was determined by venous occlusion plethysmography during administration of adenosine and dipyridamole into the brachial artery. RESULTS: The Vmax of adenosine deaminase in lymphocytes was reduced by MTX treatment (p<0.05). MTX significantly enhanced vasodilator response to adenosine (0.5 and 1.5 microg/min/dl of forearm tissue; mean (SE) FBF ratio increased from 1.2 (0.2) to 1.4 (0.2) and 2.2 (0.2) ml/dl/min, respectively, before and from 1.3 (0.1) to 1.8 (0.2) and 3.2 (0.5) ml/dl/min during MTX treatment; p<0.05). Also, dipyridamole-induced vasodilatation (30 and 100 microg/min/dl) was enhanced by MTX (FBF ratio increased from 1.2 (0.2) to 1.5 (0.3) and 1.8 (0.2), respectively, before and from 1.3 (0.1) to 1.8 (0.2) and 2.4 (0.4) during MTX treatment; p<0.05). CONCLUSIONS: MTX treatment inhibits deamination of adenosine and potentiates adenosine-induced vasodilatation. Also dipyridamole-induced vasodilatation is enhanced by MTX treatment, suggesting an increased extracellular formation of adenosine. These effects on the adenosine kinetics in humans may contribute to the therapeutic efficacy of MTX.
17896839 Rituximab: in rheumatoid arthritis. 2007 An important role for B cells in the immunopathogenesis of rheumatoid arthritis (RA) is recognized. Rituximab is a chimeric murine/human anti-CD20 monoclonal antibody that transiently depletes CD20+ B cells. A single course of rituximab (two intravenous infusions of 1,000mg given two weeks apart) with a stable dose of methotrexate significantly improved all measures of disease activity, fatigue, and health-related quality of life relative to placebo with methotrexate. This was demonstrated in the REFLEX trial, a 24-week, randomized, double-blind, double-dummy, international, phase III study in 520 patients who had active RA despite ongoing treatment with methotrexate and had experienced an inadequate response to anti-tumor necrosis factor (TNF) therapy. Patients in REFLEX (or other studies) who responded to, and required further treatment after, an initial course of rituximab continued to respond to subsequent courses of the drug. A small subgroup of patients in REFLEX continued to respond to their first course of rituximab through 48 weeks of follow-up. Long-term treatment (up to 56 weeks) with one or more courses of rituximab in REFLEX significantly inhibited joint structural damage, the first time this effect has been reported in patients with an inadequate response to TNF inhibitors. Rituximab was generally well tolerated; the majority of adverse events were related to the first infusion of the drug, were mild to moderate in severity, and were easily managed. The adverse event profile of rituximab was unchanged after repeat courses.
17611986 2756GG genotype of methionine synthase reductase gene is more prevalent in rheumatoid arth 2007 Aug OBJECTIVE: To investigate the distribution of the A2756G polymorphism of the methionine synthase reductase (MTR) gene in patients with rheumatoid arthritis (RA) treated with methotrexate (MTX) compared with a healthy control group; and to examine the relationships among the A2756G polymorphism, plasma total homocysteine (tHcy), serum folate and vitamin B12 levels, disease activity, and MTX toxicity in patients with RA. METHODS: A cross-sectional study was performed on 86 MTX-treated RA patients, consisting of a clinical interview and physical examination to determine disease activity and MTX-related adverse reactions. Genotype analysis of the MTR gene was performed. Fasting plasma tHcy, serum folate, and vitamin B12 levels were measured. Allele and genotype distributions were compared to a healthy control group. RESULTS: The frequency of the 2756GG genotype (16.3%) in the RA study group was higher than that expected in the general population (3.6%; p < 0.000001). This genotype was associated with MTX-induced accelerated rheumatoid nodulosis (MIARN). No association of disease activity variables or plasma homocysteine with MTR A2756G polymorphisms was observed. The MTR 2756GG genotype, low plasma vitamin B12 levels, and the presence of rheumatoid nodules predicted MIARN. No association of nodulosis with any other indicator of disease activity or medical treatment was found. CONCLUSION: In our population of MTX-treated RA patients the 2756GG genotype of the MTR gene was more common than expected and was associated with MIARN.
16868816 Rapid improvement in rheumatoid arthritis patients on combination of methotrexate and infl 2007 Jun The objectives of this study was to assess, using clinical and magnetic resonance imaging (MRI) criteria, the efficacy of combination infliximab therapy in patients with active rheumatoid arthritis (RA) refractory to methotrexate (MTX) treatment and to ascertain whether the changes in MRI parameters correlate with the clinical response. Four infusions of infliximab (3 mg/kg) at weeks 0, 2, 6, and 14 were added to a stable background dose of MTX in 19 patients with active disease. Clinical parameters were assessed before each infusion and at week 14. Dynamic contrast-enhanced MRI examination of the most severely affected wrist was performed at baseline and week 14. Synovitis severity, volume of synovitis, and synovial perfusion indices were evaluated. Significant improvement in all clinical disease activity parameters was seen at week 14 with reduction in C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and DAS28. Sixty-eight percent of patients achieved ACR20. MRI disease activity parameters also significantly decreased after treatment with reduction in grading of synovitis, volume of active synovitis, and perfusion enhancement slope. Significant positive correlations were seen between the baseline volume of synovitis and the pain score (r=0.65), patient global score (r=0.68), and health assessment questionnaire (HAQ) score (r=0.46). In conclusion, addition of infliximab to methotrexate rapidly reduces inflammation in longstanding patients with RA. Assessment of enhancing synovial volume and perfusion indices on serial MRI examination was helpful in documenting the effect of treatment over this short period.