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MTX Alone (mtx + alone)
Selected AbstractsEfficiency of combined methotrexate/chloroquine therapy in adjuvant-induced arthritisFUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 4 2005M.A.R.C.P. Silva Abstract The present study evaluates the effects of methotrexate (MTX) and chloroquine (CQ), and of combined MTX + CQ treatment, on the inflammatory response and on plasma and liver phosphatase and transaminase activities, employing an adjuvant-induced arthritis model in rats. Arthritis was induced by the intradermal injection of a suspension of Mycobacterium tuberculosis in mineral oil into the plantar surface of the hind paws. Development of the inflammatory response was assessed over a 21-day period. Animal groups received either: (i) MTX, administered i.p., weekly, in 0.15, 1.5, 3, 6 or 12 mg/kg doses; (ii) CQ, given intragastrically, in daily 25 or 50 mg/kg doses; or (iii) MTX + CQ, administered in two combinations (MTX1.5 mg/kg + CQ50 mg/kg, or MTX6 mg/kg + CQ50 mg/kg). At the end of the experimental period, the animals were anesthetized and killed, blood and liver samples were collected and prepared for measurement of acid and alkaline phosphatase (AP, ALP), and aspartate (AST) and alanine aminotransferase (ALT) activities. MTX at 6 and 12 mg/kg reduced the inflammatory response while CQ had no effect. MTX6 mg/kg + CQ50 mg/kg reduced the inflammatory response similar to MTX12 mg/kg, without affecting the bone marrow. Plasma AP and liver ALP activities were very elevated in the arthritic rats. While MTX treatment partially reduced both plasma AP and liver ALP activities at all doses used in the arthritic rats, CQ treatment reduced plasma AP, but increased liver AP activity. MTX + CQ treatment decreased plasma AP and liver ALP activities in the arthritic rats to control values. Plasma and liver AST activities were unaltered in the arthritic rats, and were unaffected by treatment. However, plasma and liver ALT activities were significantly reduced in the arthritic rats. While MTX or CQ treatment did not alter plasma transaminase activity in the arthritic rats, after MTX + CQ treatment, plasma ALT activity returned to normal values. In conclusion, the present data suggest that MTX + CQ treatment provides more effective anti-inflammatory protection against adjuvant-induced arthritis than does MTX alone, reverting the alterations in enzyme activities induced by this inflammatory disease in rats. [source] Immunization responses in rheumatoid arthritis patients treated with rituximab: Results from a controlled clinical trial,ARTHRITIS & RHEUMATISM, Issue 1 2010Clifton O. Bingham III Objective To examine immunization responses in patients with rheumatoid arthritis (RA) treated with rituximab and to investigate the effects of rituximab-induced CD20+ B cell depletion on immune responses to tetanus toxoid (T cell,dependent antigen), pneumococcal polysaccharide (T cell,independent antigen), and keyhole limpet hemocyanin (KLH) (neoantigen) and on delayed-type hypersensitivity (DTH). Methods In a controlled trial, we enrolled 103 patients with active RA receiving a stable dose of methotrexate (MTX). Tetanus toxoid, pneumococcal polysaccharide, and KLH vaccines as well as a Candida albicans skin test were administered to 1 group of patients receiving rituximab plus MTX (called rituximab-treated patients) for 36 weeks and to 1 group of patients receiving MTX alone for 12 weeks. The primary end point was the proportion of patients with a ,4-fold rise in antitetanus IgG levels. Antitetanus, antipneumococcal, and anti-KLH serum IgG levels were measured prior to and 4 weeks following vaccine administration. The DTH response to C albicans was measured 2,3 days following placement. Results Responses to tetanus toxoid vaccine (,4-fold rise) were similar in both groups (39.1% of rituximab-treated patients and 42.3% of patients treated with MTX alone). The ability to maintain a positive DTH response to the C albicans skin test was comparable in both groups (77.4% of rituximab-treated patients and 70% of patients treated with MTX alone), showing no effect of rituximab treatment. Rituximab-treated patients had decreased responses to pneumococcal polysaccharide vaccine (57% of patients had a 2-fold rise in titer in response to ,1 serotype, compared with 82% of patients treated with MTX alone) and to KLH vaccine (47% of patients had detectable anti-KLH IgG, compared with 93% of patients treated with MTX alone). Conclusion Recall responses to the T cell,dependent protein antigen tetanus toxoid as well as DTH responses were preserved in rituximab-treated RA patients 24 weeks after treatment. Responses to neoantigen (KLH) and T cell,independent responses to pneumococcal vaccine were decreased, but many patients were able to mount responses. These data suggest that polysaccharide and primary immunizations should be administered prior to rituximab infusions to maximize responses. [source] Long-term safety and effectiveness of etanercept in children with selected categories of juvenile idiopathic arthritis,ARTHRITIS & RHEUMATISM, Issue 9 2009E. H. Giannini Objective This study was undertaken to evaluate the long-term safety and effectiveness of etanercept alone or in combination with methotrexate (MTX) in children with selected categories of juvenile idiopathic arthritis (JIA). Methods Patients ages 2,18 years with rheumatoid factor (RF),positive or RF-negative polyarthritis, systemic JIA, or extended oligoarthritis were eligible for the study. Patients received MTX alone (,10 mg/m2/week [,0.3 mg/kg/week], maximum dosage 1 mg/kg/week), etanercept alone (0.8 mg/kg/week, maximum dose 50 mg), or etanercept plus MTX for 3 years in an open-label, nonrandomized study. Safety was assessed by measuring rates of adverse events, and effectiveness was assessed using the physician's global assessment of disease activity and the pediatric total joint assessment. Results A total of 197, 103, and 294 patients were enrolled in the MTX, etanercept, and etanercept plus MTX groups, respectively. Exposure-adjusted rates of adverse events were similar among the 3 treatment groups (18.3, 18.7, and 21.6 per 100 patient-years in the MTX, etanercept, and etanercept plus MTX groups, respectively). Respective rates per 100 patient-years of serious adverse events (4.6, 7.1, and 6.0) and medically important infections (1.3, 1.8, and 2.1) were also similar among the 3 treatment groups. Scores for physician's global assessment and total active joints improved from baseline, and improvement was maintained for the duration of the study. Conclusion These data confirm the findings of other long-term studies and suggest that etanercept or etanercept plus MTX has an acceptable safety and effectiveness profile in children with selected categories of JIA. Improvement was maintained for 3 years in those continuing to receive medication. [source] Golimumab, a human anti,tumor necrosis factor , monoclonal antibody, injected subcutaneously every four weeks in methotrexate-naive patients with active rheumatoid arthritis: Twenty-four,week results of a phase III, multicenter, randomized, double-blind, placebo-controlled study of golimumab before methotrexate as first-line therapy for early-onset rheumatoid arthritis,ARTHRITIS & RHEUMATISM, Issue 8 2009Paul Emery Objective To assess the safety and efficacy of golimumab in methotrexate (MTX),naive patients with active rheumatoid arthritis (RA). Methods MTX-naive patients with RA (n = 637) were randomized to receive placebo plus MTX (group 1), golimumab 100 mg plus placebo (group 2), golimumab 50 mg plus MTX (group 3), or golimumab 100 mg plus MTX (group 4). Subcutaneous injections of golimumab or placebo were administered every 4 weeks. The dosage of MTX/placebo capsules started at 10 mg/week and escalated to 20 mg/week. The primary end point, the proportion of patients meeting the American College of Rheumatology 50% improvement criteria (achieving an ACR50 response) at week 24, required significant differences between groups 3 and 4 combined (combined group) versus group 1 and significant differences in a pairwise comparison (group 3 or group 4 versus group 1). Results An intent-to-treat (ITT) analysis of the ACR50 response at week 24 did not show a significant difference between the combined group and group 1 (38.4% and 29.4%, respectively; P = 0.053), while a post hoc modified ITT analysis (excluding 3 untreated patients) of the ACR50 response showed statistically significant differences between the combined group and group 1 (38.5% versus 29.4%; P = 0.049) and between group 3 (40.5%; P = 0.038) but not group 4 (36.5%; P = 0.177) and group 1. Group 2 was noninferior to group 1 for the ACR50 response at week 24 (33.1%; 95% confidence interval lower bound ,5.2%; predefined delta value for noninferiority ,10%). The combination of golimumab plus MTX demonstrated a significantly better response compared with placebo plus MTX in most other efficacy parameters, including response/remission according to the Disease Activity Score in 28 joints. Serious adverse events occurred in 7%, 3%, 6%, and 6% of patients in groups 1, 2, 3, and 4, respectively. Conclusion Although the primary end point was not met, the modified ITT analysis of the primary end point and other prespecified efficacy measures demonstrated that the efficacy of golimumab plus MTX is better than, and the efficacy of golimumab alone is similar to, the efficacy of MTX alone in reducing RA signs and symptoms in MTX-naive patients, with no unexpected safety concerns. [source] Treatment of early rheumatoid arthritis: A randomized magnetic resonance imaging study comparing the effects of methotrexate alone, methotrexate in combination with infliximab, and methotrexate in combination with intravenous pulse methylprednisolone,ARTHRITIS & RHEUMATISM, Issue 12 2007Patrick Durez Objective To compare the effects of methotrexate (MTX), alone or in combination with intravenous (IV) methylprednisolone (MP) or infliximab, on magnetic resonance imaging (MRI),detected synovitis, bone edema, and erosive changes in patients with early rheumatoid arthritis (RA). Methods Forty-four patients with early RA were randomized to receive MTX alone (MTX group), MTX plus IV MP (IV MP group), or MTX plus infliximab (infliximab group), infused on day 0 and weeks 2, 6, 14, 22, 30, 38, and 46. Gadolinium-enhanced MRI scans of the metacarpophalangeal joints, wrists, and metatarsophalangeal joints were performed at baseline, week 18, and week 52. Results Scores for MRI-detected synovitis and bone edema improved over time in the 3 groups, with significantly lower synovitis scores in the infliximab group compared with the MTX group and significantly lower bone edema scores in the infliximab group compared with the MTX and the IV MP groups. Scores for MRI-detected erosion significantly increased over time in all groups. There were no differences in erosion scores between the MTX group and the other groups. It is of note that patients treated with IV MP showed more significant progression in MRI-detected erosions compared with patients treated with infliximab. At week 22, response rates according to the American College of Rheumatology 20% improvement criteria (ACR20), the ACR50, and the ACR70 were significantly higher in both the IV MP group and the infliximab group compared with the MTX group. At week 52, remission was achieved in 40% of patients in the MTX group and in 70% of patients in the IV MP and infliximab groups. Health Assessment Questionnaire scores improved significantly over time in all groups, with patients receiving IV MP experiencing significantly more improvement compared with patients treated with MTX alone. No severe side effects were observed, except 1 case of MTX-related pneumonitis. Conclusion The combination of MTX and infliximab is superior to MTX alone for reducing MRI-detected signs of synovitis and bone edema in patients with early RA. Progression of MRI-detected erosion was greater in patients treated with MTX plus IV MP compared with that in patients who received MTX plus infliximab. [source] Musculoskeletal abnormalities of the tibia in juvenile rheumatoid arthritisARTHRITIS & RHEUMATISM, Issue 3 2007Elena M. O. Felin Objective To characterize local bone geometry, density, and strength, using peripheral quantitative computed tomography (pQCT), compared with general bone characteristics as measured using dual x-ray absorptiometry (DXA), and to assess their relationship to disease-related factors in children with juvenile rheumatoid arthritis (JRA). Methods Forty-eight children ages 4,18 years with JRA (17 pauciarticular, 23 polyarticular, 8 systemic) were compared with age-matched healthy controls (n = 266). Measurements included cortical and trabecular bone geometry, density, and strength at the distal and midshaft tibia determined by pQCT, and whole-body, lumbar spine, and femoral neck measurements by DXA. Results Methotrexate (MTX) was prescribed to 23 of 48 patients (47.9%) and glucocorticoids and MTX were prescribed to 15 of 48 patients (31.3%), with the greatest use in children with systemic JRA. All JRA patients had decreased tibia trabecular bone density, cortical bone size and strength, and muscle mass. Children with systemic JRA had lower femoral neck densities. Systemic JRA was associated with a shorter, less mineralized skeleton, while a narrower, less mineralized skeleton was observed in polyarticular JRA. The tibia diaphysis was narrower with decreased muscle mass, but normal, size-adjusted bone mineral in all subtypes indicated a localized effect of JRA on bone. Patients exposed to glucocorticoids and MTX or to glucocorticoids or MTX alone had greatly reduced trabecular density, cortical bone geometry properties, and bone mineral content, muscle mass, and bone strength. Conclusion Children with JRA have decreased skeletal size, muscle mass, trabecular bone density, cortical bone geometry, and strength. Not surprisingly, these bone abnormalities are more pronounced in children with greater disease severity. [source] Disconnect between inflammation and joint destruction after treatment with etanercept plus methotrexate: Results from the trial of etanercept and methotrexate with radiographic and patient outcomesARTHRITIS & RHEUMATISM, Issue 10 2006Robert Landewé Objective To determine the relationship between disease activity and radiographic progression of joint destruction in patients with rheumatoid arthritis (RA) treated with methotrexate (MTX), those treated with etanercept, and those treated with the combination of MTX plus etanercept. Methods Baseline, 12-month, and 24-month data from the Trial of Etanercept and Methotrexate with Radiographic and Patient Outcomes database were analyzed. The dependent variable was the 1-year change in the modified Sharp/van der Heijde score (Sharp score); therefore, 2 interval changes per patient were available. Interval change in the Sharp score was modeled by time (years), treatment, disease activity, and the interaction (disease activity × treatment). Disease activity was reflected by the time-averaged Disease Activity Score (taDAS) and the time-averaged C-reactive protein (taCRP) level, which were calculated per 1-year interval. Generalized mixed linear modeling (GMLM) was used to adjust for within-patient correlation. Results GMLM confirmed a significant interaction between treatment and the taCRP level and taDAS with respect to the change in Sharp score (P = 0.012 and P = 0.03, respectively). In patients treated with MTX alone, radiographic progression increased with an increasing taCRP level or taDAS, although progression rates were low in patients whose disease was in remission and in those with low-to-moderate disease activity. This relationship was less clear in patients treated with etanercept and was absent in those who received combination therapy. Conclusion Combination therapy with MTX plus etanercept uncouples the classic relationship between disease activity and radiographic progression in patients with RA. [source] The safety of infliximab, combined with background treatments, among patients with rheumatoid arthritis and various comorbidities: A large, randomized, placebo-controlled trialARTHRITIS & RHEUMATISM, Issue 4 2006Rene Westhovens Objective To assess the risk of serious infections following 22 weeks of infliximab therapy, and to further characterize the safety profile of infliximab in combination with background treatments during 1 year in patients with rheumatoid arthritis (RA) with various comorbidities. Methods Patients with active RA despite receiving methotrexate (MTX) were randomly assigned to receive infusions of placebo (group 1, n = 363), 3 mg/kg infliximab (group 2, n = 360), or 10 mg/kg infliximab (group 3, n = 361) at weeks 0, 2, 6, and 14. At week 22, patients in placebo group 1 began receiving 3 mg/kg infliximab, and patients in group 3 continued to receive an infliximab dose of 10 mg/kg. Patients in group 2 who failed to meet predefined response criteria received increasing doses of infliximab in increments of 1.5 mg/kg. Results At week 22, the relative risk of developing serious infections in groups 2 and 3, compared with group 1, was 1.0 (95% confidence interval [95% CI] 0.3,3.1, P = 0.995) and 3.1 (95% CI 1.2,7.9, P = 0.013), respectively. The incidence of serious adverse events was 7.8% in groups 2 and 3 compared with 7.5% in group 1. From week 22 to week 54, 11.8%, 9.9%, and 10.3% of patients in groups 1, 2, and 3, respectively, reported occurrences of serious adverse events. Through week 54, 1 patient in group 1, 2 patients in group 2, and 4 patients in group 3 developed active tuberculosis. Conclusion The risk of serious infections in patients receiving the approved infliximab dose of 3 mg/kg plus MTX was similar to that in patients receiving MTX alone. Patients receiving the unapproved induction regimen of 10 mg/kg infliximab plus MTX followed by a 10 mg/kg maintenance regimen had an increased risk of serious infections through week 22. [source] Elucidation of the relationship between synovitis and bone damage: A randomized magnetic resonance imaging study of individual joints in patients with early rheumatoid arthritisARTHRITIS & RHEUMATISM, Issue 1 2003Philip G. Conaghan Objective To simultaneously image bone and synovium in the individual joints characteristically involved in early rheumatoid arthritis (RA). Methods Forty patients with early, untreated RA underwent gadolinium-enhanced magnetic resonance imaging (MRI) of the second through fifth metacarpophalangeal joints of the dominant hand at presentation, 3 months, and 12 months. In the first phase (0,3 months), patients were randomized to receive either methotrexate alone (MTX) or MTX and intraarticular corticosteroids (MTX + IAST) into all joints with clinically active RA. The MTX-alone group received no further corticosteroids until the second phase (3,12 months), when both groups received standard therapy. Results In the first phase, MTX + IAST reduced synovitis scores more than MTX alone. There were significantly fewer joints with new erosions on MRI in the former group compared with the latter. During the second phase, the synovitis scores were equivalent and a similar number of joints in each group showed new erosions on MRI. In both phases, there was a close correlation between the degree of synovitis and the number of new erosions, with the area under the curve for MRI synovitis the only significant predictor of bone damage progression. In individual joints, there was a threshold effect on new bone damage related to the level of synovitis; no erosions occurred in joints without synovitis. Conclusion In early RA, synovitis appears to be the primary abnormality, and bone damage occurs in proportion to the level of synovitis but not in its absence. In the treatment of patients with RA, outcome measures and therapies should focus on synovitis. [source] Treatment of rheumatoid arthritis with anakinra, a recombinant human interleukin-1 receptor antagonist, in combination with methotrexate: Results of a twenty-four,week, multicenter, randomized, double-blind, placebo-controlled trialARTHRITIS & RHEUMATISM, Issue 3 2002Stanley Cohen Objective To evaluate the efficacy and safety of anakinra in combination with methotrexate (MTX) in patients with active rheumatoid arthritis (RA). Methods Patients with moderate-to-severe active RA who were receiving MTX for 6 consecutive months, with stable doses for ,3 months (those with disease duration of >6 months but <12 years) were randomized into 6 groups: placebo or 0.04, 0.1, 0.4, 1.0, or 2.0 mg/kg of anakinra administered in a single, daily, subcutaneous injection. The primary efficacy end point was the proportion of subjects who met the American College of Rheumatology 20% improvement criteria (attained an ACR20 response) at week 12. Results A total of 419 patients were randomized in the study. Patient demographics and disease status were similar in the 6 treatment groups. The ACR20 responses at week 12 in the 5 active treatment plus MTX groups demonstrated a statistically significant (P = 0.001) dose-response relationship compared with the ACR20 response in the placebo plus MTX group. The ACR20 response rate in the anakinra 1.0-mg/kg (46%; P = 0.001) and 2.0-mg/kg (38%; P = 0.007) dose groups was significantly greater than that in the placebo group (19%). The ACR20 responses at 24 weeks were consistent with those at 12 weeks. Similar improvements in anakinra-treated subjects were noted in individual ACR components, erythrocyte sedimentation rate, onset of ACR20 response, sustainability of ACR20 response, and magnitude of ACR response. Anakinra was safe and well tolerated. Injection site reaction was the most frequently noted adverse event, and this led to premature study withdrawal in 7% (1.0-mg/kg group) to 10% (2.0-mg/kg group) of patients receiving higher doses. Conclusion In patients with persistently active RA, the combination of anakinra and MTX was safe and well tolerated and provided significantly greater clinical benefit than MTX alone. [source] Folinic acid protects against suppression of growth by Methotrexate in miceBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 4 2001M. Perwaiz Iqbal Abstract The objective of this study was to investigate whether folinic acid supplementation would protect young mice against suppression of growth by methotrexate (MTX). Four equal groups of Balb/c young male mice (5 animals in each group; mean±SD body weight 9.64±0.85 g, in their rapid growth phase) were subjected to the following drug treatment: One group was given MTX (3.5 mg/kg body weight) intraperitoneally on every 2nd day, another received folinic acid (7.0 mg/kg body weight) intraperitoneally every 2nd day. The third group was given both of these drugs (MTX on every 2nd day and folinic acid 8 h post-MTX injection). The fourth group was injected with physiological saline every other day to serve as a control group. Total body weight, food and water consumption by animals in each group were monitored every second day for a period of 3 weeks. After this period mice were sacrificed and liver, spleen and kidneys were excised, weighed and analyzed for MTX and dihydrofolate reductase activity. A small segment of the proximal part of small intestine and small pieces of liver and kidney were also removed to study morphological changes. Compared to the groups, which received folinic acid alone, folinic acid plus MTX or physiological saline, mean increase in body weight (6.8±0.8 g) of mice over a period of 3 weeks was minimal in the group receiving MTX alone (one-way ANOVA p=0.0001). The mean weights of liver and kidney in this group receiving MTX alone were also found to be significantly less than the mean weights of these organs in the 3 groups (p<0.001). The negative effect on growth of animals appears not only due to malabsorption but inhibition of pathway of de novo DNA synthesis may also be involved. This is supported by loss of villous pattern in small intestine of mice treated with MTX alone and increased accumulation of free MTX and decreased dihydrofolate reductase in the liver of the group receiving MTX alone as compared with the group receiving MTX plus folinic acid. The data indicate that the administration of folinic acid protects mice against suppression of growth by MTX. On the basis of these observations it can be deduced that patients suffering from juvenile rheumatoid arthritis or acute lymphoblastic leukaemia receiving MTX over a long period of time might be at a risk of experiencing short-term suppression of growth, however they could benefit from supplementation with folinic acid. Copyright © 2001 John Wiley & Sons, Ltd. [source] | ||||||||||