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ID PMID Title PublicationDate abstract
14714042 [Treatment with etanercept in chronic polyarthritis]. 2003 Sep 25 BACKGROUND: In randomised trials, treatment with anti-tumour necrosis factor alpha drugs has been shown to be efficacious for patients with rheumatoid arthritis. We analysed the effectiveness and toxicity of etanercept treatment in our day-to-day rheumatology practice at the University Hospital of Northern Norway. MATERIAL AND METHODS: Patients with active polyarthritis who had failed at least three different disease-modifying anti-rheumatic drugs including methotrexate and/or combination therapy were consecutively included in an open study when they started etanercept therapy (25 mg twice per week subcutaneously). During follow up we noted the number of swollen and tender joints, took visual analogue scores (0-100 millimetre) for pain and global well-being, administered the Modified Health Assessment Questionnaire, performed laboratory tests, and took note of side effects. RESULTS: Between April 1999 and July 2001, etanercept treatment was initiated in 71 patients. An ACR-20 response (20% improvement according to American College of Radiology criteria) occurred in 57% of patients after one month of treatment and in 70 % after three months, ACR-50 response in 24% and 42%, and ACR-70 response in 6% and 20%. While half of all patients reported side effects, only five patients (7%) discontinued treatment because of them. INTERPRETATION: Etanercept is effective therapy for many patients with severe chronic polyarthritis in clinical practice. Short-term side effects occur more frequently than reported and seem less frequent with concomitant methotrexate therapy. Long-term side effects are still unknown and require close monitoring.
12096221 Methotrexate in the treatment of rheumatoid arthritis. I. In vitro effects on cells of the 2002 Jul OBJECTIVE: Low-dose methotrexate (MTX) is often used in the treatment of rheumatoid arthritis (RA). To be effective, treatment must be long-term, and there are concerns that MTX may impair bone formation in a population already predisposed to osteoporosis. The purpose of this investigation was to determine the direct effects of MTX at clinically relevant doses on the growth and differentiation of human cells of the osteoblast (bone-forming) lineage. METHODS: Cells derived from the marrow stroma (BMSC) and trabecular surfaces [human bone-derived cells (HBDC)] of adult ribs were cultured in the absence or presence of MTX (1-1000 nM). To promote the differentiation and further maturation of cells of the osteoblast lineage, one half of the cultures were treated additionally with 10 nM dexamethasone (Dx). RESULTS: In cultures of BMSC, treatment with MTX (+/-Dx) did not affect the total number of colonies that formed or the expression of the developmental markers STRO-1 and alkaline phosphatase (AP). At concentrations > or =10 nM, however, there was a statistically significant reduction in the number of cells harvested at the end of primary culture. In cultures of HBDC, treatment with MTX (in the presence of Dx) did not affect cell number or the expression of AP. CONCLUSIONS: At concentrations > or =10 nM, treatment with MTX inhibits the proliferation of primitive marrow stromal cells, but not their ability to undergo osteogenic differentiation. The proliferation and further maturation of cells of the osteoblast lineage is not affected by treatment with MTX. These findings are reassuring for clinicians using MTX in the treatment of RA.
15082469 A multicentre, double blind, randomised, placebo controlled trial of anakinra (Kineret), a 2004 Sep OBJECTIVE: To assess the efficacy and safety of 100 mg daily anakinra (Kineret), a recombinant form of the naturally occurring interleukin 1 receptor antagonist, plus methotrexate (MTX) in reducing the signs and symptoms of rheumatoid arthritis (RA). METHODS: Patients with active RA (n = 506) despite current treatment with MTX were enrolled in this multicentre, double blind, randomised, placebo controlled study. Patients received subcutaneous injections of anakinra 100 mg/day or placebo. They were assessed monthly for 6 months for improvement in signs and symptoms of RA and for adverse events. The primary efficacy measure was the percentage of patients attaining ACR20 response at week 24. RESULTS: Significantly greater proportions of patients treated with anakinra compared with placebo achieved ACR20 (38% v 22%; p<0.001), ACR50 (17% v 8%; p<0.01), and ACR70 (6% v 2%; p<0.05) responses. The response to anakinra was rapid; the proportion of patients with an ACR20 response at the first study assessment (4 weeks) was twice as high with anakinra as with placebo (p<0.005). Clinically meaningful and statistically significant responses were also seen in individual components of the ACR response (for example, Health Assessment Questionnaire, pain, C reactive protein levels, and erythrocyte sedimentation rate). Anakinra was well tolerated, with a safety profile, similar to that of placebo with one exception: mild to moderate injection site reactions were more common with anakinra than with placebo (65% v 24%). CONCLUSIONS: This study confirms previous observations from a dose-ranging study showing that anakinra, in combination with MTX, is an effective and safe treatment for patients with RA who have inadequate responses to MTX alone.
12887234 Invasive pulmonary aspergillosis soon after therapy with infliximab, a tumor necrosis fact 2003 Jul BACKGROUND: Infliximab is a chimeric monoclonal antibody against tumor necrosis factor (TNF)-alpha, used for the treatment of Crohn's disease and rheumatoid arthritis. Recently, an increased risk of infection due to Mycobacterium tuberculosis and rare cases of invasive fungal disease have been reported following infliximab therapy. CASE REPORT: A 73-year-old woman with chronic rheumatoid arthritis who had been treated with methotrexate, leflunomide, and prednisone was given the first of three doses of infliximab in June 2001. In July 2001, she presented with cough, and in August, she had a right upper lobe infiltrate that was treated with levofloxacin without improvement. In October, the patient had right upper and middle lobe infiltrates on a chest X-ray and computed tomography scan. At bronchoscopy, an endobronchial mass was biopsied, which demonstrated Aspergills fumigatus. Our patient had frequently accompanied her daughter on visits to another medical center following a stem cell transplant, where her daughter was instructed to wear a mask during all visits because of extensive building construction. We postulate that our patient may have acquired pulmonary aspergillosis during this period. Literature reviews on granulomatous diseases following infliximab therapy and hospital-acquired aspergillosis are presented. CONCLUSION: The temporal relationship between the administration of infliximab and A. fumigatus infection in this patient suggests a causal relationship and possible healthcare-associated acquisition. These data underscore the importance of both patient and family education on prevention strategies when potent immune-modulating medications such as infliximab have been prescribed.
12364628 Rescue of combination therapy failures using infliximab, while maintaining the combination 2002 Oct OBJECTIVE: To assess the possible clinical and biological rescue of rheumatoid arthritis (RA) in 16 patients who were still active despite intensive combination therapy after receiving infliximab following the Anti-Tumour necrosis factor Trial in Rheumatoid Arthritis with Concomitant Therapy (ATTRACT) schedule. METHODS: Sixteen patients who were still active despite combination therapy with optimal doses of methotrexate (MTX 15-17.5 mg/week) and cyclosporin A (CsA 2.5-3.5 mg/day) received infliximab. Ten received their combination plus infliximab (Combi), and six received infliximab plus MTX alone (Mono). The follow-up was carried out for 30 weeks in all patients and for 46 weeks in eight. Efficacy and safety were examined. RESULTS: At entry, the mean disease activity score (DAS) was 5.6 (all patients had a DAS >3.7). After therapy, eight of 10 patients in Combi and four out of six in Mono showed an improvement of >50% in the initial swollen joint count, yet only one patient reached 50% improvement in the initial DAS after 30 weeks, and one patient had a DAS <2.4 (low disease activity). Of the eight patients who reached 46 weeks of follow-up, three showed an improvement in DAS of 50% and two had a DAS <2.4. When considering the change over time, the difference between DAS at entry and at week 30 was statistically significant only in patients receiving MTX plus CsA, while it was not significant in those receiving MTX only. Two patients developed recurrent febrile upper respiratory infections in the Combi therapy group, while two had a single febrile infection in the MTX alone group. Two patients became strongly anti-cardiolipin positive (IgM >40 MPL) and one developed a coronary syndrome. CONCLUSION: Infliximab can be added incrementally to MTX plus CsA, with favourable results in terms of efficacy and safety over time in severe rapidly aggressive and progressive RA. Finally, minor evidence emerged for a stronger efficacy of the Combi treatment compared with Mono.
12371632 Is there an association of plasma homocysteine levels with vascular involvement in patient 2002 Jul OBJECTIVE: To assess whether or not plasma homocysteine levels play a part in vascular involvement in Behçet's syndrome (BS). METHODS: 74 consecutive BS patients fulfilling the criteria of the International Study Group for BS, 35 healthy control (HC) and 14 rheumatoid arthritis (RA) patients on methotrexate (MTX) were studied. BS patients were then classified as those with and without vascular involvement. Fasting plasma homocysteine, folate, and vitamin B12 concentrations were measured by enzyme immunoassay and chemiluminescent immunoassay methods respectively. RESULTS: Plasma homocysteine levels were found to be higher in the BS patients than in the healthy control (16.08 +/- 7.5 vs. 12.9 +/- 6.3 micromol/L, p < 0.03). The homocysteine levels in the RA group on MTX were higher compared with both the BS and HC groups (28.7 +/- 9.9; p < 0.0001). No remarkable difference pertaining to homocysteine levels was found between BS patients with or without thrombosis (p < 0.86). Hyperhomocysteinemia was also detected in 11 out of 22 (50%) of the patients with vascular involvement, which proved to be of no significant difference in comparison with those without vascular involvement (20/52, 38%; chi2 = 0.26, p > 0.05). Active BS smokers exhibited a higher concentration of homocysteine in contrast to non-smoker BS sufferers (20 +/- 8.4 vs 14.1 +/- 6.1 micromol/l; p < 0.004). Smoking was determined to have a positive correlation with vascular involvement (r = 0.26, p < 0.046), as well as with homocysteine levels (r = 0.31, p < 0.012) in BS. Upon logistic regression analysis, smoking was found to have a significant relationship with vascular involvement (odds ratio 3.12 [95% CI 2.02-4.22] p = 0.04). There was no significant difference between the study groups with respect to their B12 vitamin and folate levels. We were unable to make any correlation between homocysteine and vitamin B12 or folate in any of the groups (p > 0.05). CONCLUSIONS: No association was found between homocysteine levels and vascular involvement in our BS patients. We determined that smoking seems to pose a risk for vascular involvement in BS patients.
14677194 The compliance-questionnaire-rheumatology compared with electronic medication event monito 2003 Nov OBJECTIVE: To validate the 19-item Compliance-Questionnaire-Rheumatology (CQR) against the "gold standard" in compliance measurement, electronic medication event monitoring. METHODS: Among 127 consenting patients, 81 with rheumatoid arthritis taking nonsteroidal antiinflammatory drugs (13 diclofenac, 20 naproxen) or disease modifying antirheumatic drugs (25 sulfasalazine, 23 methotrexate), 17 patients with polymyalgia rheumatica taking prednisone, and 29 patients with gout taking daily prophylactic colchicine (n = 12) or the uric acid lowering drugs allopurinol (10) or benzbromaron (7), 104 used their medication from a regular medication bottle fitted with a special cap containing microelectronics capable of recording time and date of opening and closing, defined as a medication event. Data were processed for the following: (1) the percentage of prescribed medication events during the study period (taking compliance) and (2) the percentage of days with the prescribed number of medication events (i.e., correct dosing). Satisfactory compliance was defined as taking compliance or correct dosing > 80%, while unsatisfactory compliance was defined as taking compliance or correct dosing < or = 80%. All patients were informed about the monitoring, and were followed for 6 months (gout: 1 year). At baseline 85 patients completed a set of questionnaires including the 19-item CQR. RESULTS: A total of 85 patients who had complete questionnaire and electronic monitoring data were analyzed. Multiple linear regression analyses showed that the total, weighted CQR score significantly and adequately predicts taking compliance (p = 0.001, r2 = 0.46) and correct dosing (p = 0.004, r2 = 0.42). Discriminant analyses showed that specificity and sensitivity to detect good taking compliance were 95% and 62%, respectively, with a prevalence of good compliance of 52%. The predictive value to detect unsatisfactory taking compliance was 86%, and to detect good taking compliance was 83%. The likelihood ratio of the CQR-19 to detect low taking compliance was 11.6. Four items were especially predictive: fear of forgetting to take the drug, being able to function well, routines in daily life, and side effects (combined r2 = 0.35). CONCLUSION: These results support the validity of the Compliance Questionnaire Rheumatology.
12957697 Endothelial dysfunction in young patients with long-term rheumatoid arthritis and low dise 2003 Sep OBJECTIVE: Cardiovascular mortality is excessive in patients with rheumatoid arthritis (RA). It has been proposed that the chronic inflammatory state of RA contributes to accelerated atherosclerosis. The aim of this study was to determine whether endothelial dysfunction, an early sign of arteriosclerosis, is present in young, long-term RA patients receiving standard methotrexate (MTX) therapy. Furthermore, we tested whether etanercept (ENC), a TNF-alpha receptor blocker, resulted in improved endothelial function compared to MTX in the same patients. METHODS: We studied eight RA patients twice: (1) on MTX and (2) after MTX washout and receiving ENC. Eight healthy volunteers matching for age, gender, height, weight and conventional cardiovascular risk factors served as control (C). All participants received intrabrachial infusions of increasing doses of acetylcholine (ACh, endothelium-dependent vasodilator) and glyceryl-trinitrate (GTN, endothelium-independent vasodilator). Forearm blood flow (FBF) was measured by bilateral venous occlusion plethysmography. RESULTS: Disease activity of RA was comparably low during both MTX and ENC (DAS 28 3.9+/-0.3 and 3.5+/-0.3). FBF in response to ACh was reduced in RA compared to C (P<0.01). Switching from MTX to ENC failed to improve vascular responsiveness to ACh. GTN comparably increased FBF in all groups. CONCLUSIONS: Our study for the first time demonstrates that long-term RA is associated with manifested endothelial dysfunction. Switching from MTX to ENC in stable RA patients has no beneficial effect on endothelial function.
12848626 Bioavailability of oral vs. subcutaneous low-dose methotrexate in patients with Crohn's di 2003 Jul 1 BACKGROUND: Oral methotrexate and folic acid are partly absorbed by a common intestinal transporter. AIM: : To determine the relative bioavailability of oral low-dose methotrexate administered with and without concomitant folic acid vs. subcutaneous administration in patients with stable Crohn's disease. METHODS: Ten patients were randomized to receive their regular maintenance dose of methotrexate (15-25 mg) for three consecutive weeks: orally, orally with 5 mg folic acid or subcutaneously. Blood samples were drawn at specified intervals during 24 h, and methotrexate levels were determined by fluorescence immunoassay. Areas under the curve extrapolated to infinity (AUC infinity ) were compared between the three routes. RESULTS: The geometric mean AUC infinity values (95% confidence intervals) were 360 nmol x h/L (301-430 nmol x h/L), 261 nmol x h/L (214-318 nmol x h/L) and 281 nmol x h/L (209-377 nmol x h/L) per milligram of methotrexate administered for subcutaneous, oral and oral with folic acid administration, respectively (P < 0.05 and P < 0.01 for oral with folic acid and oral vs. subcutaneous administration, respectively). The geometric mean relative bioavailabilities (95% confidence intervals) were 0.73 (0.62-0.86) and 0.77 (0.60-0.99) for oral and oral with folic acid administration, respectively (difference not significant). CONCLUSIONS: In patients with stable Crohn's disease, the oral bioavailability of methotrexate is highly variable and averages 73% of that of subcutaneous administration. Concomitant folic acid has no significant effect on the bioavailability. Dose adjustments based on individual pharmacokinetic assessment should be considered when switching patients from parenteral to oral therapy.
12140038 Multiple bilateral eyelid molluscum contagiosum lesions associated with TNFalpha-antibody 2002 Aug PURPOSE: To demonstrate a patient developing multiple bilateral eyelid molluscum contagiosum lesions after initiation of TNFalpha-antibody therapy for rheumatoid arthritis. DESIGN: Single interventional case report. METHODS: Clinical, histopathologic, and immunologic-serological findings are presented. RESULTS: A 67-year-old patient with a 5-year history of rheumatoid arthritis had been treated with prednisone and methotrexate for the last 5 years. After initiation of additional TNFalpha-antibody treatment, complaints from rheumatoid arthritis subsided, but multiple bilateral molluscum contagiosum lesions of upper and lower eyelids occurred despite normal or only slightly reduced CD(4) (420-178/ microl) and CD(8) counts (143-58/microl). Histopathologic evaluation of the excised warts confirmed the clinical diagnosis. Under continued therapy, the warts have been recurring for 12 months. CONCLUSION: TNFalpha-antibody treatment for rheumatoid arthritis may compromise the host response to molluscum contagiosum, especially if methotrexate is given additionally. Patients should be informed about this potential complication.
15146410 Combination therapy with etanercept and anakinra in the treatment of patients with rheumat 2004 May OBJECTIVE: To determine the potential for additive or synergistic effects of combination therapy with the selective anti-tumor necrosis factor alpha agent etanercept and the anti-interleukin-1 agent anakinra. METHODS: Two hundred forty-four patients in whom rheumatoid arthritis (RA) was active despite methotrexate therapy were treated with subcutaneous etanercept only (25 mg twice weekly), full-dosage etanercept (25 mg twice weekly) plus anakinra (100 mg/day), or half-dosage etanercept (25 mg once weekly) plus anakinra (100 mg/day) for 6 months in a double-blind study at 41 centers in the US. Patients had never previously received anticytokine therapy. Patient response was measured with the American College of Rheumatology (ACR) core set criteria, a health-related quality-of-life questionnaire, and the Disease Activity Score. Safety was assessed by the number of adverse events and clinical laboratory values. Plasma concentrations of both agents and antibody formation against both agents were also assessed. RESULTS: Combination therapy with etanercept plus anakinra provided no treatment benefit over etanercept alone, regardless of the regimen, but was associated with an increased safety risk. Thirty-one percent of the patients treated with full-dosage etanercept plus anakinra achieved an ACR 50% response, compared with 41% of the patients treated with etanercept only. This result was not statistically significant (P = 0.914). The incidence of serious infections (0% for etanercept alone, 3.7-7.4% for combination therapy), injection-site reactions, and neutropenia was increased with combination therapy. Combination therapy had no effect on the pharmacokinetics or immunogenicity of either agent. CONCLUSION: Combination therapy with etanercept and anakinra provides no added benefit and an increased risk compared with etanercept alone and is not recommended for the treatment of patients with RA.
15340127 Lumiracoxib does not affect methotrexate pharmacokinetics in rheumatoid arthritis patients 2004 Oct BACKGROUND: Methotrexate and nonsteroidal antiinflammatory drugs are frequently coadministered in the treatment of rheumatoid arthritis (RA). OBJECTIVE: To evaluate the effect of lumiracoxib, a novel cyclooxygenase-2 selective inhibitor, on methotrexate pharmacokinetics and short-term safety in patients with RA. METHODS: This multicenter, randomized, double-blind, placebo-controlled crossover study enrolled 18 patients (mean age 49.1 y) with stable RA. Patients were randomized to receive methotrexate 7.5-15 mg orally once weekly plus either lumiracoxib 400 mg/day or placebo for 7 days. Patients then received the other treatment combination for an additional 7 days. Serial blood and urine were collected for 24 hours after the methotrexate dose on day 1 (methotrexate alone) and days 8 and 15 (combination treatment). RESULTS: Plasma methotrexate pharmacokinetics (AUC(0-t), maximum concentration [C(max)], time to C(max)) and methotrexate protein binding were similar for methotrexate alone (108.0 ng.h/mL, 26.7 ng/mL, 1.5 h, and 57.1%, respectively), methotrexate/lumiracoxib (110.2 ng.h/mL, 27.5 ng/mL, 1.0 h, and 53.7%, respectively), and methotrexate/placebo (101.8 ng.h/mL, 22.6 ng/mL, 1.0 h, and 57.0%, respectively). Similarly, no clinically significant difference was found in the urinary excretion of methotrexate. Mean exposure to the 7-OH metabolite was lower when methotrexate was given with lumiracoxib compared with placebo, shown by a reduction in AUC and C(max), although similar amounts of the metabolite were recovered in urine following both lumiracoxib and placebo. Coadministration of methotrexate and lumiracoxib was well tolerated. CONCLUSIONS: Lumiracoxib had no significant effect on the pharmacokinetics, protein binding, or urinary excretion of coadministered methotrexate in patients with RA.
14577718 Treatment compliance and dosage administration among rheumatoid arthritis patients receivi 2003 Oct OBJECTIVE: To examine treatment compliance and dosage administration associated with infliximab, etanercept, and methotrexate therapy for rheumatoid arthritis (RA). STUDY DESIGN: Retrospective analysis using administrative and claims data from a large US health plan. PATIENTS AND METHODS: Patients were Medicare or commercial enrollees in a health plan with a pharmacy benefit and had a diagnosis of RA. The first (index) claim for infliximab, etanercept, or methotrexate occurred between July 1, 1998, and December 31, 2000. Continuous enrollment in the plan was required from 182 days before to 365 days after the index claim. Treatment groups were compared according to compliance (defined as the actual number of therapy administrations or filled prescriptions divided by the expected number) and changes in dosage administration over time. The costs of infliximab therapy also were explored. RESULTS: A total of 2662 patients (infliximab = 141; etanercept = 853; and methotrexate = 1668) were included in the analyses. Infliximab patients were older and more likely to have a Medicare benefit. In addition, infliximab patients had more comorbidities and had greater medical costs preceding the index claim. Compliance with at least 80% of the expected dosages was significantly lower for etanercept (odds ratio [OR] 0.462; 95% confidence interval [CI] 0.290-0.736) and methotrexate (OR 0.385; 95% CI 0.245-0.604) patients than infliximab patients. Methotrexate patients had the largest dosage increases (61.6%), followed by infliximab (37.4%) and etanercept (7.4%) patients. Assuming 6.5 dosages per year, the annual cost of infliximab was dollars 10446 to dollars 12363, or dollars 1887 to dollars 1902 per administration, depending on site of service. CONCLUSIONS: Compliance is higher with infliximab compared with etanercept or methotrexate; whereas, fewer etanercept patients change dosages. The cost of infliximab was lower than expected based on previous predictions, even with a 37% increase in dosage.
12010788 Lymphomas in rheumatoid arthritis patients treated with methotrexate: a 3-year prospective 2002 Jun 1 A national prospective study was designed to collect all cases of lymphoma appearing in patients with rheumatoid arthritis (RA) treated with methotrexate (MTX) throughout France over a period of 3 years. A total of 25 cases of lymphoma were recorded, 18 cases of non-Hodgkin lymphoma (NHL), 3 of which were associated with the presence of Epstein-Barr virus (EBV) in lymphoma cells, and 7 cases of Hodgkin disease (HD), 5 of them associated with EBV. Among the 8 patients who were treated by MTX withdrawal alone, 3 underwent remission, but 2 of them had a relapse, the third patient with clonal EBV-associated large granular lymphocytes T-cell NHL remaining alive in complete remission. The estimated annual incidence rate of NHL in RA patients treated with MTX was 33.3.10(-5) (0-80.5) among men and 16.7.10(-5) (0-33.3) among women. There was no significant excess with the French population as a comparison: the standardized mortality ratio (SMR) adjusted for age and sex was 1.07 (0.6-1.7). The estimated annual incidence rate of HD among men and women was, respectively, 27.8.10(-5) (0-70.1) and 2.8.10(-5) (0- 9.6). The incidence of HD was significantly increased compared with the French incidence, with an SMR adjusted for age and sex of 7.4 (3.0-15.3; P <.001). Thus, this 3-year prospective study indicated that, whereas the risk of NHL was not significantly increased in RA patients treated with MTX, the incidence of HD appeared to be higher in these patients compared to the French population.
12503406 Treatment of experimental adjuvant arthritis with the combination of methotrexate and lyop 2002 The efficacy of combination therapy with methotrexate (MTX) and probiotic bacteria Enterococcus faecium enriched with organic selenium (EFSe) in rats with adjuvant arthritis was determined. Rats with adjuvant arthritis were given MTX (0.3 mg/kg 2-times weekly, orally); lyophilized E. faecium enriched with Se (15 mg/kg, 5 d per week, orally); and a combination of MTX plus EFSe for a period of 50 d from the immunization. Levels of serum albumin, serum nitrite/nitrate concentrations, changes in hind paw swelling, arthrogram score, bone erosions, whole body bone mineral density (BMD) and bone mineral content (BMC) were assayed in the rats as variables of inflammation and destructive arthritis-associated changes. Treatment with MTX and with the combination MTX + EFSe significantly inhibited markers of both inflammation and arthritis. Significant differences in favor of combination therapy with MTX + EFSe as compared to MTX alone were seen in serum albumin concentration, hind paw swelling and arthrogram score. Reductions in radiographic scores were also more pronounced in the combination therapy group. Combination therapy, but not MTX alone, inhibited the reduction of BMD and BMC; treatment with lyophilized EFSe alone had no significant effect on adjuvant arthritis in rats. The potent therapeutic effect of low dosage MTX therapy in combination with lyophilized EFSe on adjuvant arthritis in rats was shown.
15052856 [Unexpected complication in an elderly lady suffering from rheumatoid arthritis]. 2004 Mar 3 A 66-year old female suffering from rheumatoid arthritis was treated with methotrexate and intra-articular steroid injections. She had gone through pulmonary tuberculosis at the age of 2 years, also, surgery had been performed 2 years ago because of perforated sigmoid diverticulitis. The patient now presented with episodes of abdominal pain and diarrhea as well as occasional night sweats. Laboratory investigation (normal BSR, CRP and white blood cell counts) did not indicate the presence of an inflammatory process, such as reoccurrence of diverticulitis. However, leukocyturia was repetitively found in this patient with the conventional urine culture yielding no significant bacterial growth. Further urine investigation did not indicate infection with Chlamydia trachomatis or Neisseria gonorrhoeae. Ziehl Neelson stains of morning urinary samples did not show acid-fast rods, however, Mycobacterium tuberculosis was finally isolated by culture. Thus, urogenital tuberculosis was finally diagnosed in this patient. Infection, hematogenic dissemination, and spontaneous remission of pulmonary tuberculosis had occurred more than 60 years ago. After a long latent period, reactivation of tuberculosis happened during drug-induced immunosuppression. The patient was successfully treated with an anti-tuberculosis triple-drug therapy during 2 months followed by a double-drug therapy during 4 months.
12685246 [Analysis of efficacy and safety of multiple intravenous infusion of anti-tumor necrosis f 2002 Nov The objective of the paper was compare the effects and tolerability of combined therapy of multiple intravenous infusions of anti-tumour necrosis factor-alfa (TNF-alfa) monoclonal antibody (Remicade) with methotrexate versus treatment with sodium aurothiomalate and intramuscular depot methylprednisolone in rheumatoid arthritis (RA). We investigate also the interval necessary to obtain the improvement in both treatment groups. 36 patients commencing intramuscular sodium aurothiomalate therapy with intramuscular depot methylprednisolone acetate at weeks 0, 4, 8 and 12 in addition to chrysotherapy were compared in retrospective analysis with 32 patients starting with multiple intravenous infusions of infliximab, anti-TNF-alfa monoclonal antibody (Remicade) and methotrexate at a stable dose. Patients were assessed by composite clinical score (DAS 28) and C-reactive protein during 22 weeks of therapy. At week 2 and 6 a significantly greater percentage of infliximab-treated than gold-treated RA patients achieved improvement in each clinical measurement of disease activity. At 22 week of treatment moderate and good response according to EULAR criteria was achieved in 91% of infliximab-treated patients and 58% gold treated patients (p < 0.001). Adverse events were more frequently observed in infliximab-treated patients, but only gold-treated patients discontinued treatment because adverse events (2 patients due to proteinuria, 2 patients due to mucocutaneous changes and one patient due to leucopenia). The higher percentage of adverse events in infliximab-treated patients was caused mainly by the occurrence of infusion reactions (23 reactions out of 160 infusions); most of them were mild (somnolentia and headache) and transient. Viral infections (including herpes simplex and zoster) were more common in patients treated with infliximab and methotrexate. Combination therapy of infliximab and methotrexate is more effective in reducing clinical and biochemical disease activity than gold with methylprednisolone treatment in RA patients during 22 weeks of treatment, especially in the first 6 weeks.
11945114 Safety and efficacy of disease-modifying anti-rheumatic agents: focus on the benefits and 2002 The traditional approach to the treatment of rheumatoid arthritis (RA) has been the use of nonsteroidal anti-inflammatory drugs usually in combination with a disease-modifying antirheumatic drug (DMARD) such as hydroxychloroquine, gold, sulfasalazine, methotrexate, leflunomide or cyclosporin. Each of these DMARDs has its own distinct toxicities but has also been shown to be effective in reducing signs and symptoms of disease and to some extent, reduce radiological progression. Within the past 10 years, the combination of several traditional DMARDs has been shown to have increased efficacy over monotherapy without a significant increase in toxicity in a majority of studies. Recently, the US Food and Drug Administration has approved infliximab, a chimeric monoclonal antibody to tumour necrosis factor (TNF)-alpha in combination with methotrexate, for the treatment of signs and symptoms of RA, delay of radiological progression of disease and improvement of physical function while anakinra, an interleukin-1 receptor antagonist, has been approved for the treatment of the signs and symptoms of RA either as monotherapy or in combination with methotrexate. Etanercept is the first biological response modifier approved for use in RA in the US. Double-blind, randomised controlled studies have shown etanercept to be effective therapy in patients with RA who have had inadequate response to DMARDs, in combination with methotrexate, and as early monotherapy. Similar results were seen in juvenile and psoriatic arthritis in DMARD nonresponders. Open-label studies have shown efficacy in adult Still's disease, ankylosing spondylitis, progressive systemic sclerosis, Wegener's granulomatosis and chronic uveitis. Safety issues are a concern because of the ubiquitous role of TNF. To date the only consistent adverse event seen with etanercept has been injection site reactions. Infections occur at the same rate and with the same frequency as the placebo population. There should be caution, however, with using etanercept in patients with a serious infection, or recurrent infections or patients with untreated or latent tuberculosis. As of yet there has not been seen an increase of malignancies. Rare neurological and haematological events have been noted. Etanercept has been a significant addition to the armamentarium of medications for the treatment of RA, juvenile and psoriatic arthritis. Preliminary data show that it may be well tolerated and effective in other rheumatic diseases in which there is over production of TNFalpha.
15199219 Albumin-coupled methotrexate (MTX-HSA) is a new anti-arthritic drug which acts synergistic 2004 Sep OBJECTIVE: To evaluate the anti-arthritic effects of the new inflammation-targeted drug MTX-HSA and to investigate whether peripheral blood mononuclear cells (PBMC) are potential target cells for albumin-mediated drug delivery. METHODS: The murine model of collagen-induced arthritis (CIA) was used to measure the anti-arthritic effect of MTX, MTX-HSA or a combination of both (n = 30 to 35 per group). In addition, the uptake of fluorescence-labelled albumin (AFLc-HSA) in PBMC of 14 patients with RA was measured by fluorescence-activated cell sorting (FACS). RESULTS: In equivalent doses of 7.5 mg/kg intravenously (IV) twice a week, MTX-HSA is significantly (P<0.02) superior to MTX in inhibiting the development of CIA and reducing the joint count as well as the number of affected paws. When given in lower doses as combination therapy, both drugs act synergistically (P<0.03). A mean of 96, 72 and 64% of the CD14-, CD16- and CD20-positive cells from peripheral blood of rheumatoid arthritis (RA) patients showed an uptake of albumin after incubation with AFLc-HSA in vitro. This finding was not significantly different in comparison to healthy controls. In contrast, the number of CD3-positive cells taking up albumin is increased significantly in RA patients in comparison to controls (26.3 +/- 12.9% s.d. vs 11.6 +/- 7.3% s.d.; P = 0.005). CONCLUSION: The data show that the effectiveness of MTX-HSA in CIA is superior to MTX and that both drugs act synergistically. In addition, albumin appears to be taken up by peripheral blood cells, suggesting that they might be one of the potential target cells of this novel anti-arthritic treatment approach.
15547182 Reactivation of latent Epstein-Barr virus by methotrexate: a potential contributor to meth 2004 Nov 17 BACKGROUND: Patients with rheumatoid arthritis or polymyositis treated with methotrexate (MTX) develop Epstein-Barr virus (EBV)-positive lymphomas more frequently than patients treated with other, equally immunosuppressive regimens. Here we determined whether MTX, in contrast to other commonly used medications for rheumatoid arthritis or polymyositis, is unique in its ability to induce the release of infectious EBV from latently infected cells. METHODS: The effect of MTX and other immunosuppressant drugs on EBV replication in vitro was assessed using latently infected EBV-positive lymphoblastoid and gastric carcinoma cell lines. Inhibitors of signal transduction pathways were used to define requirements for induction of lytic infection. Drug effects on transcription of the two EBV immediate-early promoters (BRLF1 and BZLF1) and on promoter constructs lacking cis-acting sequences required for activation by other effectors was examined using reporter gene assays. EBV viral load in rheumatoid arthritis and polymyositis patients receiving MTX was compared with that in patients receiving other immunosuppressive medications. Statistical tests were two-sided. RESULTS: MTX activated the release of infectious EBV from latently infected cell lines in vitro, and MTX treatment was associated with activation of the two viral immediate-early promoters in reporter gene assays. Induction of lytic EBV infection by MTX required the p38 MAP kinase, PI3 kinase, and MEK pathways and specific cis-acting motifs in the two viral immediate-early promoters. Patients treated with MTX-containing regimens had statistically significantly higher mean EBV loads in their blood than patients treated with immunosuppressing regimens that did not include MTX (40 EBV copies per 10(6) cellular genomes versus 5.1 copies; geometric mean fold difference in copies = 10.8, 95%, confidence interval = 3.0 to 38; P = .011). CONCLUSION: MTX may promote EBV-positive lymphomas in rheumatoid arthritis and polymyositis patients by its immunosuppressive properties as well as by reactivating latent EBV.
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