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Mader R.M.,Medical University of Vienna | Erlacher L.,Kaiser Franz Josef Hospital | Duhm B.,Kaiser Franz Josef Hospital | Mustak M.,Kaiser Franz Josef Hospital | And 3 more authors.
Clinical and Experimental Rheumatology | Year: 2011

Objective: Methotrexate (MTX) is a cornerstone in the treatment of rheumatoid arthritis (RA). Among its anti-proliferative activity, the anti-inflammatory mechanisms of MTX seem to play a major role in the treatment of RA. MTX reduces the production of pro-inflammatory cytokines such as interleukin (1L)-1, IL-2, IL-6 and interferon (INF)-γ, while the gene expression of anti-inflammatory Th2 cytokines like IL-4 and 1L-10 is increased - altogether resulting in the anti-inflammatory effect. As little is known about the impact of MTX on other cytokines involved in the pathogenesis of RA, the present trial investigated the effect of MTX on IL-12A and IL-18 gene expression by peripheral blood mononuclear cells (PBMCs). For comparison, the effect on IL-6 and tumour necrosis factor (TNF) was analysed. Methods: Using real-time PCR, mRNA concentrations of pro-inflammatory cytokines were determined in PBMCs from 17 patients before and during MTX therapy. Furthermore, gene expression was correlated with clinical and pharmacokinetic parameters such as methotrexate polyglutamate concentrations (Spearman's correlation coefficient). To eliminate concomitant corticosteroids as confounding factor, a subgroup analysis for methotrexate without corticosteroids was performed in 6 patients. Results: MTX statistically significantly reduced the mRNA expression of IL-12A by PBMCs in rheumatoid arthritis patients (Wilcoxon-test for paired samples, p<0.046). Consistent with other reports, IL-6 was reduced under MTX treatment. Although the combination of MTX and corticosteroids significantly reduced the gene expression of IL-18, this key molecule was unaffected by MTX without corticosteroids. Our results were further supported by a negative correlation of methotrexate polyglutamate concentrations and the mRNA expression of the pro-inflammatory cytokines IL-6 and IL-12A. Conclusion: We describe a novel effect of MTX reducing the gene expression of IL-12A independently of corticosteroid application in patients. This impact was further enhanced by a reduction of IL-12A-producing lymphocytes and neutrophils under MTX treatment. These results expand the understanding of the mechanism of action of the most widely used drug in RA. © Copyright CLINICAL AND EXPERIMENTAL RHEUMATOLOGY 2011. Source


Hobl E.-L.,Medical University of Vienna | Mader R.M.,Medical University of Vienna | Jilma B.,Medical University of Vienna | Duhm B.,Kaiser Franz Josef Hospital | And 4 more authors.
Clinical Therapeutics | Year: 2012

Background: Methotrexate (MTX) is a cornerstone in the treatment of rheumatoid arthritis. Despite its widespread use, expert opinions differ about the optimal MTX starting dosage to achieve rapid onset of action while averting increased occurrence of adverse effects. Plasma concentrations have not been assessed in previous studies that monitored clinical efficacy. Objective: This study was performed to compare the pharmacokinetic parameters and clinical response of a standard (15 mg) and an accelerated (25 mg) dosing regimen, each administered orally once a week. Methods: This randomized, controlled, double-blind, parallel, single-site study included 19 MTX-naïve patients older than 18 years with rheumatoid arthritis. Patients participated for 16 weeks. Disease activity was assessed using the Disease Activity Score in 28 joints (DAS-28) as the primary outcome parameter. Plasma MTX concentrations were measured using HPLC at weeks 1, 5, 10, and 16. Tolerability was assessed via routine blood analysis (hematology and clinical chemistry) and a patient questionnaire to monitor adverse events. Reported or observed adverse events were recorded along with information about their severity and causal relationship to the study medication. Results: Nineteen white patients (13 women and 6 men; mean age, 56 years; and mean weight, 74 kg) participated. At study entry, mean (SD) DAS-28-4v (erythrocyte sedimentation rate) was 4.73 (1.02). Health Assessment Questionnaire scores were 1.45 (0.85); for C-reactive protein, 11.45 (10.04) mg/dL; for alkaline phosphatase, 73.58 (19.91) U/L; for aspartate aminotransferase, 23.32 (7.13) U/L; and for creatinine, 0.87 (0.22) mg/dL. Although pharmacokinetic parameters such as AUC and C max were significantly higher after the accelerated dosing regimen, clinical activity scores (DAS-28) and inflammation parameters (C-reactive protein) did not indicate a significant benefit of an accelerated starting regimen. Considering toxicity, no elevation in liver function enzymes and no decrease in renal function were observed using the accelerated dosing (statistical significance set at P ≤ 0.05). No serious adverse events were noted. All observed adverse events were classified as study related. Overall, adverse events were noted in 58% of patients. Comparison of the two doses revealed that 60% of patients receiving the standard dosing regimen and 56% of patients receiving the accelerated dosing regimen reported adverse events, the most frequent being gastrointestinal. These events were generally self-limiting. Conclusions: Differences in clinical response between these two small selected patient groups who received an initial oral dose of either 15 or 25 mg MTX per week did not reach the level of statistical significance. The overall incidence of adverse effects, all classified as study related, was 58%, with 60% of patients receiving the standard dosage and 56% of patients receiving the accelerated dosing regimen reporting adverse effects. However, because of the small sample size, this study was not powered to detect differences in the incidence of adverse events between the two dosing groups. . ClinicalTrials.gov identifier: . NCT00695188. © 2012 Elsevier HS Journals, Inc. Source


Hobl E.-L.,Medical University of Vienna | Jilma B.,Medical University of Vienna | Erlacher L.,Kaiser Franz Josef Hospital | Duhm B.,Kaiser Franz Josef Hospital | And 5 more authors.
Clinical and Experimental Rheumatology | Year: 2012

Objective: Methotrexate (MTX) is a cornerstone in the treatment of rheumatoid arthritis (RA). Although in general MTX is very effective, the major drawback is the large inter-patient variability in clinical response. The circulating levels of MTX polyglutamates (MTXPGs) are supposed to correlate with clinical efficacy, therefore having a potential role in drug monitoring. However, there is a controversial discussion about the importance of methotrexate polyglutamates as outcome parameters in the therapy of rheumatoid arthritis. The aim of the present study was to investigate the formation and pharmacokinetics of MTXPGs and to correlate their concentration with clinical response in MTX-naïve patients. Methods: The pharmacokinetics of erythrocyte MTXPGs was determined in samples of nineteen MTX-naïve patients by high pressure liquid chromatography (HPLC) using post-column photo-oxidation and fluorimetric detection. The relationship between erythrocyte concentrations of MTXPGs and the primary outcome parameter DAS-28 was assessed using the Spearman's correlation coefficient. Results: The short-chain polyglutamate MTXPG2 revealed to be a potential marker for clinical outcome in rheumatoid arthritis with a statistically significant positive correlation of MTXPG2 C max levels and improvement in DAS-28 (+0.518, p=0.023) over 16 weeks. Furthermore, C max levels of MTXPG2 negatively correlated with basophils (-0.478, p=0.038) and eosinophils (-0.531, p=0.019), both pro-inflammatory cells involved in the disease. Conclusion: MTXPG2 seems to be a potential indicator for clinical response and may serve as a marker for drug monitoring. © Clinical and Experimental Rheumatology 2012. Source


Becker T.,Ludwig Boltzmann Cluster for Rheumatology | Tohidast-Akrad M.,Ludwig Boltzmann Cluster for Rheumatology | Humpeler S.,Ludwig Boltzmann Cluster for Rheumatology | Humpeler S.,Medical University of Vienna | And 7 more authors.
Acta Histochemica | Year: 2014

Patients with rheumatoid arthritis (RA) show modulated circadian rhythms of inflammatory cytokines and cortisol, which may be associated with a modified expression of clock genes. The expression of major clock genes was previously studied in synovial tissues and fibroblasts of patients with RA and osteoarthritis (OA). We therefore especially aimed to examine the localization of clock genes at the cellular level in synovial tissue. Furthermore we were interested in studying the expression of the D site of albumin promoter (albumin D-box) binding protein (DBP) at the immunohistochemical level in human samples. Methods used include the in situ expression of the clock genes Brain and muscle aryl hydrocarbon receptor nuclear translocator-like 1 (Bmal 1), Circadian Locomotor Output Cycles Kaput (Clock), Period 1 and 2 (Per 1 and Per 2), and DBP was examined by immunohistochemistry in synovial tissues of patients with RA or OA. Additionally, expression profiles of different clock genes were determined over 24. h by real time PCR in synovial fibroblasts (SFs) after a 2. h serum shock or TNF-α. Results show that all clock genes investigated were found to be expressed both in RA and OA synovial tissues. Double staining against cell specific markers revealed that clock proteins were especially seen in macrophages, SFs and B-lymphocytes. Cell counting showed that clock proteins were found in approximately 5-20% of cells. Additionally, preliminary cell culture experiments showed that TNF-α treatment resulted in differential 24. h expression profiles between RA and OA samples and also compared to the results obtained from the serum shock experiments. From our study we conclude that the major clock genes, including DBP, are expressed in samples from RA and OA patients, especially in macrophages and synovial fibroblasts, but also in B-lymphocytes. Preliminary experiments suggest that TNF-α seems to be able to modify clock gene expression in synovial fibroblasts. © 2014 Elsevier GmbH. Source


Krpan D.,Poliklinika K CENTAR | Stritzinger B.,Ludwig Boltzmann Cluster for Rheumatology | Lukenda I.,Poliklinika K CENTAR | Overbeck J.,Poliklinika K CENTAR | Kullich W.,Ludwig Boltzmann Cluster for Rheumatology
Periodicum Biologorum | Year: 2015

Objectives: To demonstrate the long-term effects of the therapeutic use of nuclear magnetic resonance (NMR) on bone mineral density (BMD) parameters in patients with osteoporosis. Methods: We enrolled 103 patients aged between 45 and 89 years who had osteoporosis with a T-score of bone mineral density less than -2.5. All patients received an osteoporosis treatment with low field nuclear magnetic resonance using a special NMR device (MBST, MedTec, Germany) for one hour per day on 10 consecutive days. At baseline and 12 months after NMR treatment the BMD was measured by DEXA. Additionally, the levels of the bone turnover markers osteocalcin and bone crosslaps (β-CTX; crosslinked telopeptides of collagen 1) were measured by immunoassays. Results: BMD and serum levels of osteocalcin increased significantly from baseline to 12 months. β-CTX remained stable. Conclusions: Under therapeutically use of NMR-Therapy, BMD-parameters increased during 12 months after a treatment block (10 x 1h). Therefore, NMR-Therapy can be considered a useful alternative or supplement to medical therapy in patients with osteoporosis. © 2015 Croatian Society of Natural Sciences. All rights reserved. Source

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