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ID PMID Title PublicationDate abstract
19100307 Inflammation in methotrexate-induced pulmonary toxicity occurs via the p38 MAPK pathway. 2009 Feb 27 Methotrexate (MTX) has been widely used for the treatment of inflammatory diseases and rheumatoid arthritis (RA), as well as a variety of tumors. However, MTX-induced toxicity is a serious and unpredictable side effect of this therapy and an important clinical problem. We used microarray analysis to examine MTX-induced gene expression in a human lung epithelial cell line (BEAS-2B) and identified 10 differentially expressed genes related to the p38 mitogen-activated protein kinase (MAPK) pathway, including IL-1beta, MKK6, and MAPKAPK2. Differential gene expression was confirmed via real-time RT-PCR. To determine the functional significance of MTX-induced p38 MAPK activation, we used a p38 MAPK inhibitor (SB203580) to block the p38 MAPK cascade. We also used protein array technology to investigate the modulated expression of pro- and anti-inflammatory cytokines in BEAS-2B cells. MTX activated IL-1beta expression and induced the phosphorylation of various proteins in the p38 MAPK cascade, including TAK1, MKK3/MKK6, p38 MAPK, MAPKAPK2, and HSP27. Finally, HSP27 activation may increase IL-8 secretion, resulting in a pulmonary inflammatory response such as pneumonitis. Although IL-1beta and IL-8 expression increased, the expression of IL-4, IL-6, IL-12, TNF-alpha, MIP-1alpha, and MIP-1beta decreased in a dose-dependent manner. These results suggest that the modulation of cytokine expression may play an important role in MTX-induced pulmonary toxicity.
17726858 [Myositis with pulmonary fibrosis and eosinophilia]. 2007 Aug 2 A 74-year old female patient suffered from dyspnoea, subfebrile body temperature, myalgias, arthralgias and presented a transitory skin rash. Further findings were an eosinophilia, synovitis, a myositis and pulmonary fibrosis. There was no evidence for a malignancy or an infectious disease. We diagnosed an Anti-Jo-1-Syndrome with a secondary Sjoegren syndrome. Immunsuppressive therapy with steroids, later in addition methotrexate led to improvement of the patient's clinical condition. Above mentioned symptoms and its differential diagnosis are discussed in this article.
19061007 A comparison of vitamin A and leucovorin for the prevention of methotrexate-induced micron 2008 Dec INTRODUCTION: Methotrexate, a folate antagonist, is a mainstay treatment for childhood acute lymphoblastic leukemia. It is also widely used in a low dose formulation to treat patients with rheumatoid arthritis. In rats, methotrexate is known to induce micronuclei formation, leading to genetic damage, while vitamin A is known to protect against such methotrexate-induced genetic damage. Leucovorin (folinic acid) is generally administered with methotrexate to decrease methotrexate-induced toxicity. OBJECTIVES: We aimed to determine whether vitamin A and leucovorin differed in their capacity to prevent formation of methotrexate-induced micronuclei in rat bone marrow erythrocytes. The present study also aimed to evaluate the effect of combined treatment with vitamin A and leucovorin on the formation of methotrexate-induced micronuclei. METHODS: Male and female Wistar rats (n=8) were injected with 20 mg/kg methotrexate (single i.p. dose). The control group received an equal volume of distilled water. The third and fourth groups of rats received vitamin A (5000 IU daily dose for 4 successive days) and leucovorin (0.5 mg/kg i.p. dose for 4 successive days), respectively. The fifth and sixth groups of rats received a combination of vitamin A and a single dose of methotrexate and a combination of leucovorin and methotrexate, respectively. The last group of rats received a combination of leucovorin, vitamin A and single dose of methotrexate. Samples were collected at 24 hours after the last dose of the treatment into 5% bovine albumin. Smears were obtained and stained with May-Grunwald and Giemsa. One thousand polychromatic erythrocytes were counted per animal for the presence of micronuclei and the percentage of polychromatic erythrocyte was determined. RESULTS: Comparison of methotrexate-treated rats with the control group showed a significant increase in the percentage of cells with micronuclei and a significant decrease polychromatic erythrocyte percentage. Combined methotrexate and vitamin A therapy and combined methotrexate and leucovorin therapy led to significant decreases in the micronuclei percentage and an increase in polychromatic erythrocyte percentage when compared to rats treated with methotrexate alone. Leucovorin was found to be more effective than vitamin A against the formation of methotrexate-induced micronuclei. CONCLUSIONS: Both vitamin A and leucovorin provided significant protection against genetic damage induced by methotrexate.
18957891 Epstein Barr virus-associated primary CNS lymphomas in elderly patients on immunosuppressi 2008 Nov Unlike primary central nervous system lymphomas (PCNSLs) in patients with AIDS or organ transplants, PCNSLs in the elderly are usually not considered to be mediated by Epstein Barr virus (EBV); hence, diagnostic studies for EBV are not routinely performed. We encountered 4 patients, 65 years or older, who developed EBV-associated PCNSLs and who had been treated with a variety of immunosuppressive drugs for different autoimmune/collagen vascular disorders, including autoimmune polyneuropathy (mycophenolate mofetil for 5 years), polymyositis (prednisone for 16 years with intermittent methotrexate, azathioprine, and cyclophosphamide), myasthenia gravis (azathioprine >10 years), and rheumatoid arthritis (methotrexate >10 years). All patients had multifocal, necrotic brain lesions typical of EBV-positive PCNSLs on neuroimaging. Withdrawing immunosuppressives lead to PCNSL regression in some patients. The patient who had received mycophenolate mofetil was treated successfully for his EBV-associated PCNSL with rituximab and methotrexate, but later developed fatal systemic malignant melanoma, which was likely immunosuppression related. The striking feature of these cases is the variety of underlying diseases-and hence accompanying medications-that can be associated with EBV-associated PCNSLs. They serve as a diagnostic alert for neuropathologists and suggest that increased testing of PCNSLs for EBV by immunohistochemistry or in situ hybridization may be warranted in any patient on any immunosuppressive medication, but particularly the elderly.
18022599 High-performance liquid chromatography separation of aminopterin-polyglutamates within red 2007 Dec Aminopterin (AMT), like the related compound methotrexate (MTX), is a drug with anticancer and antiinflammatory efficacy that works by interfering with synthetic reactions dependent on the vitamin folic acid. Red blood cell (RBC) precursors will accumulate antifolates like AMT and MTX through the same mechanism by which they take up folate. Intracellular folate and antifolates are then metabolized to polyglutamates that remain within the mature RBCs. RBC MTX has been correlated with toxicity and/or treatment efficacy among patients with acute lymphoblastic leukemia (ALL) or rheumatoid arthritis. Because AMT may offer clinically relevant advantages over MTX, we are testing whether it can be administered safely in multiagent therapy to children with ALL. Total RBC AMT was measured to monitor compliance with this oral, outpatient regimen, and to estimate AMT exposure to the bone marrow. Here we describe methods for quantifying each AMT-polyglutamate species within the RBCs of patients. The assay was linear over a concentration range of 62.5-500 nmol/L. Recovery of individual AMT-polyglutamates ranged from 85% to 92%, and the intraday coefficients of variation were 1.3% to 3.6%. Long-chain AMT-polyglutamates (triglutamate and tetraglutamate forms) accounted for over 40% of intracellular AMT within the RBCs of patients. Patients with long-chain AMT polyglutamate concentrations above the median tended to have lower mean neutrophil counts during weekly AMT therapy, which suggests that RBC AMT polyglutamate accumulation may correlate with hematologic toxicity. As AMT continues to be tested in clinical trials, the methods described here will be useful to define relationships between clinical response to AMT and RBC accumulation of AMT-polyglutamates.
17364075 Outcomes of chronic hepatitis B infection in Oriental patients with rheumatic diseases. 2007 Feb INTRODUCTION: The aim of this study was to ascertain the outcomes of chronic hepatitis B (CHB) infection following immunosuppressive therapy in 38 consecutive oriental patients with systemic rheumatic diseases. MATERIALS AND METHODS: This is a retrospective consecutive, non-comparative study. RESULTS: The majority of patients were female (26, 68.4%), predominantly Chinese (92.1%), with a mean age 54 +/- 14 years (range, 16 to 87). The mean duration of rheumatic disease was 9 +/- 11 years (range, 0.1 to 48), with rheumatoid arthritis (52.6%) and systemic lupus erythematosus (23.7%) being the most common. The mean duration of CHB infection was 6 +/- 5 years (range, 0.1 to 17), with the majority diagnosed during pre-methotrexate screening (50.0%) and asymptomatic transaminitis following initiation of immunosuppressive therapy (23.7%). Upon diagnosis of rheumatic disease, all patients had normal alanine aminotransferase (ALT). Of these, 18.2% were positive for hepatitis B e antigen (HBeAg) and 78.1% were positive for anti- HBe antibody. Twenty (52.6%) developed ALT elevation, which was more than twice the upper limit of normal in 12 patients. ALT normalised spontaneously in 12 patients without hepatic decompensation or change in therapy. Seven (18.4%) patients received lamivudine for 18 +/- 22 months (range, 2 to 61). Two patients developed YMDD mutation subsequently treated with adefovir (1) and adefovir/lamivudine (1). There were 3 (7.9%) hepatitis B virus (HBV)-unrelated deaths [infection (2), genitourinary malignancy (1)], and 1 from HBV-reactivation complicated by septicaemia. None have developed hepatocellular carcinoma. CONCLUSION: Elevated ALT occurred in 52.6% of patients, with only 18.4% requiring anti-viral therapy for HBV reactivation. HBV-related mortality was low. With the appropriate precautionary measures, prednisolone and immunosuppressants (except methotrexate and leflunomide) may be used safely in patients where clinically indicated.
17054209 Methotrexate for ankylosing spondylitis. 2006 Oct 18 BACKGROUND: Ankylosing spondylitis (AS) is a chronic inflammatory disease of unknown cause, characterised by sacroiliitis and spondylitis. Generally, treatment is limited to the alleviation of symptoms using non-steroidal anti-inflammatory drugs (NSAIDs). Recently, disease-modifying antirheumatic drugs (DMARDs) have been used for patients for whom NSAIDs do not work. Methotrexate (MTX), a widely used DMARD, is effective for rheumatoid arthritis (RA), and so might work for AS too. OBJECTIVES: To evaluate the efficacy and toxicity of MTX for treating AS. SEARCH STRATEGY: We conducted searches in any language in: CENTRAL (The Cochrane Library Issue 4, 2005); MEDLINE (1966 to November 20, 2005); EMBASE (1980 to November 20, 2005); CINAHL (1982 to November 20, 2005), and the reference sections of retrieved articles. SELECTION CRITERIA: Randomised and quasi-randomised trials examining the efficacy of MTX versus placebo, other medication, or no medication, for AS. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed unblinded trial reports for inclusion, assessed methodological quality and entered trial data into RevMan 4.2 using the double-entry facility. Disagreements were resolved by a third reviewer. In the absence of significant heterogeneity, results for continuous data were combined using weighted mean difference or standardised mean difference. Relative risk was used for dichotomous data. MAIN RESULTS: Three trials, involving 116 patients, were included. One 12-month trial compared naproxen plus MTX with naproxen alone. Two 24-week trials compared different doses of MTX with placebo. No statistically significant differences were found for the primary outcome measures of physical function, pain, spinal mobility, peripheral joints/entheses pain, swelling and tenderness, changes in spine radiographs and patient and physician global assessment. Only the response rate in one trial showed a statistically significant benefit of 36% in the MTX group compared to the placebo group (RR 3.18, 95% CI 1.03 to 9.79). This response rate was a composite index that included assessments of morning stiffness, physical well-being, Bath ankylosing spondylitis disease activity index (BASDAI), Bath ankylosing spondylitis functional index (BASFI), health assessment questionnaire for spondyloarthropathies (HAQ-S), and physician and patient global assessment. However, no single outcome showed a statistically significant difference between the MTX and placebo groups when endpoint results were compared. Therefore, this benefit of MTX is questionable. No serious side effects were reported in these trials. AUTHORS' CONCLUSIONS: There is not enough evidence to support any benefit of MTX in the treatment of AS. High-quality randomised controlled trials of longer durations and with larger sample sizes are needed to clarify the effect(s) of MTX on AS.
17051484 Emergence of Legionella pneumophila pneumonia in patients receiving tumor necrosis factor- 2006 Nov 15 BACKGROUND: Patients treated with tumor necrosis factor-alpha (TNF-alpha) antagonists have an increased risk of infection, but infection due to Legionella pneumophila has rarely been described in patients receiving such therapy. METHODS: A registry involving 486 clinical departments in France was designed by a multidisciplinary group (Recherche Axée sur la Tolérance des Biothérapies [RATIO]) to collect data on opportunistic and severe infections occurring in patients treated with TNF-alpha antagonists. All cases are reported to RATIO in accordance with national health authorities and validated by infectious disease experts. The legionellosis rate among patients treated with TNF-alpha antagonists was compared with the rate in France overall. RESULTS: We report a 1-year consecutive series of 10 cases of L. pneumophila pneumonia in France in 2004, including 6 cases treated with adalimumab, 2 treated with etanercept, and 2 treated with infliximab. The median patient age was 51 years (range, 40-69 years). Eight patients were treated for rheumatoid arthritis, 1 was treated for cutaneous psoriasis, and 1 was treated for pyoderma gangrenosum. The median duration of TNF-alpha antagonist treatment at onset of infection was 38.5 weeks (range, 3-73 weeks). Eight patients were receiving concomitant treatment with corticosteroids, and 6 were receiving treatment with methotrexate. The relative risk of legionellosis when receiving treatment with a TNF-alpha antagonist, compared with the relative risk in France overall, was estimated to be between 16.5 and 21.0. We also report a second episode of confirmed legionellosis following the reintroduction of infliximab therapy. CONCLUSIONS: L. pneumophila pneumonia is a potentially severe but curable infection that might complicate anti-TNF-alpha therapy. In patients receiving anti-TNF-alpha who develop pneumonia, legionellosis should be systematically investigated, and first-line antibiotic therapy should be efficient against L. pneumophila.
18951733 EBV-associated diffuse large B-cell lymphoma in a psoriatic treated with methotrexate. 2009 Methotrexate-associated lymphoproliferative disorder (MTX-LPD) is a lymphoid proliferation or lymphoma in a patient immunosuppressed with MTX, which is usually administered for treating autoimmune diseases. The majority of MTX-LPD cases develop in patients with rheumatoid arthritis and occasionally with psoriasis who had been treated with MTX. Here, we report on a 50-year-old Taiwanese male with severe psoriasis, who received high doses of MTX. The patient developed EBV-positive MTX-LPD at nodal and extranodal sites. The diffuse and polymorphic lymphoid infiltrate consisted predominantly of immunoblasts and plasmablasts expressing B-cell markers, CD138, Epstein-Barr virus (EBV)-LMP1, and EBNA2, and these were monotypic for kappa light chain. The tumor cells were also positive for EBV by in situ hybridization. These findings indicated a type III latency infection of EBV. The patient died of progressive disease after 19 months. A review of the previously reported cases shows that MTX-LPD, in association with psoriasis, occurs in middle-aged males. The tumors are diffuse large B-cell lymphomas with immunoblastic morphology, and frequently show plasmacytic differentiation.
17898653 Red blood cell methotrexate polyglutamate concentrations in inflammatory bowel disease. 2007 Oct Methotrexate (MTX) use in inflammatory bowel disease (IBD) is complicated by unpredictable efficacy and toxicity. In rheumatoid arthritis, total and individual red blood cell MTX polyglutamates (RBC MTXGlu1-5) correlate with disease activity and possibly toxicity, and therefore may be useful in guiding treatment. It is unclear if this applies in IBD. The aim of this pilot study was to measure total and individual RBC MTXGlu1-5 concentrations in patients with IBD to see if these relate to efficacy and adverse effects. RBC MTXGlu1--5 concentrations were measured on three occasions in 18 patients with IBD receiving MTX at a constant dose for 3 or more months. The intrapatient variability, expressed as the coefficient of variation, of RBC MTXGlu1-5 concentrations at steady state was determined, and disease activity and adverse effects were assessed against concentrations. The intrapatient coefficients of variation of individual MTXGlu1-5 varied from 12% to 27%. In Crohn's disease, higher RBC MTXGlu4&5 concentrations correlated with worse disease activity (r = 0.42 and 0.53, respectively, P
18845662 Transport of diclofenac by breast cancer resistance protein (ABCG2) and stimulation of mul 2009 Jan Diclofenac is an important analgesic and anti-inflammatory drug, widely used for treatment of postoperative pain, rheumatoid arthritis, and chronic pain associated with cancer. Consequently, diclofenac is often used in combination regimens and undesirable drug-drug interactions may occur. Because many drug-drug interactions may occur at the level of drug transporting proteins, we studied interactions of diclofenac with apical ATP-binding cassette (ABC) multidrug efflux transporters. Using Madin-Darby canine kidney (MDCK)-II cells transfected with human P-glycoprotein (P-gp; MDR1/ABCB1), multidrug resistance protein 2 (MRP2/ABCC2), and breast cancer resistance protein (BCRP/ABCG2) and murine Bcrp1, we found that diclofenac was efficiently transported by murine Bcrp1 and moderately by human BCRP but not by P-gp or MRP2. Furthermore, in Sf9-BCRP membrane vesicles diclofenac inhibited transport of methotrexate in a concentration-dependent manner. We next used MDCK-II-MRP2 cells to study interactions of diclofenac with MRP2-mediated drug transport. Diclofenac stimulated paclitaxel, docetaxel, and saquinavir transport at only 50 microM. We further found that the uricosuric drug benzbromarone stimulated MRP2 at an even lower concentration, having maximal stimulatory activity at only 2 microM. Diclofenac and benzbromarone stimulated MRP2-mediated transport of amphipathic lipophilic drugs at 10- and 250-fold lower concentrations, respectively, than reported for other MRP2 stimulators. Because these concentrations are readily achieved in patients, adverse drug-drug interactions may occur, for example, during cancer therapy, in which drug concentrations are often critical and stimulation of elimination via MRP2 may result in suboptimal chemotherapeutic drug concentrations. Moreover, stimulation of MRP2 activity in tumors may lead to increased efflux of chemotherapeutic drugs and thereby drug resistance.
17475902 Functional characterization of human proton-coupled folate transporter/heme carrier protei 2007 Aug The functional characteristics of human proton coupled folate transporter (hPCFT)/heme carrier protein (HCP) 1 were investigated. hPCFT/HCP1 expressed transiently in human embryonic kidney 293 cells mediated the transport of folate at an acidic extracellular pH of 5.5 in a manner independent of Na(+) and insensitive to membrane potential, but its transport activity was absent at near-neutral pH. Folate transport mediated by hPCFT/hHCP1 at pH 5.5 was saturable with a K(m) of 1.67 microM and extensively inhibited by reduced folates, such as folinate, 5-methyltetrahydrofolate, and methotrexate (MTX). Sulfobro-mophthalein and 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid were also found to be potent inhibitors of hPCFT/hHCP1, but hemin was found to exhibit only minimal inhibitory effect. When expressed stably as a protein fused with green fluorescent protein (GFP-hPCFT/HCP1) in MDCKII cells, GFP-hPCFT/HCP1 was mainly localized at the apical membrane, and the cellular accumulation of MTX was higher from the apical side than from the basal side. These functional features of hPCFT/HCP1 are consistent with those of the well characterized carrier-mediated folate transport system in the small intestine, suggesting that hPCFT/HCP1 is responsible for the intestinal absorption of folate and also MTX. We also found that sulfasalazine is a potent inhibitor of hPCFT/HCP1, which would interfere with the intestinal absorption of MTX when coadministered in therapy for rheumatoid arthritis as well as folate.
16819265 [A case in which the subject was affected by Listeia meningoencephalitis during administra 2006 Jun The subject was a 22-year-old woman who developed high fever and arthralgias and eruptions in the extremities around June 2005. She sought medical advice at a nearby dermatology clinic, where hepatic dysfunction was noted on blood testing. The patient was thus hospitalized the next day. Although CRP levels were significantly high, no sign of infection was observed and bone marrow cell differentiation was normal. Adult onset Still's disease was diagnosed based on the observation of persistent high fever >39 degrees C, eruptions, increased leukocytes, pharyngeal pain, splenomegaly, hepatic dysfunction, negative autoantibody results from blood testing, and high serum ferritin levels. Administration of prednisolone 30 mg/day was initiated, but proved ineffective. Steroid pulse therapy was conducted, and the subject was transferred to our medical facility for continued treatment. Attempts were made to control the disease using combined steroid and cyclosporine administration; but exacerbation of high serum ferritin levels and hepatic dysfunctions were observed, so a second course of steroid pulse therapy was conducted. Symptoms improved temporarily, but steroid levels were difficult to reduce. Cyclosporine was therefore replaced by methotrexate, and administration of infliximab was initiated. In the course of treatment, administration of a sulfamethoxazole/trimethoprim combination was initiated, but was discontinued due to suspicion of drug-induced hepatic injury. A second administration of infliximab was conducted in late August, and rapid improvements in clinical symptoms and abnormal test values was observed. However, high fever and headache developed suddenly in early September. Based on the results of spinal fluid testing, blood and spinal fluid cultures and MRI of the head, Listeria meningoencephalitis was diagnosed. Diplopia and impaired consciousness occurred during the disease course, and formation of a brain abscess was observed on imaging. However, symptoms were controlled by long-term combination administration of ampicillin and gentamicin. Administration of infliximab was discontinued for treatment of adult onset Still's disease, and steroid levels were reduced following double-membrane filtration plasma exchange. On follow-up, no relapse of symptoms or abnormalities in blood test values were observed, so the subject was discharged from our medical facility in December 2005. In treatment for rheumatic diseases, a dramatic improvement in treatment results for pathologies displaying tolerance against conventional treatments has been acquired with the development of biological drugs. However, opportunistic infections represent a serious problem, and appropriate preventative measures are required. The present report describes a case in which the subject was affected by Listeria meningoencephalitis during administration of infliximab for steroid-dependent adult Still's disease. Since listeriosis is one of the complications, along with tuberculosis, that warrants precautionary measures, this case is reported and discussed.
19035488 Atheroprotective effects of methotrexate on reverse cholesterol transport proteins and foa 2008 Dec OBJECTIVE: To determine whether methotrexate (MTX) can overcome the atherogenic effects of cyclooxygenase 2 (COX-2) inhibitors and interferon-gamma (IFNgamma), both of which suppress cholesterol efflux protein and promote foam cell transformation in human THP-1 monocyte/macrophages. METHODS: Message and protein levels of the reverse cholesterol transport proteins cholesterol 27-hydroxylase and ATP-binding cassette transporter A1 (ABCA1) in THP-1 cells were evaluated by real-time polymerase chain reaction and immunoblot, respectively. Expression was evaluated in cells incubated in the presence or absence of the COX-2 inhibitor NS398 or IFNgamma, with and without MTX. Foam cell transformation of lipid-laden THP-1 macrophages was detected with oil red O staining and light microscopy. RESULTS: MTX increased 27-hydroxylase message and completely blocked NS398-induced down-regulation of 27-hydroxylase (mean +/- SEM 112.8 +/- 13.1% for NS398 plus MTX versus 71.1 +/- 4.3% for NS398 alone; P < 0.01). MTX also negated COX-2 inhibitor-mediated down-regulation of ABCA1. The ability of MTX to reverse inhibitory effects on 27-hydroxylase and ABCA1 was blocked by the adenosine A2A receptor-specific antagonist ZM241385. MTX also prevented NS398 and IFNgamma from increasing transformation of lipid-laden THP-1 macrophages into foam cells. CONCLUSION: This study provides evidence supporting the notion of an atheroprotective effect of MTX. Through adenosine A2A receptor activation, MTX promotes reverse cholesterol transport and limits foam cell formation in THP-1 macrophages. This is the first reported evidence that any commonly used medication can increase expression of antiatherogenic reverse cholesterol transport proteins and can counteract the effects of COX-2 inhibition. Our results suggest that one mechanism by which MTX protects against cardiovascular disease in rheumatoid arthritis patients is through facilitation of cholesterol outflow from cells of the artery wall.
18031504 A pilot study of pharmacokinetically guided dosing of oral methotrexate in the initial pha 2008 Jan BACKGROUND: Clinical studies of low-dose oral methotrexate (MTX) in the treatment of psoriasis and rheumatoid arthritis document a large interpatient variability in the pharmacokinetics of MTX, including its polyglutamates (MTXPGs) in erythrocytes (RBC). This can be a factor contributing to the variability of therapeutic and toxic effects. AIM: This pilot trial aimed to investigate the MTXPG concentrations in RBC as well as their relation to therapeutic and adverse effects during the initial 4 months of pharmacokinetically guided therapy with a divided-dose schedule (three doses of MTX separated by 12-h intervals once a week). SUBJECTS AND METHODS: Sixteen psoriatic patients (4 men and 12 women; mean age, 53 years; range, 28-69 years) with moderate-to-severe chronic plaque psoriasis [mean Psoriasis Area and Severity Index (PASI) = 24; range, 9-42] were enrolled in the study. Concentrations of plasma MTX and that of MTXPGs in RBC were assayed using liquid chromatography methods. The area under the concentration-time curve of plasma MTX in the interval 0-8 h post-dose (AUC(0-8 h)) was measured after a test bolus dose of 10 mg, and the starting weekly dose was individualized in order to achieve the target AUC(0-8 h) of 1800 nmol.h/L. The PASI, biochemistry, and haematology tests and MTXPGs levels in RBC were evaluated at baseline and at 4-week intervals. RESULTS: The AUC(0-8 h )achieved 1360 +/- 425 nmol.h/L (mean +/- SD: range, 778-2400 nmol.h/L). The mean (range) of individualized doses was 14.5 mg/week (7.5-22.5 mg). The mean (SD) steady-state concentration of total MTXPGs observed between days 85 to 110 reached 113 (34.6) nmol/L (range, 66.1-174 nmol/L). The PASI decreased from 24.0 +/- 8.0 (mean +/- SD) at baseline to 8.0 +/- 6.1 at day 110 (P < 0.001). Thirteen patients (87%) achieved a greater than 50% improvement in baseline PASI, and seven (47%) experienced a greater than 75% improvement. There was no relationship between the percent improvement from baseline PASI and the steady-state concentration of MTXPGs in RBC. All patients tolerated MTX well. Throughout the study period, there was a continuous increasing trend in the geometric mean values of the mean corpuscular volume from 92.6 to 96.4 fL (P < 0.001) and of plasma homocysteine from 9.5 to 12.3 micromol/L (P < 0.005). The geometric mean serum alanine aminotransferase (ALT) activity slightly increased from 0.49 to 0.80 microkat/L (P < 0.05). However, only two patients had the ALT activity transiently elevated above twice the upper limit of normal. CONCLUSION: Results of this pilot trial show that the steady-state levels of MTXPGs in RBC vary less than threefold between patients and did not correlate with the change in PASI observed after 4 months of therapy with an individualised weekly dose of MTX. Whether pharmacokinetically guided dosing can improve the results of psoriasis therapy with MTX should be prospectively tested in large controlled studies.
30000400 Methotrexate. 2006 Most sources consider breastfeeding to be contraindicated during maternal high-dose antineoplastic drug therapy with methotrexate. An abstinence period of at least 1 week after chemotherapy doses of methotrexate has been suggested.[1] Chemotherapy may adversely affect the normal microbiome and chemical makeup of breastmilk.[2] Women who receive chemotherapy during pregnancy are more likely to have difficulty nursing their infant.[3] Maternal doses of methotrexate up to 92 mg (1.12 mg/kg) produce low levels in milk, leading some authors to state that low single or weekly doses, such as those used for ectopic pregnancy or rheumatoid arthritis, are of low risk to the breastfed infant,[4-8] although some expert opinion warns against this use.[9-13] Withholding breastfeeding for 24 hours after a weekly low dose of methotrexate may decrease the infant's dose by 40%.[14-16] If breastfeeding during long-term, low-dose methotrexate use is undertaken, monitoring of the infant's complete blood count and differential could be considered.
20870100 Rheumatoid arthritis. 2010 Sep 25 Rheumatoid arthritis is characterised by persistent synovitis, systemic inflammation, and autoantibodies (particularly to rheumatoid factor and citrullinated peptide). 50% of the risk for development of rheumatoid arthritis is attributable to genetic factors. Smoking is the main environmental risk. In industrialised countries, rheumatoid arthritis affects 0·5-1·0% of adults, with 5-50 per 100 000 new cases annually. The disorder is most typical in women and elderly people. Uncontrolled active rheumatoid arthritis causes joint damage, disability, decreased quality of life, and cardiovascular and other comorbidities. Disease-modifying antirheumatic drugs (DMARDs), the key therapeutic agents, reduce synovitis and systemic inflammation and improve function. The leading DMARD is methotrexate, which can be combined with other drugs of this type. Biological agents are used when arthritis is uncontrolled or toxic effects arise with DMARDs. Tumour necrosis factor inhibitors were the first biological agents, followed by abatacept, rituximab, and tocilizumab. Infections and high costs restrict prescription of biological agents. Long-term remission induced by intensive, short-term treatment selected by biomarker profiles is the ultimate goal.
20877764 Rheumatoid arthritis. 2010 Sep BACKGROUND: Rheumatoid arthritis is a chronic disease that can cause irreversible joint damage and significant disability. With a prevalence of 1%, it has a considerable cost to the community. Diagnosis is based on a combination of clinical and laboratory features. Patients typically present with a symmetrical polyarthritis of the small joints of the hands and feet accompanied by early morning stiffness and, occasionally, constitutional symptoms. OBJECTIVE: This review discusses the role of the general practitioner in the diagnosis and early management of rheumatoid arthritis. DISCUSSION: It is increasingly recognised that there is a 'window of opportunity' within which disease modifying antirheumatic drug therapy should be commenced to arrest progressive disease and joint destruction. Methotrexate is usually the first line agent in the management of rheumatoid arthritis but simple analgesia and nonsteroidal anti-inflammatory drugs are also important for symptom control.
19447771 Methotrexate, rheumatoid arthritis and infection risk: what is the evidence? 2009 Aug Low-dose MTX administered weekly remains a mainstay in the therapy of RA. There is a belief amongst rheumatologists that RA patients taking MTX have both an increased risk and severity of infection. Here we review the published data on the risks of infection associated with the use of MTX in patients with RA and make some recommendations for managing MTX in patients with infection.
21044431 Methotrexate pharmacogenetics in rheumatoid arthritis. 2010 Sep Rheumatoid arthritis (RA) is a systemic inflammatory arthritis that can not only result in permanent joint damage, but is associated with high morbidity and mortality. Disease-modifying antirheumatic drugs (DMARDs) are the mainstay of treatment in RA. DMARDs improve the symptoms of joint pain and swelling, but more importantly, prevent the progression of joint damage. Methotrexate (MTX) is the first-line DMARD in RA with over two decades worth of excellent long-term efficacy and safety. However, there is significant variability in patients' response to MTX, both in efficacy and toxicity. Recent advances in genetics, particularly pharmacogenetics, may permit the prediction, a priori, of an individual patient's response to MTX. In this review, we highlight recent published literature on the pharmacogenetics of MTX in RA. Pharmacogenetics may be a useful means of optimising MTX therapy in patients with RA.