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Similar lipid level changes in early rheumatoid arthritis patients following 1-year treat-to-target strategy with adalimumab plus methotrexate versus placebo plus methotrexate: secondary analyses from the randomised controlled OPERA trial.
Mašić, D, Stengaard-Pedersen, K, Løgstrup, BB, Hørslev-Petersen, K, Hetland, ML, Junker, P, Østergaard, M, Ammitzbøll, C, Möller, S, Christensen, R, et al
Rheumatology international. 2021;(3):543-549
Abstract
To compare changes in low-density lipoprotein cholesterol and other lipids in patients with rheumatoid arthritis (RA) randomised to a 1-year treat-to-target strategy with either adalimumab plus methotrexate or placebo plus methotrexate. Prespecified secondary analyses from the OPERA trial, where 180 early and treatment-naïve RA patients received methotrexate 20 mg once weekly in combination with either placebo or subcutaneous adalimumab 40 mg every other week. Serum lipid levels were measured at baseline and after 1 year. Changes in lipid levels were analysed using mixed linear models based on the intention-to-treat (ITT) population. Overall, 174 patients were included in the ITT population (adalimumab plus methotrexate n = 86; placebo plus methotrexate n = 88). Differences between changes in lipid levels were low-density lipoprotein cholesterol 0.18 mmol/l [95% CI - 0.05 to 0.42], total cholesterol 0.27 mmol/l [- 0.002 to 0.54], high-density lipoprotein cholesterol 0.05 mmol/l [- 0.06 to 0.15], triglycerides 0.11 mmol/l [- 0.08 to 0.29], very-low-density lipoprotein cholesterol 0.03 mmol/l [- 0.05 to 0.12], and non-high-density lipoprotein cholesterol 0.22 mmol/l [- 0.02 to 0.46]. In early RA patients treated to tight control of inflammation over a period of 1 year with either adalimumab plus methotrexate or placebo plus methotrexate, changes in lipid levels were similar. Trial registration number: NCT00660647.
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Sustained Drug Treatment Alters the Gut Microbiota in Rheumatoid Arthritis.
Mei, L, Yang, Z, Zhang, X, Liu, Z, Wang, M, Wu, X, Chen, X, Huang, Q, Huang, R
Frontiers in immunology. 2021;:704089
Abstract
Several studies have investigated the causative role of the microbiome in the development of rheumatoid arthritis (RA), but changes in the gut microbiome in RA patients during drug treatment have been less well studied. Here, we tracked the longitudinal changes in gut bacteria in 22 RA patients who were randomized into two groups and treated with Huayu-Qiangshen-Tongbi formula (HQT) plus methotrexate (MTX) or leflunomide (LEF) plus MTX. There were differences in the gut microbiome between untreated (at baseline) RA patients and healthy controls, with 37 species being more abundant in the RA patients and 21 species (including Clostridium celatum) being less abundant. Regarding the functional analysis, vitamin K2 biosynthesis was associated with RA-enriched bacteria. Additionally, in RA patients, alterations in gut microbial species appeared to be associated with RA-related clinical indicators through changing various gut microbiome functional pathways. The clinical efficacy of the two treatments was further observed to be similar, but the response trends of RA-related clinical indices in the two treatment groups differed. For example, HQT treatment affected the erythrocyte sedimentation rate (ESR), while LEF treatment affected the C-reactive protein (CRP) level. Further, 11 species and 9 metabolic pathways significantly changed over time in the HQT group (including C. celatum, which increased), while only 4 species and 2 metabolic pathways significantly changed over time in the LEF group. In summary, we studied the alterations in the gut microbiome of RA patients being treated with HQT or LEF. The results provide useful information on the role of the gut microbiota in the pathogenesis of RA, and they also provide potentially effective directions for developing new RA treatments.
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Iontophoretic delivery of methotrexate in the treatment of palmar psoriasis: A randomised controlled study.
Andanooru Chandrappa, NK, Channakeshavaiah Ravikumar, B, Rangegowda, SM
The Australasian journal of dermatology. 2020;(2):140-146
Abstract
BACKGROUND/OBJECTIVES Palmoplantar psoriasis is a localised variant of psoriasis. Topical therapy is the preferred treatment modality, but in severe and recalcitrant cases, systemic drugs like methotrexate are prescribed, with potential for significant adverse effects. Iontophoresis is gaining popularity in enhancing the transdermal delivery of drugs in ionic state. This study was undertaken to evaluate and compare the efficacy of topical methotrexate by iontophoresis technique with clobetasol propionate 0.05% ointment in the treatment of palmar psoriasis. METHODS This was a prospective randomised controlled study conducted on patients with palmar psoriasis. Group 1 patients (n = 31) were treated with once weekly iontophoretic delivery of methotrexate over 6 sittings, and group 2 patients (n = 31) were treated with clobetasol propionate 0.05% ointment, twice daily for 6 weeks. Severity of palmar psoriasis was assessed by modified Palmoplantar Pustular Psoriasis Area and Severity Index (m-PPPASI), and treatment was considered as satisfactory when there was >50% improvement. RESULTS Sixty two patients were recruited, of which 50 completed the study. Eight out of 25 (32%) patients in group 1 and 12 out of 25 (48%) patients in group 2 showed satisfactory improvement at the end of 6 weeks. However, this difference was statistically not significant (P = 0.25). Burn injury was noted in 12 (48%) group 1 patients with no adverse effects in group 2. CONCLUSION Iontophoretic delivery of methotrexate is a promising therapeutic modality, the efficacy of which is comparable to that of clobetasol propionate ointment in the treatment of palmar psoriasis.
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Comprehensive exploratory autoantibody profiling in patients with early rheumatoid arthritis treated with methotrexate or tocilizumab.
Teitsma, XM, Devenport, J, Jacobs, JWG, Pethö-Schramm, A, Borm, MEA, Budde, P, Bijlsma, JWJ, Lafeber, FPJG
PloS one. 2020;(12):e0241189
Abstract
BACKGROUND We sought to identify immunoglobin G autoantibodies predictive of early treatment response to methotrexate, the recommended first-line therapy for patients with newly diagnosed rheumatoid arthritis, and to the interleukin-6 receptor inhibitor biologic tocilizumab, initiated as the first disease-modifying anti-rheumatic drug. MATERIALS AND METHODS In baseline sera of a subset of patients with newly diagnosed rheumatoid arthritis in the U-Act-Early study, selected based on specific responder/non-responder criteria using the Disease Activity Score assessing 28 joints (DAS28) within the first 20 weeks, we measured immunoglobin G antibody reactivity against 463 protein antigens and performed supervised cluster analysis to identify predictive autoantibodies for treatment response. The analysis subset comprised 56 patients in the methotrexate arm (22 responders, 34 non-responders) and 50 patients in the tocilizumab arm (34 responders, 16 non-responders). For comparison, these analyses were also performed in 50 age- and gender-matched healthy controls. RESULTS Increased reactivity in responders versus non-responders was found in the methotrexate arm against two antigens-DOT1-like histone lysine methyltransferase (p = 0.009) and tropomyosin (p = 0.003)-and in the tocilizumab arm against one antigen-neuro-oncological ventral antigen 2 (p = 0.039). Decreased reactivity was detected against two antigens in the methotrexate arm-G1 to S phase transition 2 (p = 0.023) and the zinc finger protein ZPR1 (p = 0.021). Reactivity against the identified antigens was not statistically significant in either treatment arm for patients with rheumatoid factor-positive versus-negative or anti-cyclic citrullinated test-positive versus test-negative rheumatoid arthritis (p ≥ 0.06). CONCLUSIONS Comprehensive profiling of baseline sera revealed several novel immunoglobin G autoantibodies associated with early treatment response to methotrexate and to tocilizumab in disease-modifying anti-rheumatic drug-naive patients with rheumatoid arthritis. These findings could eventually yield clinically relevant predictive markers, if corroborated in different patient cohorts, and may facilitate future benefit in personalised healthcare.
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Efficacy of Oral Vitamin A in Reducing β-hCG Levels in Low-Risk Gestational Trophoblastic Neoplasia Patients.
Hidayat, YM, Darmadi A, E, Rachmayati, S, Kusumah, WP, Djuwantono, T, Pramatirta, AY, Suardi, D
Asian Pacific journal of cancer prevention : APJCP. 2020;(11):3325-3329
Abstract
OBJECTIVE Low-risk gestational trophoblastic neoplasia (GTN) is generally treated with single agent chemotherapy and methotrexate (MTX) as a first-line therapy. Vitamin A helps to increase trophoblast cell regression, as well as to decrease β-hCG levels. Vitamin A also increases the effectiveness of MTX by inducing more malignant cell death than MTX alone. Therefore, the aim of the current study was to analyze the changes in β-hCG levels in low-risk GTN patients following vitamin A administration. METHODS This study was a randomized clinical trial, which examined initial serum vitamin A and β-hCG levels in GTN patients before and after three cycles of MTX therapy. Patients were given vitamin A supplementation of 6,000 IU (1.8 mg RAEs) per day, and the changes in serum β-hCG were observed after three cycles. Patients were grouped by β-hCG levels (decreased or stagnant). RESULTS A total of 32 low-risks GTN patients were divided into the intervention group (16 patients who received vitamin A supplementation) and the control group (16 patients who did not receive vitamin A supplementation). In the intervention group, the average initial β-hCG level was 170,949.3 ± 354,452.1 mIU/mL, and the average β-hCG post-cycle level was 1,611.9 ± 3,652.5 mIU/mL. In the control group, the average initial β-hCG level was 178,834.1 ± 2913844.6 mIU/mL, and the average β-hCG post-cycle level was 25,388.5 ± 58,437.7 mIU/mL. CONCLUSION In patients with low-risk GTN who underwent MTX chemotherapy, the levels of β-hCG and the incidence of chemo resistance in the intervention group were lower than those in the control group. Older age may also influence the incidence of chemo resistance in GTN patients. Oral administration of 6,000 IU vitamin A could help to reduce β-hCG levels in low-risk GTN patients who receive MTX chemotherapy.
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Higher baseline global leukocyte DNA methylation is associated with MTX non-response in early RA patients.
Gosselt, HR, van Zelst, BD, de Rotte, MCFJ, Hazes, JMW, de Jonge, R, Heil, SG
Arthritis research & therapy. 2019;(1):157
Abstract
BACKGROUND Low-dose methotrexate (MTX) is the first-line therapy in early rheumatoid arthritis (eRA). Up to 40% of eRA patients do not benefit from MTX therapy. MTX has been shown to inhibit one-carbon metabolism, which is involved in the donation of methyl groups. In this study, we investigate baseline global DNA methylation and changes in DNA methylation during treatment in relation to clinical non-response after 3 months of MTX treatment. METHODS Two hundred ninety-four blood samples were collected from the Treatment in the Rotterdam Early Arthritis Cohort (tREACH, ISRCTN26791028), a multicenter, stratified single-blind clinical trial of eRA patients. Global DNA (hydroxy)methylation was quantified using liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS) and validated with a global DNA LINE-1 methylation technique. MTX response was determined as ΔDAS28. Additionally, patients were stratified into two response groups according to the European League Against Rheumatism (EULAR) response criteria. Associations between global DNA methylation and response were examined using univariate regression models adjusted for baseline DAS28, baseline erythrocyte folate levels, and body mass index (BMI). RESULTS Higher baseline global DNA methylation was associated with less decrease of DAS28 (β = 0.15, p = 0.013) and with MTX non-response (OR = 0.010, 95% CI = 0.001-0.188). This result was validated in LINE-1 elements (β = 0.22, p = 0.026). Changes in global DNA (hydroxy)methylation were not associated with MTX response over 3 months. CONCLUSIONS These results show that higher baseline global DNA methylation in treatment naïve eRA patients is associated with decreased clinical response after 3 months of treatment of eRA patients and can be further evaluated as a predictor for MTX therapy non-response. TRIAL REGISTRATION ISRCTN, ISRCTN26791028 , registered 23 August 2007-retrospectively registered.
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Safety and Impact of Low-dose Methotrexate on Endothelial Function and Inflammation in Individuals With Treated Human Immunodeficiency Virus: AIDS Clinical Trials Group Study A5314.
Hsue, PY, Ribaudo, HJ, Deeks, SG, Bell, T, Ridker, PM, Fichtenbaum, C, Daar, ES, Havlir, D, Yeh, E, Tawakol, A, et al
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2019;(11):1877-1886
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BACKGROUND Chronic inflammation in treated HIV infection is associated with mortality and atherosclerotic cardiovascular disease (ASCVD). We evaluated the safety and potential efficacy of low-dose methotrexate (LDMTX) in treated HIV. METHODS This was a phase 2 randomized, double-blind, multicenter trial in adults ≥40 years old with treated HIV, with CD4+ T-cell count ≥400 cells/μL and with/at increased risk for ASCVD. Participants received LDMTX (5-15 mg/week) or placebo (plus folic acid) for 24 weeks and were followed for an additional 12 weeks. Primary endpoints were safety and brachial artery flow-mediated dilation (FMD). RESULTS The 176 participants (90% male) had a median (Q1, Q3) age of 54 (49, 59) years. LDMTX was associated with decreases in CD4+ T cells at week 24 and CD8+ T cells at weeks 8, 12, and 24. Eleven participants (12.8%) experienced safety events in the LDMTX group vs 5 (5.6%) in placebo (Δ = 7.2%, upper 1-sided 90% CI, 13.4%; Pnoninferiority = .037). Week 24 change in FMD was 0.47% with LDMTX and 0.09% with placebo (P = .55). No inflammatory markers changed differentially with LDMTX compared to placebo. CONCLUSIONS Adults with HIV and increased ASCVD risk treated with LDMTX had more safety events than with placebo, but the prespecified noninferiority margin of 15% was not exceeded. LDMTX had no significant effect on endothelial function or inflammatory biomarkers but was associated with a significant decrease in CD8+ T cells. The balance of risks and potential benefits of LDMTX in this population will require additional investigation. CLINICAL TRIALS REGISTRATION NCT01949116.
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Baseline metabolic profiles of early rheumatoid arthritis patients achieving sustained drug-free remission after initiating treat-to-target tocilizumab, methotrexate, or the combination: insights from systems biology.
Teitsma, XM, Yang, W, Jacobs, JWG, Pethö-Schramm, A, Borm, MEA, Harms, AC, Hankemeier, T, van Laar, JM, Bijlsma, JWJ, Lafeber, FPJG
Arthritis research & therapy. 2018;(1):230
Abstract
BACKGROUND We previously identified, in newly diagnosed rheumatoid arthritis (RA) patients, networks of co-expressed genes and proteomic biomarkers associated with achieving sustained drug-free remission (sDFR) after treatment with tocilizumab- or methotrexate-based strategies. The aim of this study was to identify, within the same patients, metabolic pathways important for achieving sDFR and to subsequently study the complex interactions between different components of the biological system and how these interactions might affect the therapeutic response in early RA. METHODS Serum samples were analyzed of 60 patients who participated in the U-Act-Early trial (ClinicalTrials.gov number NCT01034137) and initiated treatment with methotrexate, tocilizumab, or the combination and who were thereafter able to achieve sDFR (n = 37); as controls, patients were selected who never achieved a drug-free status (n = 23). Metabolomic measurements were performed using mass spectrometry on oxidative stress, amine, and oxylipin platforms covering various compounds. Partial least square discriminant analyses (PLSDA) were performed to identify, per strategy arm, relevant metabolites of which the biological pathways were studied. In addition, integrative analyses were performed correlating the previously identified transcripts and proteins with the relevant metabolites. RESULTS In the tocilizumab plus methotrexate, tocilizumab, and methotrexate strategy, respectively, 19, 13, and 12 relevant metabolites were found, which were subsequently used for pathway analyses. The most significant pathway in the tocilizumab plus methotrexate strategy was "histidine metabolism" (p < 0.001); in the tocilizumab strategy it was "arachidonic acid metabolism" (p = 0.018); and in the methotrexate strategy it was "arginine and proline metabolism" (p = 0.022). These pathways have treatment-specific drug interactions with metabolites affecting either the signaling of interleukin-6, which is inhibited by tocilizumab, or affecting protein synthesis from amino acids, which is inhibited by methotrexate. CONCLUSION In early RA patients treated-to-target with a tocilizumab- or methotrexate-based strategy, several metabolites were found to be associated with achieving sDFR. In line with our previous observations, by analyzing relevant transcripts and proteins within the same patients, the metabolic profiles were found to be different between the strategy arms. Our metabolic analysis further supports the hypothesis that achieving sDFR is not only dependent on predisposing biomarkers, but also on the specific treatment that has been initiated. TRIAL REGISTRATION ClinicalTrials.gov, NCT01034137 . Registered on January 2010.
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Uterine artery embolization combined with local infusion of methotrexate and 5- fluorouracil in treating ectopic pregnancy: A CONSORT-compliant article.
Gao, J, Li, X, Chen, J, Gong, W, Yue, K, Wu, Z
Medicine. 2018;(5):e9722
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BACKGROUND To compare the efficiency and safety of uterine artery embolization (UAE) combined with local infusion of methotrexate (MTX) or MTX and 5-fluorouracil (5-FU) in the treatment of ectopic pregnancy (EP). METHODS One hundred women with EP were prospectively enrolled from December 2012 to February 2015 and randomly allocated into 2 groups. One group was treated with UAE combined MTX, and the other with UAE combined with MTX and 5-FU. Local MTX was administrated at a dose of 80 to 120 mg, based on the initial β-human chorionic gonadotropin (β-HCG) levels, and 5-FU was given intra-arterially at a uniform dose of 0.5 g. RESULTS Bilateral UAE was successfully performed in all 100 patients, 88 of whom were clinically successfully treated, 45 (91.8%) in the MTX group, and 43 (87.8%) in the MTX + 5-FU group; 89% of the patients achieved normalization of β-HCG below 70,000 mIU/mL within 14 to 21 days postoperatively. The time to successful β-HCG resolution was 26.74 ± 5.57 days for patients receiving MTX + UAE treatment, and 27.57 ± 5.08 days for those treated with additional 5-FU. Six patients had subsequent intramuscular injections of MTX and 6 had a unilateral salpingectomy after the treatment failure. Mild immediate side effects accounted for 24.5% in the sole MTX and 58.3% in MTX + 5-FU group. CONCLUSION A combination of UAE and intrauterine infusion of MTX showed comparable efficiency to UAE combined with a local infusion of MTX and 5-FU in treating EP patients with the intention to preserve fertility.
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Improved Survival for Children and Young Adults With T-Lineage Acute Lymphoblastic Leukemia: Results From the Children's Oncology Group AALL0434 Methotrexate Randomization.
Winter, SS, Dunsmore, KP, Devidas, M, Wood, BL, Esiashvili, N, Chen, Z, Eisenberg, N, Briegel, N, Hayashi, RJ, Gastier-Foster, JM, et al
Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2018;(29):2926-2934
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PURPOSE Early intensification with methotrexate (MTX) is a key component of acute lymphoblastic leukemia (ALL) therapy. Two different approaches to MTX intensification exist but had not been compared in T-cell ALL (T-ALL): the Children's Oncology Group (COG) escalating dose intravenous MTX without leucovorin rescue plus pegaspargase escalating dose, Capizzi-style, intravenous MTX (C-MTX) regimen and the Berlin-Frankfurt-Muenster (BFM) high-dose intravenous MTX (HDMTX) plus leucovorin rescue regimen. PATIENTS AND METHODS COG AALL0434 included a 2 × 2 randomization that compared the COG-augmented BFM (ABFM) regimen with either C-MTX or HDMTX during the 8-week interim maintenance phase. All patients with T-ALL, except for those with low-risk features, received prophylactic (12 Gy) or therapeutic (18 Gy for CNS3) cranial irradiation during either the consolidation (C-MTX; second month of therapy) or delayed intensification (HDMTX; seventh month of therapy) phase. RESULTS AALL0434 accrued 1,895 patients from 2007 to 2014. The 5-year event-free survival and overall survival rates for all eligible, evaluable patients with T-ALL were 83.8% (95% CI, 81.2% to 86.4%) and 89.5% (95% CI, 87.4% to 91.7%), respectively. The 1,031 patients with T-ALL but without CNS3 disease or testicular leukemia were randomly assigned to receive ABFM with C-MTX (n = 519) or HDMTX (n = 512). The estimated 5-year disease-free survival ( P = .005) and overall survival ( P = .04) rates were 91.5% (95% CI, 88.1% to 94.8%) and 93.7% (95% CI, 90.8% to 96.6%) for C-MTX and 85.3% (95% CI, 81.0%-89.5%) and 89.4% (95% CI, 85.7%-93.2%) for HDMTX. Patients assigned to C-MTX had 32 relapses, six with CNS involvement, whereas those assigned to HDMTX had 59 relapses, 23 with CNS involvement. CONCLUSION AALL0434 established that ABFM with C-MTX was superior to ABFM plus HDMTX for T-ALL in approximately 90% of patients who received CRT, with later timing for those receiving HDMTX.