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ID PMID Title PublicationDate abstract
34214354 The maximum dose and duration in the therapy single use methotrexate to achieve remission 2021 Jun 25 OBJECTIVES: One of the treatments for rheumatoid arthritis (RA) was methotrexate which a disease modifying antirheumatic drug therapy. The use of methotrexate required the right dose and length of therapy to achieve remission. The effectivity of methotrexate could be accounted by disease activity score 28 (DAS28) as a tool has been used clinically with a combination number of tender joints, swollen joints, erythrocyte sedimentation rate, and global clinical assessment by the patient. The aim of this study was to determine the effective dose and length of therapy methotrexate was measured by DAS28 score. METHODS: This research was a cross-sectional study and data was collected from patient medical records in Saiful Anwar Hospital, Malang, from February to July 2018. The research has been given ethical clearance. The inclusion criteria for the 88 subjects were men and women, over 20 years of age, usage of only methotrexate for at least three months, an erythrocyte sedimentation rate score, uncomplicated inflammatory bowel disease, cancer, and systemic lupus erythematosus. All data obtained was entered in formula DAS28. The Statistic analysis used both Pearson and Spearman's rank correlation. RESULTS: Only 16 patients achieved remission. There were not significant correlation in statistical analysis between DAS score and cumulative dose (r=-0.091; p=0.400), average dose (r=0.043; p = 0.692), maximum dose (r=0.074; p=0.492), and length of therapy (r=-0.075; p = 0.489). The initial dose of therapy methotrexate was different and the length of therapy was adjusted to the patient's health condition. CONCLUSIONS: The maximum dose and length of therapy methotrexate was required to achieve remission in RA.
34344706 Olokizumab, a monoclonal antibody against interleukin 6, in combination with methotrexate 2022 Apr OBJECTIVE: To evaluate the efficacy and safety of olokizumab (OKZ) in patients with active rheumatoid arthritis despite treatment with methotrexate (MTX). METHODS: In this 24-week multicentre, placebo-controlled, double-blind study, patients were randomised 1:1:1 to receive subcutaneously administered OKZ 64 mg once every 2 weeks, OKZ 64 mg once every 4 weeks, or placebo plus MTX. The primary efficacy endpoint was the proportion of patients achieving an American College of Rheumatology 20% (ACR20) response at week 12. The secondary efficacy endpoints included percentage of subjects achieving Disease Activity Score 28-joint count based on C reactive protein <3.2, Health Assessment Questionnaire Disability Index at week 12, ACR50 response and Clinical Disease Activity Index ≤2.8 at week 24. Safety and immunogenicity were assessed throughout the study. RESULTS: A total of 428 patients were randomised. ACR20 responses were more frequent with OKZ every 2 weeks (63.6%) and OKZ every 4 weeks (70.4%) than placebo (25.9%) (p<0.0001 for both comparisons). There were significant differences in all secondary efficacy endpoints between OKZ-treated arms and placebo. Treatment-emergent serious adverse events (TESAEs) were reported by more patients in the OKZ groups compared with placebo. Infections were the most common TESAEs. No subjects developed neutralising antidrug antibodies. CONCLUSIONS: Treatment with OKZ was associated with significant improvement in signs, symptoms and physical function of rheumatoid arthritis without discernible differences between the two regimens. Safety was as expected for this class of agents. Low immunogenicity was observed. Trial registration number NCT02760368.
33333119 Rational design of metal-organic frameworks to deliver methotrexate for targeted rheumatoi 2021 Feb 10 Methotrexate (MTX) has been used as an anchor drug for the treatment of rheumatoid arthritis (RA), while the patients with chronic MTX administration suffer from severe side-effects. To this end, targeted delivery of MTX by nanomedicine has attracted great interest. In this work, we aimed to employ metal-organic frameworks (MOFs) as nanocarrier to deliver MTX by virtue of its facile and green preparation and exceptionally high drug loading. While MTX could be easily and effectively loaded via different MOF construction strategies, such as direct coordination, physical encapsulation, and covalent conjugation, we found that most of the MTX loading MOFs showed premature and burst drug release, attributable to the unstable coordination between MTX and metals. To address this issue, we rationally designed the MOFs by conjugating MTX with tannic acid (TA) at 2:1 M ratio and then coordinating with ferric ion (Fe(3+)), followed by surface modification of hyaluronic acid (HA). The resulting MOFs achieved ultra-high drug loading (45%) and sustained drug release, and could selectively recognize the diseased cells for anti-inflammatory effect. The in vivo therapeutic evaluation suggested that the MOFs could enhance the anti-rheumatic activity of MTX while minimizing its toxic effects by targeted drug delivery, resulting in improved therapeutic index. This work provides a biocompatible nano-platform to deliver MTX for RA treatment, and importantly, calls for special attention to the gap between MOFs design and their biological applications, and the gap needs to be filled by careful evaluation of in vivo stability and burst drug release.
33769067 miRNAs as potential biomarkers of treatment outcome in rheumatoid arthritis and ankylosing 2021 Apr Common autoimmune, inflammatory rheumatic diseases including rheumatoid arthritis and ankylosing spondylitis can lead to structural and functional disability, an increase in mortality and a decrease in the quality of a patient's life. To date, the core of available therapy consists of nonsteroidal anti-inflammatory drugs, glucocorticoids and conventional synthetic disease-modifying antirheumatic drugs, like methotrexate. Nowadays, biological therapy including anti-TNF, IL-6 and IL-1 inhibitors, as well as antibodies targeting IL-17 and Janus kinase inhibitors have been found to be helpful in the management of rheumatic conditions. The review provides a summary of the current therapy strategies with a focus on miRNA, which is considered to be a potential biomarker and possible answer to the challenges in the prediction of treatment outcome in patients with rheumatoid arthritis and ankylosing spondylitis.
34583381 Methotrexate Intolerance: A Complex Belief System. 2021 Sep An estimated 11%-33% of persons taking methotrexate for rheumatoid arthritis (RA) are intolerant to this medication. Medications for RA are often discontinued or changed because of patient intolerance. Yet, intolerance is a poorly defined perspective, specifically the patient's perspective. This study used descriptive qualitative methodologies to describe methotrexate intolerance from the perspective of adult patients with RA. Semistructured, audio-recorded individual interviews were conducted with 14 adult English-speaking patients with RA who had been prescribed, were taking, or had ever taken methotrexate. Methotrexate intolerance involves a complex belief system involving 3 themes: beliefs about the risk of methotrexate, beliefs about the benefits of methotrexate, and beliefs about the threat of RA. Participants reported a threshold by which perceived risks and benefits of methotrexate were weighed against perceived risks of RA. The critical underpinnings of the largely undefined and unique patient perspective of methotrexate intolerance are described.
32896266 Biological and targeted-synthetic disease-modifying anti-rheumatic drugs with concomitant 2021 Jul OBJECTIVES: To determine the real-life efficacy, safety, and drug-retention rates of leflunomide (LEF) or methotrexate (MTX) as a synthetic DMARD used in combination with biological DMARDs for rheumatoid arthritis (RA). METHODS: The TReasure database is a web-based, prospective, observational cohort of RA and spondyloarthritis patients from 17 centres in different regions of Turkey and data entry was enabled since December 2017. Until May 2019, 2556 RA patients on biologic treatment were recorded. Demographic and RA-related data of 1526 patient either received LEF or MTX were compared, efficacy of both drugs compared by RA-disease activity composite indices. Reasons fordrug discontinuation also recorded. Drug retention rates were compared with Kaplan-Meier curves (log-rank test). RESULTS: Of 2556 RA patients 1526 (59.7%) were receiving concomitant LEF (n=646, 42.3%; median follow up 35 months) or concomitant MTX (n=880, 57.3%; median follow-up 32 months) at the time of initiation to their first bDMARDs. The LEF group were older and had longer disease duration, proportion of females and seropositive patients was higher in this group. In the LEF group, non-anti-TNF agents were used in higher rate. Remission rates, changes in composite indices and rate of comorbidities and adverse events were similar in both groups. The retention rate of LEF + non-anti-TNF b/tsDMARDs was higher compared to MTX + anti-TNF bDMARDs (p=0.002, log-rank). Rates of adverse events were similar in both groups. CONCLUSIONS: LEF in combination with either anti-TNF or non-anti-TNF drugs appears as an effective and safe therapeutic option at least as MTX.
33774669 MTX optimization or adding bDMARD equally improve disease activity in rheumatoid arthritis 2021 Dec 24 OBJECTIVES: The STRATEGE (Therapeutic Strategy in Patients Treated With Methotrexate for Rheumatoid Arthritis) study aimed to describe treatment strategies in current practice in RA biologic DMARD (bDMARD)-naïve patients with an inadequate response to MTX therapy, and to compare clinical efficacy of the different therapeutic strategies on disease activity after 6 months. METHODS: The main inclusion criteria of this prospective, observational, multicentre study were confirmed RA diagnosis, treatment by MTX monotherapy and need for therapeutic management modification. RESULTS: The 722 patients included had a mean (s.d.) RA duration of 5.3 (6.7) years, a mean DAS28 of 4.0 (1.1); they were all receiving MTX monotherapy, 68% oral, at a mean dose of 15.0 (4.1) mg/week. Two major strategies were identified: (i) MTX monotherapy dose and/or route optimization (72%) and (ii) bDMARD initiation ± MTX (16%). MTX dosing was modified for 70% of patients, maintained (dose and route) for 28% of patients and interrupted for 2%. bDMARDs were started when the MTX mean dose was 17.4 mg/week, 56% parenterally; MTX was maintained concomitantly for 96% of patients. Six-month follow-up results adjusted by propensity score showed that both options were equally successful in improving disease activity and physical function, with 63 and 68% of good-to-moderate EULAR responses, respectively. CONCLUSION: The STRATEGE study shows the importance of initial MTX treatment optimization before initiation of a biological treatment and emphasizes the importance of treat-to-target strategy. TRIAL REGISTRATION: ClinicalTrials.gov NCT02288520.
32779111 Dextran sulfate-modified pH-sensitive layered double hydroxide nanocomposites for treatmen 2021 Jun To reduce the side effects of methotrexate and increase its anti-inflammatory effect, we developed a drug delivery system, dextran sulfate-modified methotrexate-loaded layered double hydroxide nanocomposites (LDH-MTX-DS), with both targeting and pH-sensitivity for the treatment of rheumatoid arthritis. The nanocomposites had a mean particle size of 303.1 ± 8.07 nm, zeta potential of - 12.4 ± 0.7 mV, encapsulation efficiency of 49.64%, and loading efficiency of 16.81%. In vitro release experiments demonstrated that the drug was released faster in PBS at pH 5.5 than at pH 7.4, which reflected the pH-sensitivity of this system. Cellular uptake assays displayed higher cellular uptake rate of the dextran sulfate-modified targeting carrier compared with that of a non-targeting carrier (P < 0.01), which indicated that the LDH-MTX-DS could actively target scavenger receptors on the surface of activated RAW 264.7 cells. In vivo pharmacodynamic experiments showed that, after the second (P < 0.001) and third (P < 0.05) administrations, the preparation group exhibited significantly improved therapeutic efficacy in adjuvant-induced arthritis (AIA) rats when compared with free MTX alone. These results indicated that this drug delivery system was promising in the treatment of rheumatoid arthritis. Graphical abstract.
33929089 Exposure-response modeling of peficitinib efficacy in patients with rheumatoid arthritis. 2021 May The aim was to analyze the relationship between peficitinib exposure and efficacy response according to American College of Rheumatology (ACR) 20 criteria and 28-joint disease activity score based on C-reactive protein (DAS28-CRP) in rheumatoid arthritis (RA) patients, and to identify relevant covariates by developing exposure-response models. The analysis incorporated results from three multicenter, placebo-controlled, double-blind studies. As an exposure parameter, individual post hoc pharmacokinetic (PK) parameters were obtained from a previously constructed population PK model. Longitudinal ACR20 response rate and individual longitudinal DAS28-CRP measurements were modeled by a non-linear mixed effect model. Influential covariates were explored, and their effects on efficacy were quantitatively assessed and compared. The exposure-response models of effect of peficitinib on duration-dependent increase in ACR20 response rate and decrease in DAS28-CRP were adequately described by a continuous time Markov model and an indirect response model, respectively, with a sigmoidal E(max) saturable of drug exposure in RA patients. The significant covariates were DAS28-CRP and total bilirubin at baseline for the ACR20 response model, and CRP at baseline and concomitant methotrexate treatment for the DAS28-CRP model. The covariate effects were highly consistent between the two models. Our exposure-response models of peficitinib in RA patients satisfactorily described duration-dependent improvements in ACR20 response rates and DAS28-CRP measurements, and provided consistent covariate effects. Only the ACR20 model incorporated a patient's subjective high expectations just after the start of the treatment. Therefore, due to their similarities and differences, both models may have relevant applications in the development of RA treatment. CLINICAL TRIAL REGISTRATION: NCT01649999 (RAJ1), NCT02308163 (RAJ3), NCT02305849 (RAJ4).
33686476 Prevalence of liver fibrosis by Fibroscan in patients on long-term methotrexate therapy fo 2021 Sep INTRODUCTION: Data on the long-term use of methotrexate (MTX) causing liver fibrosis in patients with rheumatoid arthritis (RA) is sparse. Liver biopsy is the gold standard to assess fibrosis but is an invasive procedure. Transient elastography (TE) by Fibroscan is a noninvasive validated tool to detect and quantify liver fibrosis. The present study aimed to assess the prevalence of liver fibrosis by Fibroscan in patients with RA on long-term MTX therapy and its correlation with cumulative dose of MTX. METHODS: This cross-sectional study included adult patients (≥ 18 years age) of RA who had been on MTX for ≥ 3 years. The patients' records were reviewed, and the cumulative dose of MTX was calculated. Liver fibrosis was assessed by TE method, and the cutoff value of 7.1 kPa (kilopascal) was considered abnormal (liver fibrosis). Spearman's rank test was used to assess the correlation between the cumulative dose of MTX and Fibroscan score. RESULTS: Seventy-five patients were enrolled of which 69 were females (92%). The mean age was 47.2 ± 11.3 years. The mean body mass index and waist circumference were 24.8 ± 3.9 kg/m(2) and 91.6 ± 9.9 cm, respectively. The median duration and cumulative dose of MTX were 336 weeks (interquartile range,144-912 weeks) and 6300 mg (interquartile range, 2400-22,000 mg), respectively. The mean liver stiffness was 5.22 ± 2.03 kPa. Twelve patients (16%) had Fibroscan score ≥ 7.1 kPa, of which 3 patients had severe liver stiffness (9.5 to 12.5 kPa) and one patient had liver stiffness in the range of cirrhosis (> 12.5 kPa). Fibroscan scores significantly correlated with cumulative dose of MTX (r= 0.30, p = 0.008). CONCLUSIONS: Long-term MTX therapy in RA was associated with increased liver stiffness on Fibroscan. Key Points • Fibroscan is a useful tool for monitoring MTX-induced liver fibrosis. • Liver fibrosis as evidenced by increased liver stiffness on Fibroscan is prevalent among patients on long-term MTX therapy for RA.
34783244 Programmable Polymeric Microneedles for Combined Chemotherapy and Antioxidative Treatment 2021 Nov 24 Rheumatoid arthritis (RA) is a chronic inflammatory joint disease. Antioxidative treatment combined with chemotherapy holds great promise for RA treatment, and the ability to efficiently deliver drugs and antioxidants to the RA synovial joint is highly desired. Herein, we developed a programmable polymeric microneedle (MN) platform for transdermal delivery of methotrexate (MTX) and reactive oxygen species (ROS) scavengers for RA treatment. The biodegradable MNs made of polyvinylpyrrolidone (PVP) were incorporated with polydopamine/manganese dioxide (termed PDA@MnO(2)) and MTX. After insertion into skin tissue, the MNs degraded, thus enabling release of loaded MTX and PDA@MnO(2). The PDA@MnO(2) could be utilized as an MRI contrast agent in the RA synovial microenvironment. It also acted as a robust antioxidant to remove ROS and decrease RA inflammation, which when combined with the MTX-mediated chemotherapy led to an ideal outcome for RA treatments in a murine model. This work not only represents a valuable MN-assisted RA therapeutic agent transdermal delivery approach but also opens a new avenue for chemotherapy and antioxidative synergistic treatment of RA.
33965503 Shield and sword nano-soldiers ameliorate rheumatoid arthritis by multi-stage manipulation 2021 Jul 10 Rheumatoid arthritis (RA) is characterized by the outbreak of inflammation. Neutrophils, the main culprit of the outbreak of inflammation, are the first inflammatory cells to be recruited to inflamed joints and facilitate the recruitment of themselves by stimulating the release of chemokines. Here, based on neutrophils, a novel anti-inflammatory "shield and sword soldiers" strategy is established with LMWH-TOS nanoparticles (LT NPs). The hydrophilic fragment low molecular weight heparin (LMWH) acts as a shield which block the transvascular movement of neutrophils through inhibiting the adhesion cascade by binding to P-selectin on inflamed endothelium. Synergistically, MMP-9, which is secreted by the recruited neutrophils and degrade the main component of articular cartilage, is reduced by the hydrophobic fragment d-α-tocopheryl succinate (TOS), functioning as a sword. In collagen-induced arthritis (CIA) mouse model, LT NPs show significant targeting effect, and exhibit prominent therapeutic efficacy after enveloping the first-line anti-RA drug methotrexate. Our work proves that the multi-stage manipulation of neutrophils is feasible and effective, providing a new concept for RA treatment.
34017081 HLA-DRB1, IRF5, and CD28 gene polymorphisms in Egyptian patients with rheumatoid arthritis 2021 Jun This study was established to assess the effects of IRF5 rs10488631 and CD28 rs1980422 single-nucleotide polymorphisms (SNPs) and HLA-DRB1 shared epitope (SE) allele on the prognosis and disease activity of rheumatoid arthritis (RA) patients. A total of 150 RA patients and 150 healthy controls were genotyped for the selected SNPs by real-time PCR. HLA-DRB1 SE was determined using LAB Type SSO Class II DRB1 typing. Our results suggest that HLA-DRB1, CD28, and IRF5 significantly discriminated (p < 0.001) RA patients and healthy controls (OR of single HLA-DRB1 SE allele = 2.431, CI = 1.467-4.027, OR of two SE alleles = 11.152, CI = 2.479-50.159), (OR of CD28 risk allele C = 2.794, 95% CI = 1.973-3.956) and (OR of IRF5 risk allele C = 4.925, CI = 3.26-7.439). Rheumatoid factor (RF) seropositivity was associated with HLA-DRB1 SE (p < 0.001) and IRF5 risk allele (p < 0.001). ACPA was significantly associated only with IRF5 risk allele (p < 0.001). A better response to methotrexate therapy was found in HLA-DRB1 SE non-carriers, and CD28 TT patients. This study demonstrated associations of HLA-DRB1 SE, CD28, and IRF5 with the risk of RA. HLA-DRB1 SE and CD28 rs1980422 can be used as predictors of methotrexate therapy response.
35016466 Efficacy and safety of methotrexate in the treatment of rheumatoid arthritis: a retrospect 2021 Dec BACKGROUND: The clinical efficacy and safety of leflunomide (LFN) at a dose of 10 mg/day in the treatment of patients with rheumatoid arthritis (RA) is still unclear. We conducted this retrospective study to identify its efficacy and safety in comparison with methotrexate (MTX) at a dose of 10 mg/week. METHODS: We enrolled RA patients who were treated in our hospital from January 2013 to December 2020, and the American College of Rheumatology (ACR) 1987 criteria were adopted. The following data was collected: age, duration of disease, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), rheumatoid factor (RF), cyclic citrullinated peptide (CCP) antibody, white blood cell (WBC), and hemoglobin (Hb) level. The primary outcomes included the changes of the above variables and the incidence of adverse events after treatment in both groups. RESULTS: From January 2013 to December 2020, a total of 612 patients with RA treated in our hospital were screened. After excluding cases that did not meet the inclusion criteria, 33 cases remained in LFN group, and there were 59 cases in the MTX group. The baseline characteristics were similar between the LFN and MTX groups. After 24 weeks of treatment, there were still no significant differences between the two groups in all of the above variables. The infection rate was slightly higher in patients treated with MTX than those treated with LFN, while diarrhea episodes were more common in the LFN group. CONCLUSIONS: Our data indicated that compared with MTX at a dose of 10 mg/week, a low dose of LFN at 10 mg/day might be a preferable treatment choice for RA patients.
32822057 Dose tapering of biologic agents in patients with rheumatoid arthritis-results from a coho 2021 Mar OBJECTIVE: To assess the association of demographic and clinical factors with the clinical decision of tapering biologic disease modifying antirheumatic drugs (bDMARDs) in patients with rheumatoid arthritis (RA) in daily practice. METHODS: All RA patients receiving bDMARDs were documented by 14 rheumatologists when presenting in 9 specialized private practices. Statistical analyses employed multivariable logistic models for dose reduction with the covariates age, gender, disease duration until bDMARD start, smoking status, disease activity, comorbidity, functional capacity, radiographic damage, concomitant methotrexate (MTX) treatment, rheumatoid factor positivity, and glucocorticoid use. In the multivariable model (MVM), missing values were imputed. RESULTS: Data of 586 RA patients on bDMARD treatment were available, 171 of which (29%) received a reduced dose. The highest rates of patients with dose reduction were seen for rituximab (67%) and infliximab (50%). The degree of dose reduction was most prominent for rituximab (57%). In the MVM, 6/11 covariates were significantly associated with dose reduction: age (odds ratio (OR) 1.03, 95% confidence interval (CI) 1.01-1.05; P = 0.002), time between disease onset and bDMARD start (OR 1.03, 95% CI 1.01-1.06; P = 0.015), DAS 28 < 2.6 (OR 1.55, 95% CI 1.01-2.37; P = 0.045), MTX therapy (OR 1.52, 95% CI 1.03-2.25; P = 0.036), comorbidity (OR 1.20, 95% CI 1.01-1.42; P = 0.036), and glucocorticoid dose (OR 0.82, 95% CI 0.76-0.89; P < 0.001). CONCLUSION: DAS 28 remission, concomitant MTX, and lower glucocorticoid doses were positively associated with dose tapering of bDMARDs in RA patients. While this could be expected, the reason for the association with age, comorbidity, and the time between disease onset and bDMARD start is less clear. Key points • In rheumatology practice, tapering of biologic disease modifying antirheumatic drugs is feasible in nearly 30% of patients with rheumatoid arthritis. • The degree of dose reduction may exceed 50% of the recommended dose. • In a multivariable model, concomitant methotrexate is positively associated with dose tapering of biologic disease modifying antirheumatic drugs.
33186593 Traditional and modern management strategies for rheumatoid arthritis. 2021 Jan Rheumatoid arthritis (RA) is a serious disorder of the joints affecting 1 or 2% of the population aged between 20 and 50 years worldwide. RA is the foremost cause of disability in developing and Western populations. It is an autoimmune disease-causing inflammation and pain involving synovial joints. Pro-inflammatory markers, including cytokines, such as interleukin -1 (IL-1), IL-6, IL-7, IL-8, and tumor necrosis factor-α (TNF-α) are involved in RA. RA treatment involves TNF-α blockade, B cell therapy, IL-1 and IL-6 blockade, and angiogenesis inhibition. Synthetic drugs available for the treatment of RA include disease-modifying anti-rheumatic drugs (DMARD), such as cyclophosphamide, sulfasalazine, methotrexate, nonsteroidal anti-inflammatory drugs (NSAIDs), and intramuscular gold. These agents induce adverse hepatorenal effects, hypertension, and gastric ulcers. We found that patients diagnosed with chronic pain, as in RA, and those refractory to contemporary management are most likely to seek traditional medicine. Approximately 60-90% of patients with arthritis use traditional medicines. Therefore, the efficacy and safety of these traditional medicines need to be established. The treatment for RA entails a comprehensive multidisciplinary strategy to reduce pain and inflammation and to restore the activity of joints. The potential medicinal plants exhibiting anti-arthritic and anti-rheumatic pharmacological activity are reviewed here.
34175381 Hepatotoxic potentials of methotrexate: Understanding the possible toxicological molecular 2021 Jun 30 Methotrexate (MTX) is one of the most effective and widely used drugs in the management of autoimmune and dermatological diseases. Rheumatoid arthritis and psoriasis patients who are under long term MTX-therapy are at high risk of developing a liver injury. Accumulation of intracellular MTX-polyglutamate (MTX-PG), a metabolite of MTX triggers oxidative stress, inflammation, steatosis, fibrosis, and apoptosis in hepatocytes. MTX-PG causes oxidative stress in the liver by inducing lipid peroxidation thereby releasing reactive oxygen species and suppressing antioxidant response elements. MTX-PG induces several pro-inflammatory signaling pathways and cytokines such as tumor necrosis factor-α, nuclear factor kappa B and interleukin 6 (IL-6), IL- β1, IL-12. MTX-PG depletes hepatic folate level and decreases RNA and DNA synthesis leading to hepatocyte death. MTX-PG inhibits 5-aminoimidazole-4-carboxamide ribonucleotide transformylase enzyme and thereby causes accumulation of intracellular adenosine, which causes activation of hepatic stellate cells, extracellular matrix accumulation and hepatic fibrosis. MTX-PG induces hepatocytes apoptosis by activation of caspase 3 via the intrinsic pathway. Clinically, aggravation of underlying fatty liver to non-alcoholic steatohepatitis with fibrosis seems to be an important mechanism of liver injury in MTX-treated RA patients. Therefore, there is a need for monitoring liver injury in RA, psoriatic and cancer patients with NAFLD and fibrosis risk factors during MTX treatment. This review summarizes the possible molecular mechanism of MTX-induced hepatotoxicity. It may pave the way for early detection of liver injury and develop novel strategies for treating MTX mediated hepatotoxicity.
34768991 Methotrexate Alters the Expression of microRNA in Fibroblast-like Synovial Cells in Rheuma 2021 Oct 26 We aimed to investigate the effect of methotrexate (MTX) on microRNA modulation in rheumatoid arthritis fibroblast-like synovial cells (RA-FLS). RA-FLS were treated with MTX for 48 h. We then performed miRNA array analysis to investigate differentially expressed miRNAs. Transfection with miR-877-3p precursor and inhibitor were used to investigate the functional role of miR-877-3p in RA-FLS. Gene ontology analysis was used to investigate the cellular processes involving miR-877-3p. The production of cytokines/chemokines was screened by multiplex cytokine/chemokine bead assay and confirmed by ELISA and quantitative real-time PCR. The migratory and proliferative activities of RA-FLS were analyzed by wound healing assay and MKI-67 expression. MTX treatment altered the expression of 13 miRNAs (seven were upregulated and six were downregulated). Among them, quantitative real-time PCR confirmed that miR-877-3p was upregulated in response to MTX (1.79 ± 0.46-fold, p < 0.05). The possible target genes of miR-877-3p in RA-FLS revealed by the microarray analysis were correlated with biological processes. The overexpression of miR-877-3p decreased the production of GM-CSF and CCL3, and the overexpression of miR-877-3p inhibited migratory and proliferative activity. MTX altered the miR-877-3p expression on RA-FLS, and this alteration of miR-877-3p attenuated the abundant production of cytokines/chemokines and proliferative property of RA-FLS.
32475009 Safety and Tolerability of Subcutaneous Methotrexate in Routine Clinical Practice. 2021 Sep OBJECTIVE: To show the safety and efficacy of subcutaneous (SC) methotrexate (MTX) compared to oral MTX, alternative disease-modifying antirheumatic drugs (DMARDs) monotherapy, biologic monotherapy, and combinations (conventional and biologic combination groups) in routine clinical practice. METHODS: Clinical and laboratory data were retrospectively analyzed for rheumatology clinic attendances at a large Northeast England hospital trust between January 2014 and January 2018. Rates of adverse events and stop events (transaminitis [serum alanine aminotransferase level of >80 units/liter] or neutropenia [neutrophil count of <2.0 × 10(9) /liter]) were calculated, with adjustment for duration of DMARD exposure. RESULTS: In the present study, 8,394 patients received DMARDs, with 2,093 patients receiving oral MTX and 949 patients receiving SC MTX. The median dose was 15 mg (interquartile range [IQR] 10-20 mg) for oral MTX, and 20 mg (IQR 15-25 mg) for SC MTX (P < 0.0001). Continuation rates were higher for SC MTX therapy when adjusted for follow-up duration, with a rate ratio (RR) of 1.54 (95% confidence interval [95% CI] 1.40-1.70) (P < 0.0001). For the time period assessed, 2,382 patients experienced 4,358 adverse events, with 1,711 incidents of transaminitis and 2,647 incidents of neutropenia recorded. Significantly fewer adverse events were observed in patients who received SC MTX monotherapy versus those who received biologic and combination DMARD therapies (P < 0.01). Compared to oral MTX, SC MTX was associated with a nonsignificant trend toward lower rates of neutropenia, but only a slightly higher rate of transaminitis (RR 1.26 [95% CI 1.07-1.48]) (P = 0.006), despite significantly higher doses of MTX. CONCLUSION: Subcutaneous MTX is safe in routine clinical practice. This is the largest study yet reported on SC MTX and provides observational data that SC MTX is continued longer and better tolerated in patients compared to other therapy groups, especially oral MTX.
34774696 Transdermal release of methotrexate by cationic starch/poly(vinyl alcohol)-based films as 2022 Jan 5 Methotrexate (MTX) is a common drug used for rheumatoid arthritis (RA) treatment; however, a series of adverse effects associated with its oral or subcutaneous administration is reported. Transdermal delivery of MTX is an alternative to abate these issues, and the use of drug delivery systems (DDS) based on polymeric films presents an impressive potential for this finality. Based on this, in this study, we report the preparation of films made by cationic starch (CSt), poly(vinyl alcohol) (PVA), and chondroitin sulfate (ChS) to incorporate and release MTX, as well as the in vivo evaluation in model of rheumatoid arthritis in mice. CSt/PVA and CSt/PVA/ChS-based films (with and without MTX) were prepared using a simple protocol under mild conditions. The films loaded with 5 w/w-% of MTX exhibited appreciable drug loading efficiency and distribution. The MTX permeation through the layers of porcine skin demonstrated that most of the drug permeated was detected in the medium, suggesting that the formulation can provide a systemic absorption of the MTX. In vivo studies performed in an arthritis-induced model in mice demonstrated that the MTX-loaded films were able to treat and attenuate the symptoms and the biochemical alterations related to RA (inflammatory process, oxidative stress, and nociceptive behaviors). Besides, the pharmacological activity of MTX transdermally delivery by the CSt/PVA and CSt/PVA/ChS films was comparable to the MTX orally administered. Based on these results, it can be inferred that both films are prominent materials for incorporation and transdermal delivery of MTX in a practical and non-invasive manner.