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ID PMID Title PublicationDate abstract
29372595 Methotrexate might reduce ischemic stroke in patients with rheumatoid arthritis: a populat 2018 Aug AIM: To investigate the effects of hydroxychloroquine, sulfasalazine and methotrexate on ischemic stroke in patients with rheumatoid arthritis (RA). METHODS: This population-based retrospective cohort study included 7904 RA patients and 15 808 non-RA patients between 2000 and 2010. All of the participants were sampled from the National Health Insurance Research Database (NHIRD) of Taiwan. Using univariate analyses, these two groups of patients were compared to evaluate the differences in disease-modifying anti-rheumatic drugs usage and demographic variables. Cox proportional hazard models and Schoenfeld residuals test were performed to estimate the hazard ratios for ischemic stroke and proportional hazard assumptions of these drugs, respectively. RESULTS: The mean age of participants was about 53 years old, and about 70% of RA patients were women. The hazard ratio for ischemic stroke was 1.21 (95% CI: 1.10-1.34; P < 0.01) in the case group compared with the control group, and this significant difference persisted throughout the 10-year period. With respect to RA patients, while hydroxychloroquine showed an insignificant protective effect on ischemic stroke, sulfasalazine and methotrexate were found out to have inconsistent effects during these 10 years. The proportional hazard assumption test of methotrexate at > 0.5 defined daily dose (8.75 mg/week) was violated at a significant level after adjustment (P = 0.0002). CONCLUSIONS: At a dosage of > 0.5 defined daily dose, short-term methotrexate might decrease ischemic stroke risk in RA patients, while hydroxychloroquine and sulfasalazine were neutral.
29314738 Long-term efficacy and safety of add-on tacrolimus for persistent, active rheumatoid arthr 2018 Mar AIM: To assess the long-term efficacy and safety of adding tacrolimus for patients with active rheumatoid arthritis (RA) despite anti-tumor necrosis factor (TNF) therapy with methotrexate. METHODS: Consecutive patients who were treated with adding tacrolimus onto anti-TNF therapy with methotrexate for active RA despite anti-TNF therapy with methotrexate, were retrospectively analyzed in terms of treatment response, achieving remission, subsequent treatment tapering and adverse events. RESULTS: Fifteen patients could be analyzed. Median symptom duration was 2.9 years and prior duration of anti-TNF therapy was 40 weeks. Median value of Disease Activity Score in 28 joints was 4.6. Five, eight and two were on infliximab, etanercept and adalimumab at the onset of tacrolimus, respectively. At 2 years, the proportions of patients achieving responses of American College of Rheumatology 50, 70 and 90, were 80%, 73% and 40%, respectively, and those achieving remission as defined by Simplified Disease Activity Index ≤ 3.3 were 67%. All patients could discontinue oral glucocorticoids and 10 had been successfully withdrawn from anti-TNF therapy for more than 1 year at the final observation. CONCLUSION: Adding tacrolimus onto anti-TNF therapy is a promising therapeutic option with sustained benefit for refractory RA patients despite treatment with anti-TNF therapy combined with methotrexate.
30148440 Risk of hospitalisation for serious bacterial infections in patients with rheumatoid arthr 2019 Jan OBJECTIVES: The aims of this study were to define the risk of serious bacterial infections in patients receiving specific biological disease-modifying anti-rheumatic drugs (bDMARDs) and evaluating the effect of concomitant synthetic DMARDs (sDMARDs) in a large population-based sample of rheumatoid arthritis (RA) deriving from an administrative health database. METHODS: Data were extracted from health databases of Lombardy Region, Italy (2004-2013), as a part of the RECord-linkage On Rheumatic Diseases (RECORD) study. Patients with RA treated with approved bDMARDs were included. Hospitalisations for bacterial infections were evaluated by hospital discharge forms. The association between drug exposure and infections was assessed by survival models, with time-dependent covariates. Results are presented as hazard ratios (HR) and 95%CI, crude and adjusted for pre-specified confounders (sex, age, disease duration, Charlson Comorbidity Index, previous biologics, previous infections, use of methotrexate, leflunomide, corticosteroids, non-steroidal anti-inflammatory drugs). RESULTS: 4,656 RA patients with at least one bDMARD prescription were included, for a total of 7,601 biological courses; 3,603 (77.4%) women with a mean (SD) age of 55.8 (12.7) years. Crude incidence rate of hospitalised infection ranged from 0.14 to 2.95 per 1000 person-years. After multivariable adjustment, abatacept users (HR 0.29, 95%CI 0.10-0.82) had significantly lower risk of infections compared to etanercept. Concurrent treatment with methotrexate (0.72, 0.52-0.99) reduced the overall risk of infection while glucocorticoids increased it (1.09 per mg/day, 1.06-1.11). CONCLUSIONS: In RA patients treated with bDMARDs, abatacept was associated with the lowest risk of infections; overall risk was mitigated by concomitant methotrexate and increased by glucocorticoids in a dose-dependent manner.
29679159 Notch-1 siRNA and Methotrexate towards a Multifunctional Approach in Rhematoid Arthritis M 2018 Apr 20 PURPOSE: Rheumatoid arthritis (RA) is a chronic inflammatory disease and Notch pathway plays a pivotal role in synoviocytes involved in progression of RA. METHODS: Herein, we have designed a self-assembled polymeric micelles based on polycaprolactone-polyethylene glycol (PCL-PEG) and polyethylenimine-polyethylene glycol (PEI-PEG) was prepared and loaded with methotrexate and Notch-1 siRNA for the effective treatment of rheumatoid arthritis. RESULTS: The MTX/siRNA-loaded polymeric micelles (siM-PM) showed appreciable cellular uptake in Raw264.7 cells which were activated with LPS and did not exhibit any toxicity to Raw264.7 and HUVEC cells. The AUC of siM-PM was 4-fold higher compared to that of free MTX while t1/2 was 6 fold for siM-PM compared to that of free drug indicating the superior pharmacokinetic parameters. Importantly, siM-PM significantly reduced the paw thickness and slowed the disease progression remarkably, indicating that siM-PM is very effective in recovering the edema in arthritic animals. Importantly, 2-fold decrease in arthritic score was observed in siM-PM treated group at the end of day 24. The data clearly reveals anti-inflammatory effect of combinational nanoparticle due to the sequence specific downregulation of Notch-1 expression in the RA clinical models. CONCLUSIONS: Overall, nanomedicine-based delivery of MTX and siRNA could overcome the side effects of small molecules and could improve the therapeutic effect of siRNA in rheumatoid arthritis.
29667551 Circulating miR-10a as Predictor of Therapy Response in Rheumatoid Arthritis Patients Trea 2018 BACKGROUND: Anti-inflammatory drugs and DMARDs, especially methotrexate, have dramatically improved the outlook of RA patient. However, in some patients the treatment effect is still not satisfactory and needs to change therapeutic regimen in time. So, timely prediction of patient treatment effect is particularly important. METHODS: miRNAs are a large family of highly conserved noncoding genes and some of them become potential biomarker of disease diagnosis. Circulating miR-10a was detected by qRT-PCR. Receiver operating characteristic (ROC)curve analyses were performed for circulating miR-10a in RA diagnosis and predictor of therapy effectiveness in RA patients treated with methotrexate. RESULTS AND CONCLUSION: In the present study, we found that the circulating miR-10a was significantly decreased in RA patients compared to osteoarthritic patients and healthy people. Importantly, circulating miR-10a was up-regulated in RA patients treated with MTX. Moreover, we identified circulating miR-10a that may serve as a biomarker of RA diagnosis and predictor of therapy effectiveness in rheumatoid arthritis patients treated with methotrexate.
29325724 Rheumatoid Arthritis, Disease Modifying Agents, and Periprosthetic Joint Infection: What D 2018 Apr The incidence of periprosthetic joint infection (PJI) among patients with rheumatoid arthritis (RA) is 1.6× greater than in patients undergoing the same procedure for osteoarthritis. This higher risk "may" be due to the immunosuppressive therapies for RA patients including corticosteroids, such as prednisone, and disease-modifying antirheumatic drugs (DMARDs), such as methotrexate. There is a debate about the role of DMARDs in increasing the incidence of subsequent PJI. Studies show conflicting results, with some demonstrating no significant increase in the rates of PJI and some finding otherwise. The International Consensus Meeting on PJI recommended that DMARDs should be halted prior to an elective total joint arthroplasty based on their half-life. Moreover, the International Consensus Meeting stated that cessation of immunosuppressant medications should be performed in consultation with and under the direction of the treating physician. In this review, we aimed to provide an introduction to the available treatment options and cover the recommendations on the treatment protocols for RA patients who undergo elective total joint arthroplasty.
29701040 [Clinical therapeutic effects on rheumatoid arthritis treated with the assisted therapy of 2018 Mar 12 OBJECTIVE: To evaluate the clinical therapeutic effects and safety on rheumatoid arthritis (RA) treated with acupuncture at the points detected with thermosensitive moxibustion in Zhuang medicine combined with western medication. METHODS: A total of 168 RA patients in compliance with the inclusive criteria were collected and randomized into an observation group and a control group, 84 cases in each one. In the control group, in reference to the updated guideline of new drugs by the European League Against Rheumatism (EULAR) in 2013, the medication scheme was formulated for oral administration, methotrexate tablet 7.5 mg, once a week; salazosulfapyridine enteric-coated tablets, 100 mg, twice a day; hydroxychloroquine sulfate tablets, 20 mg, twice a day; and meloxicam tablets, 15 mg, once a day. In the observation group, besides the treatment as the control group, the acupuncture therapy at the points detected with thermosensitive moxibustion in Zhuang medicine was given. The mild moxibustion was applied near to the affected joint with the moxa material of Zhuang herbal medicine to detect the sensitization points. Afterwards, the acupuncture technique of Zhuang medicine was given on those points, without any manipulation applied. The needles were retained for 30 min, once daily. The treatment for 2 weeks was as one course, continuously for 2 courses. The indexes were observed before and after treatment in the two groups including gripping power, the time of morning stiffness, the swollen joint count 28 (SJC 28), the tender joint count 28 (TJC 28), the disease activity score 28 (DAS 28), the score of patient global assessment of disease activity (PtGA) and the score of provider global assessment of disease activity (PhGA), as well as rheumatoid factors (RF), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR) and anti-cyclic peptide containing citrulline (A-CCP). The clinical therapeutic effects were evaluated in the two groups. RESULTS: After 4-week treatment, a total of 163 patients accomplished the clinical trial, 81 cases in the observation group and 82 cases in the control group. The results of gripping power, the time of morning stiffness, SJC 28, TJC 28, PtGA, PhGA, DAS 28, RF, CRP, ESR and A-CCP were all improved as compared with those before treatment (all P<0.05). In 4 weeks of treatment, the results of gripping power, the time of morning stiffness, SJC 28, TJC 28, PtGA, PhGA, DAS 28, as well as CRP and ESR in the observation group were better than those in the control group (all P<0.05). The results of RF and A-CCP were not different significantly between the two groups (both P>0.05). The total effective rate was 85.19% (69/81) in the observation group, higher than 70.73% (58/82) in the control group (P<0.05). CONCLUSION: The acupuncture therapy at the points detected with thermosensitive moxibustion in Zhuang medicine achieves the satisfactory clinical effects with few adverse effects.
29584787 Factors affecting walking ability in female patients with rheumatoid arthritis. 2018 OBJECTIVE: To determine the factors associated with gait parameters in female patients with rheumatoid arthritis (RA). METHODS: The gait analysis was performed in a large cohort of RA patients, and three basic gait parameters (step length, cadence and gait speed) were calculated. Clinical and laboratory data were also collected. Factors associated with gait parameters were analyzed using multivariable linear regression in the three models with forced entry. Then, we divided those patients with Health Assessment Questionnaire disability index (HAQ) scores ≤ 0.5 into two groups according to their gait speed that were compared to identify the characteristics of patients with a good HAQ score but poor walking ability. RESULTS: A total of 318 female patients were analyzed. Knee extension strength had the strongest positive association with all three gait parameters (P < 0.0001), while methotrexate use was also positively associated with all three gait parameters (step length: P < 0.05, cadence: P < 0.05 in model 1 and 2; P < 0.01 in model 3, gait speed: P < 0.01). The disease activity score was negatively associated with step length and gait speed (step length, gait speed: P < 0.01 in model 1 and 2; P < 0.05 in model 3). 26% of patients with good HAQ scores showed slow gait speed. Patients with good HAQ scores and slow gait speed had higher disease activity scores (P < 0.05) and lower knee extension strength (P < 0.0001) than those with good HAQ scores and normal gait speed. CONCLUSIONS: High knee extension strength, low disease activity and administration of methotrexate were strongly associated with good walking ability in female patients with RA. And, even if patients showed good HAQ scores, about quarter of those patients had poor walking ability, and they showed higher disease activity, lower knee extension strength, compared to the patients with normal gait speed.
29278339 Determinants of Patient's Global Assessment of Disease Activity and Physician's Global Ass 2018 Nov OBJECTIVES: To assess the determinants of Patient's Global Assessment of Disease Activity (PtGA) and Physician's Global Assessment of Disease Activity (PhGA) in overall and Japanese patients with rheumatoid arthritis (RA) from two large randomized controlled trials. METHODS: Post hoc analysis of overall and Japanese RA patients who had previous inadequate responses to methotrexate or who had no/minimal previous disease-modifying antirheumatic drug treatment. We examined correlations between PtGA/PhGA and tender joint count in 28 joints (TJC28), swollen joint count in 28 joints (SJC28), inflammatory markers, pain visual analog scale (VAS), and other patient-reported outcomes at baseline, Week 12, and Week 24. Determinants of PtGA/PhGA were identified. RESULTS: In overall populations, pain VAS was the main determinant of PtGA, whereas TJC28 was the main determinant of PhGA in both studies. In Japanese populations, consistent with overall populations, pain VAS was the main determinant of PtGA in both studies; in contrast to overall populations, pain VAS and SJC28/TJC28 played an important role in PhGA. CONCLUSION: Pain was the most important determinant of PtGA, whereas determinants of PhGA varied between populations/studies and were mostly explained by pain/joint counts. Physicians should be aware of patients' perceptions of disease activity when performing assessments/prescribing treatments.
29520081 Evaluation of a clinical pharmacogenetics model to predict methotrexate response in patien 2018 Jul Variability of response to treatment hinders successful management of rheumatoid arthritis (RA). Consequently, a clinical pharmacogenetics model for predicting response to methotrexate (CP-MTX) has been previously proposed that includes four clinical variables (disease activity, sex, the presence of rheumatoid factor and smoking status) and four SNPs (rs2236225, rs17602729, rs1127354, and rs2372536) in genes of the folate pathway. It showed good performance, but failed to attract attention, likely, in relation with lack of clear clinical benefit. Here, we have revised the value of the CP-MTX model directly addressing its clinical benefit by focusing on the expected benefit-cost of the predictions. In addition, our study included a much larger number of RA patients (n = 720) in MTX monotherapy than previous studies. Benefit of CP-MTX prediction was defined as the patients that would have received combination therapy as first treatment because they were correctly predicted as non-responders to MTX monotherapy. In contrast, cost of CP-MTX prediction was defined as the responder patients that were wrongly predicted as non-responders. Application of CP-MTX predictions to our patients showed a good benefit-cost relationship, with half of the 66.7% non-responders to MTX monotherapy rightly directed to alternative treatments (a benefit of 33.3%) at the cost of 8.5% wrongly predicted non-responders. These benefits-costs were consistent with reanalysis of the previously published studies. Therefore, predictions of CP-MTX showed a good benefit-cost relationship for informing MTX prescription.
29901407 Vaccination with a Novel Antigen-Specific Tolerizing DNA Vaccine Encoding CCOL2A1 Protects 2019 Jan Antigen-specific tolerizing DNA vaccines are one of the most promising strategies for rheumatoid arthritis (RA) treatment. They act by inducing potent immune tolerance instead of generalized immunosuppression. Recently, we developed a novel antigen-specific tolerizing DNA vaccine pcDNA-CCOL2A1 coding for chicken type II collagen (CCII) and confirmed its potent therapeutic efficacy in an established rat model of collagen-induced arthritis (CIA). Here we report the prophylactic vaccination efficacy of a single 300 μg/kg dose of pcDNA-CCOL2A1 against CIA incidence, severity, and onset. CCOL2A1 transcripts were detected in the blood of CIA rats 14-42 days after intramuscular injection by 300 μg/kg pcDNA-CCOL2A1. The expression of CCOL2A1 transcripts increased quickly on day 21, peaked at day 28, and then gradually decreased thereafter. Importantly, a single prophylactic vaccination of pcDNA-CCOL2A1 14 days before CIA establishment significantly reduced CIA incidence and severity, deferred its onset, and was as efficacious as the current gold standard drug, methotrexate. The marked effects on CIA incidence and severity closely corresponded to the expression of CCOL2A1. Furthermore, prophylactic vaccination with pcDNA-CCOL2A1 markedly decreased serum content of anti-type II collagen (CII) immunoglobulin G (IgG) antibodies, induced Th1-to-Th2 and Tc1-to-Tc2 shifts, and decreased the percentages of CD4(+)CD29(+) and Th17 T cells. Prophylactic vaccination with pcDNA-CCOL2A1 also downregulated various Th1 cytokines, while upregulating both the Th2-type cytokine interleukin-10 and the Th3-type cytokine transforming growth factor β. Our results indicate that the pcDNA-CCOL2A1 DNA vaccine acts as a highly efficient inducer of specific immunotolerance that could be a promising option for RA treatment in the near future.
30249062 Inhibitory Effect of Methotrexate on Rheumatoid Arthritis Inflammation and Comprehensive M 2018 Sep 23 Rheumatoid arthritis (RA) is a common autoimmune disease. The inflammation in joint tissue and system endanger the human health seriously. Methotrexate have exhibited a satisfactory therapeutic effect in clinical practice. The aim of this research was to establish the pharmacological mechanism of methotrexate on RA therapy. Collagen induced arthritic rats were used to identify how methotrexate alleviates inflammation in vivo. Lipopolysaccharide-induced inflammatory proliferation in macrophages was also be detected in vitro. The activation level of Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and Nucleotide binding domain and leucine-rich repeat pyrin 3 domain (NLRP3)/Caspase-1 and related cytokines were examined by real-time PCR and western blotting or quantified with the enzyme-linked immunosorbent assay. Comprehensive metabolomics analysis was performed to identify the alteration of metabolites. Results showed that treating with methotrexate could alleviate the inflammatory condition, downregulate the activation of NF-κB and NLRP3/Caspase-1 inflammatory pathways and reduce the level of related cytokines. Docking interaction between methotrexate and caspase-1 was visualized as six H-bonds indicating a potential inhibitory effect. Metabolomics analysis reported three perturbed metabolic inflammation related pathways including arachidonic acid, linoleic acid and sphingolipid metabolism. These findings indicated that methotrexate could inhibit the onset of inflammation in joint tissue by suppressing the activation of NF-κB and NLRP3/Caspase-1 pathways and regulating the inflammation related metabolic networks.
30175777 Factors Predicting the Therapeutic Response to Methotrexate in Japanese Patients with Rheu 2018 Methotrexate (MTX) is used widely as a first-line drug for the treatment of rheumatoid arthritis (RA) worldwide. There are large interindividual differences in the therapeutic response to MTX, but it is not known which factors influence them. We therefore investigated predictive factors associated with the therapeutic response to MTX in a hospital-based cohort study. Japanese adult RA outpatients prescribed MTX were enrolled and their characteristics were collected from the electronic medical records. The European League Against Rheumatism (EULAR) response criteria were used as the response to MTX therapy. The observation period was 1 year after beginning MTX administration. Sixteen types of single-nucleotide polymorphisms were investigated using the real-time PCR method. Associations between the MTX response and patient characteristics were evaluated using the multivariate logistic regression model. Among 70 Japanese adult RA outpatients, 52 were classified as MTX responders. In multivariate analysis, patients with the solute carrier family 19 member 1 (SLC19A1) 80G>A A/A genotype had a better response than those with the A/G or G/G genotype, and patients with the C allele of γ-glutamyl hydrolase (GGH) 16T>C had a better response than those with the T/T genotype.This study showed that the therapeutic response to MTX in Japanese RA patients was associated with the genetic polymorphisms of SLC19A1 80G>A and GGH 16T>C in actual clinical practice.
30315988 Update of French society for rheumatology recommendations for managing rheumatoid arthriti 2019 Mar The 2014 French Society for Rheumatology (Société Française de Rheumatologie, SFR) recommendations about the management of rheumatoid arthritis (RA) have been updated by a task force composed of 12 expert rheumatologists, 2 patient self-help group representatives, and an occupational therapist. The material used by the task force included recent EULAR recommendations, a systematic literature review, and expert opinion. Four general principles and 15 recommendations were developed. The general principles emphasize the need for shared decision-making between the rheumatologist and the patient and for a global management program including both pharmacological and non-pharmacological treatments. The recommendations deal with the diagnostic strategy for RA, treatment targets, management organization, drug selection based on the treatment line and prognostic factors, management of remissions, and global patient management. Disease-modifying anti-rheumatic drug (DMARD) therapy should be started as early as possible. Validated composite scores should be determined at regular intervals to assess disease activity - according to the tight disease control concept - to achieve the treatment target, i.e., a remission. Methotrexate is the recommended first-line DMARD. The treatment should be optimized when methotrexate is poorly tolerated or inadequately effective. While waiting for conventional synthetic DMARDs to take effect, glucocorticoid therapy can be used, for a brief period to keep the cumulative dose low. When a sustained remission without structural progression is achieved in a patient who is not taking glucocorticoid therapy, targeted therapy de-escalation according to tight disease control principles should be considered. Patients should be periodically screened for comorbidities and their risk factors, which should be evaluated and treated.
30101636 Anti-cyclic citrullinated peptide antibodies, 28-joint Disease Activity Score, and magneti 2019 Jan OBJECTIVE: To investigate the clinical and radiographic status, and to identify baseline predictors of functional status and erosive progression at 11 years' follow-up of early rheumatoid arthritis (RA) patients. METHODS: Patients enrolled in the Danish investigator-initiated randomized controlled CIMESTRA trial, which investigated a 2 year treat-to-target intervention with methotrexate and intra-articular glucocorticoids with or without cyclosporine, were followed up. The 28-joint Disease Activity Score (DAS28), Health Assessment Questionnaire (HAQ) score, and total Sharp van der Heijde score (TSS) were assessed at baseline and 11 years. Baseline magnetic resonance imaging (MRI) of unilateral wrists was scored (OMERACT RAMRIS). Multivariable linear regression analyses of baseline variables [TSS, HAQ, DAS28, age, anti-cyclic citrullinated peptide (anti-CCP) status, gender, MRI erosion score, MRI synovitis score, MRI bone marrow oedema score] were performed in 96 patients with HAQ(11yrs) and ∆TSS(0-11yrs) as dependent variables. Since outcomes were similar in the two treatment arms, data were pooled. RESULTS: In total, 120 of 160 patients completed 11 years' follow-up. They were 63 (55-72) years old, 68% were in DAS28 remission (≤ 2.4), HAQ(11yrs) was 0.25 (0-0.75), mean ∆TSS(0-11yrs) was 0.96 ± 1.52 units/year; 53%, 20%, and 27% received conventional treatment, biologics, and no treatment, respectively; and 34% had not progressed radiographically since baseline. Increased DAS28 (p = 0.02) and anti-CCP (p = 0.03) predicted HAQ(11yrs), whereas anti-CCP (p = 0.03) and MRI bone marrow oedema (p = 0.01) predicted ∆TSS(0-11yrs) in multivariable analyses. CONCLUSIONS: Early and strict synovitis suppression with methotrexate and intra-articular glucocorticoids led to persistently high remission rates and limited erosive progression at 11 years. In this well-treated cohort, baseline anti-CCP status, DAS28, and MRI bone marrow oedema predicted functional status and/or erosive progression.
30594247 Recapitulation of methotrexate hepatotoxicity with induced pluripotent stem cell-derived h 2018 Dec 29 BACKGROUND: Methotrexate (MTX) is widely used for the treatment of rheumatoid arthritis (RA). The drug is cost-effective, but sometimes causes hepatotoxicity, requiring a physician's attention. In this study, we simulated hepatotoxicity by treating hepatocytes derived from RA patient-derived induced pluripotent stem cells (RA-iPSCs) with MTX. METHODS: RA-iPSCs and healthy control iPSCs (HC-iPSCs) were established successfully. RA-iPSCs were differentiated into hepatocytes in two-dimensional (2D) monolayers and three-dimensional (3D) hepatocyte spheroid cultures; this process required growth factors such as BMP4, bFGF, HGF, and OSM. Immunofluorescence staining and flow cytometry were performed to confirm that the mature hepatocytes expressed cytokeratin 18, anti-alpha-1 antitrypsin, and albumin. MTX toxicity was evaluated via monitoring of cell viability, alanine aminotransferase, and mitochondrial status after MTX treatment in 2D and 3D cultures. RESULTS: RA-iPSCs generated from three RA patients suffering from MTX-induced hepatotoxicity differentiated into the endoderm lineage, hepatoblasts, and hepatocytes. In 2D culture, RA-iPSC-derived hepatocytes were more sensitive to MTX than healthy controls. A 3D culture system using hepatocyte spheroids also successfully recapitulated MTX-induced hepatotoxicity. The 3D culture system had several advantages, including longer culture periods under more complex conditions. CONCLUSIONS: A patient-derived iPSC platform could recapitulate MTX toxicity. Simulation of drug toxicity in vitro may help clinicians choose safer drugs or less toxic doses.
30567538 Therapeutic benefits of Indole-3-Carbinol in adjuvant-induced arthritis and its protective 2018 Dec 19 BACKGROUND: Rheumatoid arthritis (RA) being an incapacitating disease requires early effective intervention. Considering Methotrexate (MTX)- the first line of treatment for RA- intoxicates the liver; therefore, alternative therapies with similar efficacy yet lower cytotoxicity are desired. Indole-3-Carbinol (I3C) which is found in cruciferous vegetables was examined for its possible therapeutic potentials in comparison with MTX by investigating its anti-inflammatory, anti-arthritic, anti-oxidant, and hepatoprotective potentials in adjuvant-induced arthritis (AIA) rat model. METHODS: Arthritis was induced in Sprague Dawley rats by injection of Complete Freund's Adjuvant (CFA). Arthritic rats were treated with I3C and/or MTX. To examine the anti-inflammatory and anti-arthritic effect, the following parameters were assessed: body weight, macroscopic scoring of the hind paw, the level of the pivotal cytokines (TNF-α, IL-6) heavily involved in the pathogenesis, spleen index, and erythrocyte sedimentation rate. At a histological level, the tibiotarsal joint was stained with several specific stains. To assess the hepatoprotective and anti-oxidant effects, several oxidative stress parameters were monitored, and the liver histology was examined. RESULTS: Both I3C and MTX attenuated the inflammation that was aggravated by arthritis by downregulating the inflammatory markers and mediators and alleviating the histopathological changes affecting the tibiotarsal joint. I3C attenuated the liver impairment that was initiated by arthritis and MTX treatment. It did so by downregulating the pro-oxidants and up-regulating the anti-oxidant defenses and by reducing the pathological changes affecting the liver. CONCLUSION: Our results suggest that I3C is as potent as MTX as an anti-inflammatory and anti-arthritic agent. In addition, I3C does so while protecting the liver from damage as opposed to MTX.
29968400 Effectiveness of biologics in Australian patients with rheumatoid arthritis: a large obser 2018 Oct BACKGROUND: The comparative effectiveness of biologic treatment regimens in a real world Australian population is unknown. AIM: To assess the effectiveness of biological disease-modifying anti-rheumatic drugs (bDMARD) as monotherapy or in combination with methotrexate and/or other conventional DMARD (cDMARD) for the treatment of rheumatoid arthritis (RA). METHODS: A retrospective, non-interventional study was conducted that investigated the use of bDMARD in adult patients with RA in routine clinical practice. Data were extracted from the Optimising Patient Outcomes in Australian Rheumatology - Quality Use of Medicines Initiative database. Real-world effectiveness was measured using the 28-joint disease activity score (DAS28) and clinical disease activity index (CDAI) by treatment group at baseline, weeks 12 and 24. RESULTS: A total of 2970 patients was included with a median (min-max) age of 60.0 (19.0-94.0) years and median (min-max) duration of RA before first bDMARD treatment of 6.0 (0.2-58.3) years. A total of 1177 patients received more than one bDMARD during the analysis period of 1 January 1997 to 15 August 2015. Patients had 4922 treatment 'episodes' (defined as a cycle of continuous individual bDMARD prescribing in a single patient). Patients received a mean (SD) of 1.7 (1.0) episodes of treatment with median (min-max) treatment duration of 0.7 (0-11.8) years; median treatment duration was higher with the first treatment episode. bDMARD were most commonly initiated in combination with methotrexate (73.9% of episodes) and least commonly as monotherapy (9.9% of episodes). Median (min-max) baseline DAS28 decreased from 5.3 (0-8.7) with the first bDMARD to 3.7 (0-8.8) with the second. Median baseline CDAI similarly decreased. CONCLUSIONS: Patients tended to persist longer on their first bDMARD treatment. bDMARD as monotherapy or in combination appear to be accepted treatment strategies in the real world.
29616303 Serum drug levels of biologic agents in the management of rheumatoid arthritis and spondyl 2018 Jun The utility of monitoring drug levels in rheumatoid arthritis and spondyloarthritis patients on biological therapy is called into question. The objective was to study relevant clinical questions on the topic, i.e., (1) whether drug levels predict relapse in patients whose biologic was optimized because of remission or low disease activity; (2) whether information about drug levels influences the prognosis of patients with primary or secondary failure to a biological therapy; and (3) whether methotrexate (MTX) influences the association between drug levels and response. Medline, Embase, Cochrane databases were screened, from inception to December 2016 in search for all studies related to the three research questions about. Overall characteristics and outcomes of the studies were collected in a table of evidence and the quality of the studies was assessed with the Newcastle-Ottawa scale or the GRADEpro. Two studies responded the first question, 5 the second, and 7 the third. Studies were small and with limitations, but suggest that measurement drug levels may be useful in patients in remission; that higher drug levels predict a longer relapse-free optimization, and in patients with failure to a biological agent, treatment may need individual adjustment according to the presence of drug levels or antidrug-antibodies. In addition, MTX influences the association between response and drug levels. Monitoring drug levels would allow optimal use of current biological therapies, but more studies and of better quality are needed to draw definitive conclusions.
29512532 [Homeostasis and Disorder of Musculoskeletal System.Progress in the treatment of rheumatoi 2018 Rheumatoid arthritis is a systemic autoimmune disease characterized by inflammation and joint damage that causes significant morbidity and mortality. Rapid and appropriate intervention using disease-modifying anti-rheumatic drugs(DMARDs)is prerequisite to halt joint destruction and long-term functional disabilities. Recent progress in the treatment strategy has brought about paradigm shift for the management of the disease, namely, the combined use of methotrexate, a synthetic DMARD, and a biologic DMARD targeting TNF, IL-6 and T cells has revolutionized treatment of rheumatoid arthritis. Clinical remission is now realistic targets for the treatment, achieved by a large proportion of rheumatoid arthritis patients, which leads to structural remission without damage in bone and cartilage as well as functional remission. Furthermore, orally available small but strong molecules targeting Janus kinase(JAK)are emerging. When DMARDs are prescribed, appropriate selection of DMARDs, adequate screening, regular monitoring and systemic management are required.