The use of methotrexate in rheumatoid arthritis

OBJECTIVE: To address the long-term efficacy and toxicity issues related to methotrexate (MTX) and compare it with other disease-modifying antirheumatic drugs (DMARDs). METHODS: Review of the international literature on the clinical use of MTX in rheumatoid arthritis (RA) disease. RESULTS: MTX has emerged as a relatively safe and effective treatment for RA that compares favorably with other therapies, particularly because of its considerably longer median drug survival. The toxicity profile of MTX is well established and includes serious and sometimes fatal liver disease, pneumonitis, and cytopenias. Hence, regular and careful monitoring of patients taking MTX is essential, particularly when MTX is combined with other DMARDs. Folate supplementation can reduce some of the most common side effects of MTX, but it has not yet been established whether this translates into a reduced risk of serious disease. Another potential approach to reducing the toxicity of MTX is therapeutic drug monitoring and dose individualization. However, correlations between pharmacokinetics and clinical response have been addressed in only a few studies and with conflicting results. CONCLUSIONS: MTX is an effective DMARD with a relatively safe profile compared with other therapies. Folate supplementation can significantly reduce the risk of MTX toxicity. Finally, it is essential that patients be monitored carefully to reduce the potential serious toxicities of MTX.     

来氟米特及甲氨蝶呤对早期严重类风湿关节炎的治疗作用

目的研究来氟米特及甲氨蝶呤联合运用对早期严重类风湿关节炎临床症状，特别是对关节损害的作用。方法108例早期严重类风湿关节炎患者随机分为来氟米特组、来氟米特＋甲氨蝶呤组及来氟米特＋羟氯喹组，治疗前作相应的临床、实验室及影像学检查，以来氟米特30mg／d，连续2天后改为20mg／d，甲氨蝶呤10mg／w，羟氯喹400mg／d治疗12个月后，再评价患者临床、实验室及影像学的改变。结果来氟米特组、来氟米特＋甲氨蝶呤组及来氟米特＋羟氯喹组治疗12个月后，关节疼痛数明显减少，关节肿胀亦得到明显改善，晨僵时间显著缩短，其中尤以来氟米特＋甲氨蝶呤效果明显。关节侵蚀及Larsen-Dale积分在来氟米特＋甲氨蝶呤组改善亦较其他两组显著。但血沉及C反应蛋白改变不显著。结论来氟米特及甲氨蝶呤联合运用对早期类风湿关节炎的临床症状及关节损害的改善具有明显的效果。     

双醋瑞因联合甲氨蝶呤治疗老年类风湿关节炎的临床分析

目的探讨双醋瑞因联合甲氨蝶呤治疗老年类风湿关节炎患者的临床疗效。方法回顾性分析2017年11月-2020年11月在河北北方学院附属第一医院住院治疗的100例老年类风湿关节炎患者的临床资料,根据不同的治疗方法分为试验组(n=50)和对照组(n=50)。对照组采用甲氨蝶呤治疗,试验组采用双醋瑞因联合甲氨蝶呤治疗。2组疗程均为12周。观察并比较2组治疗前后炎性细胞因子[白细胞介素-1(IL-1)、转化生长因子-β(TGF-β)]表达水平、红细胞沉降率(ESR)和类风湿因子(RF)表达水平、相关临床症状指标(关节肿胀个数、关节压痛个数及晨僵持续时间)、关节功能分级及不良反应。结果治疗12周后,2组IL-1、ESR、RF表达水平均较本组治疗前明显下降(P<0.05),TGF-β较本组治疗前明显上升(P<0.05),关节肿胀个数、关节压痛个数及晨僵持续时间较本组治疗前明显降低(P<0.05),且试验组IL-1、ESR、RF表达水平均较对照组明显下降(P<0.05),TGF-β较对照组明显上升(P<0.05),关节肿胀个数、关节压痛个数及晨僵持续时间较对照组明显降低(P<0.05)。2组治疗后关节功能分级差异无统计学意义(P>0.05)。结论双醋瑞因联合甲氨蝶呤可有效的降低老年类风湿关节炎患者炎性水平,恢复自身免疫系统平衡,减少关节疼痛和肿胀,减少晨僵时间,但未能改善已受损的关节功能。     

Efficacy and safety of tofacitinib in Japanese patients with rheumatoid arthritis by background methotrexate dose: A post hoc analysis of clinical trial data

Abstract

Objectives: Tofacitinib is an oral JAK inhibitor for the treatment of rheumatoid arthritis (RA). We investigated concomitant methotrexate (MTX) dose on tofacitinib efficacy/safety in Japanese RA patients.

Methods: This post hoc analysis pooled data from a 3-month phase 2 study (NCT00603512) and a 24-month phase 3 study (NCT00847613). Patients (N= 254) received tofacitinib (low-dose (1 or 3?mg), 5?mg, 10?mg) twice daily (BID) or placebo, with low-dose (>0 to 8?mg/week) or high-dose (>8?mg/week) MTX. Efficacy (ACR20/50/70 and DAS28-4 (ESR)<2.6 response rates; changes from baseline (CFB) in DAS28-4 (ESR) and HAQ-DI) and safety (adverse events (AEs), discontinuations due to AEs, serious AEs, and deaths) were assessed through month 3.

Results: At month 3, ACR20/50/70 response rates, mean DAS28-4 (ESR) CFB and HAQ-DI CFB were similar across MTX doses and generally greater for all tofacitinib doses versus placebo. AE rates with low-dose/high-dose MTX were: placebo, 28.6%/52.9%; tofacitinib low-dose, 50.0%/66.7%; 5?mg BID, 56.5%/64.3%; 10?mg BID, 73.8%/67.7%.

Conclusion: Tofacitinib efficacy in Japanese RA patients may be unaffected by background MTX dose. AE rates with low-dose versus high-dose MTX were lower with placebo, tofacitinib low-dose or 5?mg BID, but not 10?mg BID, with no apparent differences across system organ class/laboratory parameters.     

Infliximab versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a preliminary study from China

Aim: To report the efficacy and safety of infliximab in the treatment of active rheumatoid arthritis (RA) in Chinese patients. Methods: This is a multicentre double‐blind placebo controlled study. Patients with active RA despite being on a stable dose of methotrexate were randomly assigned to receive either infliximab 3 mg/kg body weight or placebo infusion at weeks 0, 2, 6 and 14. All patients continued their stable dose of methotrexate throughout the study. Patients were assessed at weeks 0, 2, 6, 14 and 18 for the American College of Rheumatology (ACR) 20%, 50% and 70% response (ACR20, 50 and 70, respectively). Health assessment questionnaire (HAQ), erythrocyte sedimentation rate (ESR), c‐reactive protein (CRP), duration of morning stiffness and adverse effects were monitored. Results: Infliximab was effective in improving the disease activity of RA with significant ACR20 response observed at week 2 (infliximab vs. placebo 52.87%vs. 13.95%, P < 0.05). Significant differences in the ACR20 and ACR50 response rates between the two treatment groups were also observed at week 18 (75.86% and 43.68% of patients receiving infliximab vs. 48.84% and 25.58% and 13.95% of patients on placebo, P = 0.0003 and P = 0.011, respectively). Infliximab was generally well tolerated. The rate of adverse events and withdrawal due to adverse events were similar between the two groups. Most adverse reactions were transient. One patient in the infliximab group developed tuberculosis during the study. One patient in the placebo group developed antinuclear antibodies without obvious signs of systemic lupus erythematosus. Conclusion: In this preliminary study, infliximab infusions, at a dose of 3 mg/kg body weight given at various intervals over 14 weeks, were effective in controlling the signs and symptoms of active RA in Chinese. Infliximab also appeared to be well tolerated. Further studies involving a larger number of patients over a more prolonged period will further evaluate the long‐term efficacy and safety of infliximab in this group of patients.     

ORIGINAL ARTICLE: Lack of association between elevated mean red cell volume and haematological toxicity in patients receiving long‐term methotrexate for rheumatoid arthritis

Aims: It has been suggested that elevated mean red cell volume (MCV) may be a predictor of haematological toxicity in rheumatoid arthritis (RA) patients receiving methotrexate (MTX). We wished to identify whether there was an association between MCV, red cell folate and haematological toxicity in patients on MTX monotherapy for the long‐term management of RA. Methods: Evidence of haematological toxicity was sought by note review of patients recruited in a cross‐sectional study of MTX monotherapy in RA. Retrospective data included MCVs from before MTX initiation and after 3 and 6 months of treatment. Data were collected prospectively every 6 months for up to 2 years after enrolment. Any record of cytopenia or the development of haematological malignancy was recorded from commencement of MTX until the present day. Red cell folate concentrations were tested on enrolment to the study. Results: A total of 165 patients was included, 74.5% female, median disease duration 7 years (range 3 months–57 years). The median duration of MTX treatment was 74.9 months (range 10–241 months) giving 1030.2 patient‐years of MTX exposure. Twenty‐four patients (14.5%) had a MCV > 98 fL on study entry. Evidence of haematological abnormality was found in six patients (3.6%); chronic lymphocytic leukaemia (1), persistent lymphocytosis (1), persistent monocytosis (1) and neutropenia (3). There was no association between red cell folate or MCV and haematological toxicity. Conclusion: Neutropenia and pancytopenia are rare side‐effects of MTX therapy in this cohort. Elevated MCV or low mean red cell folate does not appear to be associated with haematological malignancy or toxicity in this cohort of patients on long‐term MTX therapy.     

Leflunomide in Pakistani patients with rheumatoid arthritis: prospective study in daily rheumatology practice

Introduction: Leflunomide is a disease‐modifying anti‐rheumatic drug (DMARD) for rheumatoid arthritis (RA). It has been widely studied in the West but there is no available local Pakistani data. Objective: To evaluate the efficacy and safety profile of leflunomide in Pakistani patients with RA, either alone or in combination with methotrexate. Materials and methods: A prospective, non‐comparator, open‐label study in a setting of ‘care as usual’ was performed. In this study, 63 consecutive RA patients on leflunomide were enrolled. Leflunomide dose was started with full loading in 5 (8%), half loading in 39 (62%) and without loading in 19 (30%) patients. Methotrexate was also used in 20 (32%) patients. Primary end‐point was 20% improvement in American College of Rheumatology response criteria (ACR‐20). Safety was assessed by adverse events and abnormalities in laboratory parameters. Results: Out of 63 patients, 54 (85.7%) were female. Mean age was 46 ± 12.6 years. Mean disease duration was 5.1 ± 4.5 years. Fifty‐two (86.6%) patients achieved ACR‐20 response at 6 months; 32 (53%) achieved ACR‐50 response at 6 months; 20% experienced at least one adverse event, which resolved by reducing leflunomide dose. Only seven (11%) had raised liver enzymes from baseline. Conclusion: This prospective study conducted in the setting of a daily rheumatology practice shows that leflunomide is an effective and safe DMARD in treatment of RA in Pakistani patients.     

Clinical efficacy and safety of methotrexate compared with leflunomide in the treatment of rheumatoid arthritis: A protocol for systematic review and meta-analysis

Background:Methotrexate and leflunomide are classic treatments for rheumatoid arthritis (RA), however, which is the best choice for patients of RA is still an important question clinically, and this meta-analysis is used to systematically evaluate and compare their efficacy and safety.Methods:We searched PubMed, Cochrance Library, Embase, SinoMed, China National Knowledge Infrastructure, China Science and Technology Journal Database, WanFang Data databases. The retrieval time was from the establishment to September 7, 2021. Literature screening, data extraction, and quality assessment were performed according to the Cochrane risk of bias tool. Meta-analysis of the included studies was performed using RevMan 5.3 software and Stata 12.0 software.Results:The clinical efficacy and safety of leflunomide and methotrexate are evaluated by American College of Rheumatology (ACR)20/50/70, DAS28, total effective rate, adverse reaction rate, morning stiffness, swollen joint count, tender joint count, erythrocyte sedimentation rate, C-reactive protein, and rheumatoid factor.Conclusion:The results of this meta-analysis will provide reliable evidence clinical efficacy and safety for RA. More high-quality randomized controlled trials are still needed to provide more reliable evidence for the treatment of RA.PROSPERO number:CRD42021270980     

Rheumatoid arthritis and Hailey-Hailey disease treated with methotrexate

We report a rare case of long-standing Hailey-Hailey disease in a Caucasian Portuguese 69-year-old woman, recently diagnosed with rheumatoid arthritis. The patient's skin lesions remained active and exudative despite topical and oral treatments with corticosteroids, tetracyclines, antifungals, and oral treatment with azathioprine. After introduction of methotrexate for rheumatoid arthritis treatment, the skin lesions regressed, with significant impact on the patient's quality of life. This case report supports the clinical evidence of methotrexate's potential role in Hailey-Hailey disease treatment.     

Assessing joint destruction in the knees of patients with rheumatoid arthritis by using a semi-automated software for magnetic resonance imaging: therapeutic effect of methotrexate plus etanercept compared with methotrexate monotherapy

Objectives: To evaluate the prevention of knee joint destruction and clinical efficacy of methotrexate (MTX) plus etanercept (ETN) compared with MTX monotherapy in patients with rheumatoid arthritis (RA) by using semi-automated software for magnetic resonance imaging (MRI) scan analysis.

Materials and methods: This study enrolled patients with active moderate-to-severe RA who displayed an inadequate response to oral MTX at screening. Patients were assigned to receive either MTX plus ETN or MTX monotherapy (≥10?mg/week). The primary endpoint was the quantitative knee cartilage volume using our software developed for MRI scan analysis.

Results: A total of 18 female patients were enrolled in this study and allocated to the MTX?+?ETN group (n?=?9) or the MTX monotherapy group (n?=?9). At 52 weeks, the quantitative knee cartilage volume was significantly reduced compared with baseline in both groups (MTX plus ETN group: 2.3?±?2.3?cm³; MTX monotherapy group: 2.4?±?1.6?cm³); however, the difference was not significant.

Conclusion: The semi-automated software for MRI scan analysis can reveal useful and potentially clinically important information about the characteristics of knee joint destruction in patients with RA.     

Reduction of methotrexate and glucocorticoids use after the introduction of biological disease-modifying anti-rheumatic drugs in patients with rheumatoid arthritis in daily practice based on the IORRA cohort

Objectives: To evaluate usage patterns for methotrexate (MTX) and/or glucocorticoids in rheumatoid arthritis (RA) patients receiving biological disease-modifying antirheumatic drugs (bDMARDs) in daily practice.

Methods: Data from RA patients who commenced treatment with bDMARDs (infliximab [IFX], etanercept [ETN], tocilizumab [TCZ], or adalimumab [ADA]) from 2008 to 2010 were extracted from the Institute of Rheumatology, Rheumatoid Arthritis (IORRA) database. The proportions of patients taking concomitant MTX and glucocorticoids and doses of these medications were evaluated before and 2 years after initiation of each bDMARD.

Results: A total of 470 RA patients who had initiated a bDMARD (IFX: n?=?98, ETN: n?=?181, TCZ: n?=?90, and ADA: n?=?101) were evaluated. The proportion of patients taking MTX decreased over time among ETN and TCZ users, while it increased among ADA users. The MTX dose decreased over time among IFX, ETN, and TCZ users, but not among ADA users. Although the rate of glucocorticoid use and dose decreased after bDMARD initiation in all four bDMARD groups, approximately 50% of patients continued to receive glucocorticoids 2 years after bDMARD initiation.

Conclusion: MTX and glucocorticoid use and doses in daily practice were commonly reduced after the initiation of bDMARDs, with the dose adjustment varied depending on the bDMARD.     

A case of emphysematous pyelonephritis in a patient with rheumatoid arthritis taking corticosteroid and low‐dose methotrexate

Rheumatoid arthritis (RA) is a systemic autoimmune disease that is characterized by chronic synovial inflammation. Patients with RA have increased risk of infection; this is related to RA itself or the adverse effects of medication. In this report, we describe a case of emphysematous pyelonephritis in a patient with RA associated with AA amyloidosis and steroid‐induced diabetes mellitus who was taking corticosteroid and low‐dose methotrexate.