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The Cochrane Database of Systematic... Feb 2024Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease in childhood. Methotrexate has broad immunomodulatory properties and is the most commonly used... (Review)
Review
BACKGROUND
Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease in childhood. Methotrexate has broad immunomodulatory properties and is the most commonly used disease-modifying antirheumatic drug (DMARD). This is an update of a 2001 Cochrane review. It supports a living guideline for children and young people with JIA.
OBJECTIVES
To assess the benefits and harms of methotrexate for children and young people with juvenile idiopathic arthritis.
SEARCH METHODS
The Australian JIA Living Guideline Working Group created a registry of all randomised controlled trials (RCTs) of JIA by searching CENTRAL, MEDLINE, Embase, and trials registries. The date of the most recent search of online databases was 1 February 2023.
SELECTION CRITERIA
We searched for RCTs that compared methotrexate with placebo, no treatment, or another DMARD (with or without concomitant therapies) in children and young people (aged up to 18 years) with JIA.
DATA COLLECTION AND ANALYSIS
We used standard Cochrane methods. The main comparison was methotrexate versus placebo. Our outcomes were treatment response, sustained clinically inactive disease, function, pain, participant global assessment of well-being, serious adverse events, and withdrawals due to adverse events. We used GRADE to assess the certainty of evidence for each outcome.
MAIN RESULTS
We identified three new trials in this update, bringing the total number of included RCTs to five (575 participants). Three trials evaluated oral methotrexate versus placebo, one evaluated methotrexate plus intra-articular glucocorticoid (IAGC) therapy versus IAGC therapy alone, and one evaluated methotrexate versus leflunomide. Doses of methotrexate ranged from 5 mg/m/week to 15 mg/m/week in four trials, and participants in the methotrexate group of the remaining trial received 0.5 mg/kg/week. Trial size varied from 31 to 226 participants. The average age of participants ranged from four to 10 years. Most participants were females and most had nonsystemic JIA. The study that evaluated methotrexate plus IAGC therapy versus IAGC therapy alone recruited children and young people with the oligoarticular disease subtype of JIA. Two placebo-controlled trials and the trial of methotrexate versus leflunomide were adequately randomised and blinded, and likely not susceptible to important biases. One placebo-controlled trial may have been susceptible to selection bias due to lack of adequate reporting of randomisation methods. The trial investigating the addition of methotrexate to IAGC therapy was susceptible to performance and detection biases. Methotrexate versus placebo Methotrexate compared with placebo may increase the number of children and young people who achieve treatment response up to six months (absolute difference of 163 more per 1000 people; risk ratio (RR) 1.67, 95% confidence interval (CI) 1.21 to 2.31; I = 0%; 3 trials, 328 participants; low-certainty evidence). However, methotrexate compared with placebo may have little or no effect on pain as measured on an increasing scale of 0 to 100 (mean difference (MD) -1.10 points, 95% CI -9.09 to 6.88; 1 trial, 114 participants), improvement in participant global assessment of well-being (absolute difference of 92 more per 1000 people; RR 1.23, 95% CI 0.88 to 1.72; 1 trial, 176 participants), occurrence of serious adverse events (absolute difference of 5 fewer per 1000 people; RR 0.63, 95% CI 0.04 to 8.97; 3 trials, 328 participants), and withdrawals due to adverse events (RR 3.46, 95% CI 0.60 to 19.79; 3 trials, 328 participants) up to six months. We could not estimate the absolute difference for withdrawals due to adverse events because there were no withdrawals in the placebo group. All outcomes were reported within six months of randomisation. We downgraded the certainty of the evidence to low for all outcomes due to indirectness (suboptimal dosing of methotrexate and diverse outcome measures) and imprecision (few participants and low event rates). No trials reported function or the number of participants with sustained clinically inactive disease. Serious adverse events included liver derangement, abdominal pain, and inadvertent overdose. Methotrexate plus intra-articular corticosteroid therapy versus intra-articular corticosteroid therapy alone Methotrexate plus IAGC therapy compared with IAGC therapy alone may have little or no effect on the probability of sustained clinically inactive disease or the rate of withdrawals due to adverse events up to 12 months in children and young people with the oligoarticular subtype of JIA (low-certainty evidence). We could not calculate the absolute difference in withdrawals due to adverse events because there were no withdrawals in the control group. We are uncertain if there is any difference between the interventions in the risk of severe adverse events, because none were reported. The study did not report treatment response, function, pain, or participant global assessment of well-being. Methotrexate versus an alternative disease-modifying antirheumatic drug Methotrexate compared with leflunomide may have little or no effect on the probability of treatment response or on function, participant global assessment of well-being, risk of serious adverse events, and rate of withdrawals due to adverse events up to four months. We downgraded the certainty of the evidence for all outcomes to low due to imprecision. The study did not report pain or sustained clinically inactive disease.
AUTHORS' CONCLUSIONS
Oral methotrexate (5 mg/m/week to 15 mg/m/week) compared with placebo may increase the number of children and young people achieving treatment response but may have little or no effect on pain or participant global assessment of well-being. Oral methotrexate plus IAGC injections compared to IAGC injections alone may have little or no effect on the likelihood of sustained clinically inactive disease among children and young people with oligoarticular JIA. Similarly, methotrexate compared with leflunomide may have little or no effect on treatment response, function, and participant global assessment of well-being. Serious adverse events due to methotrexate appear to be rare. We will update this review as new evidence becomes available to inform the living guideline.
Topics: Child; Female; Humans; Adolescent; Aged; Child, Preschool; Male; Methotrexate; Arthritis, Juvenile; Leflunomide; Australia; Antirheumatic Agents; Glucocorticoids; Pain
PubMed: 38334147
DOI: 10.1002/14651858.CD003129.pub2 -
RMD Open Jan 2024An important consideration in the treatment of patients with psoriatic arthritis (PsA) is whether the addition of methotrexate (MTX) to biologics has greater efficacy... (Meta-Analysis)
Meta-Analysis
INTRODUCTION
An important consideration in the treatment of patients with psoriatic arthritis (PsA) is whether the addition of methotrexate (MTX) to biologics has greater efficacy than biologic monotherapy with respect to efficacy outcomes in these patients.
OBJECTIVES
To conduct a network meta-analysis (NMA) comparing biologics by treatment class with and without MTX for treatment of adults with active PsA.
METHODS
A systematic literature review (SLR) identified randomised, double-blinded, controlled trials, and a Bayesian NMA compared biologics with and without MTX by treatment class (tumour necrosis factor inhibitors (TNFi), interleukin-23 inhibitors (IL-23i) and IL-17i). Efficacy outcomes included American College of Rheumatology 20%, 50% and 70% (ACR20, ACR50 and ACR70) improvement response.
RESULTS
The SLR initially identified 31 studies, of which 17 met feasibility criteria for the NMA by containing the 'without MTX' subgroup. For ACR20 efficacy (the most robust assessment examined), all active treatments were significantly better than placebo. No statistically significant differences were demonstrated between biologic monotherapy (for all classes examined) and biologics in combination with MTX for ACR20/50. IL-17i were comparable to IL-23i, and IL-17i were significantly better than TNFi for ACR20. Although limited by fewer trials, TNFi, IL-23i and IL-17i were not statistically different for ACR50/70.
CONCLUSIONS
Concomitant use of MTX and biologics did not improve ACR efficacy outcomes versus biologic monotherapy. MTX does not appear to be necessary as a background therapy when biologics are used for the achievement of ACR20/50 responses in patients with PsA.
Topics: Adult; Humans; United States; Methotrexate; Antirheumatic Agents; Arthritis, Psoriatic; Arthritis, Rheumatoid; Antibodies, Monoclonal; Network Meta-Analysis; Bayes Theorem; Tumor Necrosis Factor Inhibitors; Biological Products
PubMed: 38296801
DOI: 10.1136/rmdopen-2023-003423 -
Oral regimen for high dose methotrexate urine alkalinization: a systematic review and meta-analysis.Daru : Journal of Faculty of Pharmacy,... Jun 2024Urine alkalinization prevents nephrotoxicity in patients receiving high-dose methotrexate (HDMTX). While the standard approach involves IV sodium bicarbonate,... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
Urine alkalinization prevents nephrotoxicity in patients receiving high-dose methotrexate (HDMTX). While the standard approach involves IV sodium bicarbonate, alternative oral bicarbonate regimens are crucial in drug shortages and outpatient settings. This study aims to review the efficacy and safety of such regimens.
METHODS
PubMed, WOS, and Scopus were systematically searched using the PRISMA protocol for relevant studies involving human subjects, including randomized clinical trials, retrospective, prospective, cohort, case reports, and case series studies. There were no restrictions on language, time, or age group. Qualified and eligible papers were used to extract data on efficacy and safety indicators, and the final relevant records were assessed for quality using the Risk of Bias in Non-Randomized Studies-of Interventions (ROBINS-I) assessment tool.
RESULTS
12 studies with 1212 participants were included in the systematic review, with pooled data from 8 studies used for meta-analysis. No significant differences in mean differences (MDs) or odds ratio (OR) were found after the oral bicarbonate regimen, except for when urine pH fell to < 7 (MD: 0.91, 95% CI: 0.32, 1.5, P < 0.05) and the incidence of diarrhea (OR: 2.92, 95% CI: 1.69, 5.05, P < 0.05).
CONCLUSION
An oral bicarbonate regimen is a safe and effective way to alkalize HDMTX urine, providing a viable and cost-effective alternative to IV protocols. Further prospective multicenter studies are necessary. Systematic review registration identifier: CRD42023379666.
Topics: Humans; Methotrexate; Administration, Oral; Sodium Bicarbonate; Hydrogen-Ion Concentration; Urine
PubMed: 38233724
DOI: 10.1007/s40199-023-00499-3 -
World Journal of Surgical Oncology Jan 2024We aimed to provide a reference based on evidence for an individualized clinical medication of high-dose methotrexate (HD-MTX) in osteosarcoma patients by evaluating the... (Meta-Analysis)
Meta-Analysis
OBJECTIVE
We aimed to provide a reference based on evidence for an individualized clinical medication of high-dose methotrexate (HD-MTX) in osteosarcoma patients by evaluating the effect of gene polymorphism on adverse reactions of HD-MTX usage.
METHODS
Several databases were combed for research on the association between gene polymorphisms and adverse reactions to HD-MTX up to January 2023. A meta-analysis and/or descriptive analysis on the incidence of HD-MTX-related adverse reactions were conducted by using clinical studies meeting inclusion criteria.
RESULTS
Twelve studies involving 889 patients were included. There were 8, 6, 5, and 4 studies related to MTHFR C677T, MTHFR A1298C, RFC1 G80A, and MDR1 C3435T polymorphisms, respectively. The results of the meta-analysis showed that the MTHFR C677T polymorphism was associated with G3-4 hepatotoxicity, G3-4 nephrotoxicity, G3-4 gastrointestinal toxicity, and G3-4 mucositis under the recessive genetic model (MM vs. Mm/mm). Limited research showed that MTHFR C677T was associated with G3-4 nephrotoxicity in the allelic genetic model (M vs. m). MTHFR A1298C polymorphism was associated with a decreased risk of adverse reactions to HD-MTX usage, without statistical significance. This review's descriptive analysis showed no significant correlation between the RFC1 G80A, and MDR1 C3435T polymorphism and adverse reactions of HD-MTX.
CONCLUSION
The MTHFR C677T mutation may enhance the risk of HD-MTX adverse reactions in osteosarcoma patients. Existing studies have not found a significant correlation between the MTHFR A1298C, RFC1 G80A, and MDR1 C3435T polymorphism and adverse reactions caused by HD-MTX. Lastly, this conclusion was limited because of few studies.
Topics: Humans; Methotrexate; Polymorphism, Genetic; Alleles; Methylenetetrahydrofolate Reductase (NADPH2); Osteosarcoma; Polymorphism, Single Nucleotide; Genotype
PubMed: 38212758
DOI: 10.1186/s12957-023-03287-0 -
Advances in Therapy Feb 2024Immune-mediated inflammatory diseases including rheumatoid arthritis (RA), psoriatic arthritis (PsA), ankylosing spondylitis (AS), non-radiographic axial... (Review)
Review
Safety of Upadacitinib in Immune-Mediated Inflammatory Diseases: Systematic Literature Review of Indirect and Direct Treatment Comparisons of Randomized Controlled Trials.
INTRODUCTION
Immune-mediated inflammatory diseases including rheumatoid arthritis (RA), psoriatic arthritis (PsA), ankylosing spondylitis (AS), non-radiographic axial spondylarthritis (nr-axSpA), atopic dermatitis (AD), ulcerative colitis (UC), and Crohn's disease (CD) pose a substantial burden on patients and their quality of life. Upadacitinib is an orally administered, selective, and reversible Janus kinase inhibitor indicated for seven conditions, but data on its safety versus other active treatments are limited. A systematic literature review of indirect and direct treatment comparisons of randomized controlled trials (RCTs) was conducted to assess the safety profile of upadacitinib.
METHODS
MEDLINE, Embase, and Cochrane Library databases were searched for indirect and direct treatment comparisons of RCTs that (1) included licensed upadacitinib dosages; (2) studied any of the seven conditions; (3) reported any adverse events (AEs), serious AEs (SAEs), AEs leading to discontinuation, major adverse cardiovascular event, venous thromboembolism, malignancies, infections or serious infections, and death; and (4) were published between January 2018 and August 2022.
RESULTS
A total of 25 studies were eligible for inclusion. SAEs, AEs leading to discontinuation, and any AEs were commonly studied. RA was the most studied condition, followed by AD and UC. Most studies (16/25, 64%) reported no statistically significant difference in the studied safety outcomes between upadacitinib and other active treatments (e.g., tumor necrosis factor blockers, interleukin receptor antagonists, integrin receptor antagonists, T cell co-stimulation modulator), or placebo (placebo ± methotrexate or topical corticosteroids). Other studies (9/25, 36%) reported mixed results of no statistically significant difference and either statistically higher (8/25, 32%) or lower rates (1/25, 4%) on upadacitinib.
CONCLUSION
Most studies suggested that upadacitinib has no statistically significant difference in the studied safety outcomes compared to active treatments or placebo in patients with RA, PsA, AS, AD, UC, and CD. A few studies reported higher rates, but findings were inconsistent with limited interpretation.
Topics: Humans; Arthritis, Psoriatic; Arthritis, Rheumatoid; Colitis, Ulcerative; Heterocyclic Compounds, 3-Ring; Methotrexate; Randomized Controlled Trials as Topic; Spondylitis, Ankylosing
PubMed: 38169057
DOI: 10.1007/s12325-023-02732-6 -
The Journal of Dermatological Treatment Dec 2024Methotrexate is an off-label therapy for atopic dermatitis. A lack of consensus on dosing regimens poses a risk of underdosing and ineffective treatment or overdosing... (Review)
Review
Methotrexate is an off-label therapy for atopic dermatitis. A lack of consensus on dosing regimens poses a risk of underdosing and ineffective treatment or overdosing and increased risk of side effects. This systematic review summarizes the available evidence on dosing regimens.A literature search was conducted, screening all randomized controlled trials (RCTs) and guidelines published up to 6 July 2023, in the MEDLINE, Embase, and Cochrane Library databases.Five RCTs and 21 guidelines were included. RCTs compared methotrexate with other treatments rather than different methotrexate dosing regimens. The start and maintenance doses in RCTs varied between 7.5-15 mg/week and 14.5-25 mg/week, respectively. Despite varied dosing, all RCTs demonstrated efficacy in improving atopic dermatitis signs and symptoms. Guidelines exhibited substantial heterogeneity but predominantly proposed starting doses of 5-15 mg/week for adults and 10-15 mg/m/week for children. Maintenance doses suggested were 7.5-25 mg/week for adults and 0.2-0.7 mg/kg/week for children. One guideline suggested a test dose and nearly half advised folic acid supplementation.This systematic review highlights the lack of methotrexate dosing guidelines for atopic dermatitis. It identifies commonly recommended and utilized dosing regimens, serving as a valuable resource for clinicians prescribing methotrexate off-label and providing input for an upcoming consensus study.
Topics: Adult; Child; Humans; Methotrexate; Dermatitis, Atopic
PubMed: 38124505
DOI: 10.1080/09546634.2023.2292962 -
Immunotherapy Feb 2024Oral conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), especially methotrexate, are the cornerstone of treating psoriatic arthritis (PsA). The... (Review)
Review
Oral conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), especially methotrexate, are the cornerstone of treating psoriatic arthritis (PsA). The use of csDMARDs with biologics has increased their efficacy in psoriasis. However, the combination of two oral DMARDs in patients with PsA has not been adequately reviewed. In this study, we explore the combinational use of methotrexate with DMARDs in PsA patients. A review was conducted using Medline (PubMed), Embase, Web of Science and the Cochrane Library, covering articles up to February 2023. Nine studies comprising 1993 participants were included. The evidence supporting combination therapy remains limited. Combinational therapy could be considered in patients with inadequate response to monotherapy or no access to biologics.
Topics: Humans; Antirheumatic Agents; Methotrexate; Arthritis, Psoriatic; Psoriasis; Biological Products
PubMed: 38112064
DOI: 10.2217/imt-2023-0139 -
BMC Ophthalmology Nov 2023Vitreoretinal lymphoma (VRL) is usually treated with a combination of intraocular methotrexate (ioMTX), high-dose intravenous methotrexate (HD-MTX), or local... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Vitreoretinal lymphoma (VRL) is usually treated with a combination of intraocular methotrexate (ioMTX), high-dose intravenous methotrexate (HD-MTX), or local radiotherapy (RT) as the first options. The effectiveness and safety of monotherapy like bruton's tyrosine kinase inhibitors (BTKi) for PVRL remain uncertain.
METHODS
A systematic review and meta-analysis of clinical trial data and conference abstracts in VRL patients treated with first-line combination therapy or monotherapy were conducted through a search of PubMed, Embase, and Scopus databases until December 2022. A total of 24 studies comprising 517 patients were included, and survival data were extracted from 279 patients due to inconsistent units across studies.
RESULTS
The combined treatment group used ioMTX + chemotherapy (in 4 studies), RT + chemotherapy (in 2 studies), ioMTX/HD-MTX based regimen (in 2 studies), ioMTX + RT + chemotherapy (in 2 studies), ioMTX + lenalidomide/BTKi (in 2 studies) and combination of multiple therapies (in 7 studies). The monotherapy group was mainly treated with oral monotherapies such as BTKi. The combination therapy had a higher overall response rate (ORR) and complete response rate (CRR) than monotherapy (ORR: 96% vs. 72%, CRR: 92% vs. 63%). Combination therapy also resulted in a longer median progression-free survival (28.8 months vs. 13 months, p = 0.012). However, the combination therapy group had more severe side effects (grade 3/4 toxicity) than the monotherapy group (45% vs. 8%).
CONCLUSION
The study showed combination therapy had better OR and CR rates, longer survival, and more toxicity than monotherapy. While BTK inhibitors were well-tolerated, long-term effectiveness needs confirmation from prospective studies. In addition, given the small number of studies of monotherapy for VRL, more studies are needed to validate its effects.
TRIAL REGISTRATION
CRD42023400305.
Topics: Humans; Methotrexate; Retinal Neoplasms; Prospective Studies; Vitreous Body; Central Nervous System Neoplasms; Lymphoma
PubMed: 37993841
DOI: 10.1186/s12886-023-03226-3 -
European Journal of Clinical... Jan 2024To develop a population pharmacokinetic (PPK) model for methotrexate (MTX) dosage for all ages, assess the association between concentration and clearance, and determine... (Meta-Analysis)
Meta-Analysis Review
PURPOSE
To develop a population pharmacokinetic (PPK) model for methotrexate (MTX) dosage for all ages, assess the association between concentration and clearance, and determine covariates affecting MTX disposition.
METHODS
We compared MTX PK profiles among neonates, children, and adults by performing a systematic literature search for published population MTX models and conducted a Monte Carlo-based meta-analysis. Subsequently, we evaluated study quality and covariates significantly affecting dosage regimens and compared LDMTX and HDMTX PK profiles.
RESULTS
Of the total 40 studies included, 34 were HDMTX, and six were LDMTX studies. For HDMTX, three studies involving neonates reported estimated apparent clearances (median, range) of 0.53 (0.27-0.77) L/kg/h; for 14 studies involving children, 0.23 (0.07-0.23) L/kg/h; and for 13 involving adults, 0.11 (0.03-0.22) L/kg/h. Neonates had a higher volume of distribution than children and adults. For LDMTX studies, apparent clearance was 0.085 (0.05-1.68) L/kg/h, and volume of distribution was 0.25 (0.018-0.47) L/kg, lower than those of HDMTX studies, with large between-subject variability. Bodyweight significantly influenced apparent clearance and volume of distribution, whereas renal function mainly influenced clearance. Mutations in certain genes reduced MTX clearance by 8-35.3%, whereas those in others increased it by 15-48%. Body surface area (BSA) significantly influenced apparent clearance with a median reduction of 51% when BSA increased in pediatric patients.
CONCLUSIONS
Methotrexate dosage regimens were primarily based on body surface area and renal function. Further studies are needed to evaluate MTX pharmacokinetics and pharmacodynamics in both children (especially infants) and adults.
Topics: Adult; Infant; Infant, Newborn; Humans; Child; Methotrexate; Antimetabolites, Antineoplastic
PubMed: 37934204
DOI: 10.1007/s00228-023-03579-0 -
Journal of Lower Genital Tract Disease Jan 2024Lichen sclerosus (LS) is a chronic, inflammatory process affecting predominantly anogenital skin, with extragenital involvement in up to 20% of cases. The mainstay of...
BACKGROUND
Lichen sclerosus (LS) is a chronic, inflammatory process affecting predominantly anogenital skin, with extragenital involvement in up to 20% of cases. The mainstay of therapy for anogenital LS is topical immunosuppression. However, in treatment-refractory cases, severe, or hypertrophic disease, systemic modalities may be used. Currently, there are no guidelines for systemic therapy in LS.
OBJECTIVE
This study aimed to provide a review of the current literature on use of systemic therapies for LS, including demographic and clinical features of LS, as well as reported outcomes.
METHODS
A primary literature search was conducted using the following databases: PubMed, Ovid, Scopus, and Web of Science, from the year the journal was published until June 2022.
RESULTS
Ultimately, 71 studies consisting of 392 patients were included. Of these, 65% (n = 254) had anogenital disease, 9% (n = 36) had extragenital disease, and 19% (n = 73) had both anogenital and extragenital disease, and in 7% (n = 29) of cases, location was not specified. The most frequent therapies, stratified by total cases, included oral retinoids (n = 227), methotrexate (n = 59), hydroxychloroquine (n = 36), and systemic steroids (prednisone, methylprednisolone, prednisolone, oral triamcinolone, and other systemic steroids) (n = 60). Overall, 76% (n = 194) of anogenital, 94% (n = 34) of extragenital, and 81% (n = 59) of patients with both anogenital and extragenital involvement were reported to have clinical or symptomatic improvement.
CONCLUSION
Overall, we found many therapies that have been used with reported success for extragenital and genital LS. However, future studies are needed to better define treatment outcomes and directly compare efficacy of different therapies for LS.
Topics: Humans; Lichen Sclerosus et Atrophicus; Methotrexate; Treatment Outcome; Skin; Steroids
PubMed: 37924260
DOI: 10.1097/LGT.0000000000000775