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Background: The main conventional systemic treatments for atopic dermatitis (AD) are methotrexate (MTX) and ciclosporin (CyA). Dupilumab was the first novel systemic agent to enter routine clinical practice. There are no head-to-head randomized controlled trials or real-world studies comparing these agents directly. Network meta-analyses provide indirect comparative efficacy and safety data and have shown strong evidence for dupilumab and CyA., Objectives: To compare the real-world clinical effectiveness and safety of CyA, dupilumab and MTX in AD., Methods: We compared the effectiveness and safety of these systemic agents in a prospective observational cohort study of adult and paediatric patients recruited into the UK-Irish Atopic eczema Systemic TherApy Register (A-STAR). Treatment effectiveness measures included Eczema Area and Severity Index (EASI), Patient-Oriented Eczema Measure (POEM), Peak Pruritus Numerical Rating Scale (PP-NRS), Dermatology Life Quality Index (DLQI) and children's DLQI (cDLQI). The minimum duration of treatment was 28 days and follow-up was 12 months. Adjusted Cox-regression analysis was used to compare the hazard ratios of achieving EASI-50, EASI-75 and EASI-90 over time, and linear mixed-effects models were used to estimate changes in efficacy scores. Treatment safety was assessed by examining adverse events (AEs) at follow-up visits., Results: We included 488 patients (311 adults and 177 children/adolescents) on dupilumab (n = 282), MTX (n = 149) or CyA (n = 57). CyA and MTX were primarily used as the first-line treatment, while dupilumab was mainly a second-line systemic treatment as per UK National Institute of Clinical and Care Excellence (NICE) recommendations. EASI-50, EASI-75 and EASI-90 were achieved more rapidly in the dupilumab and CyA groups compared with MTX. After adjustment for previous severity, the reduction in EASI, POEM, PP-NRS and DLQI was greater for patients treated with dupilumab compared with MTX. In patients with severe disease the reduction in EASI, POEM and PP-NRS was even greater with CyA. The incidence rates of AEs were similar across groups (734, 654 and 594 per 10 000 person-month on CyA, dupilumab and MTX, respectively)., Conclusions: This real-world comparison of CyA, dupilumab and MTX in AD suggests that dupilumab is consistently more effective than MTX and that CyA is most effective in very severe disease within 1 year of follow-up., Competing Interests: Conflicts of interest The full conflicts of interest statement is provided in Appendix 3., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Association of Dermatologists.)

Background: Undifferentiated arthritis (UA) is a term used to describe patients with inflammatory arthritis that has not differentiated into a specific rheumatic disease. UA may be a pre-stage of rheumatoid arthritis (RA) or another inflammatory disease or remain undifferentiated, but a substantial proportion of patients may also achieve spontaneous remission. As UA may be an early presentation of RA, rheumatologists often start methotrexate (or another csDMARD) as early as possible. There are however very little data on the potential benefits of early DMARD treatment, and longitudinal data suggests that long-term outcomes such as physical functioning hardly improved in these patients in the past decades. In the I CEA trial, we investigate if it is beneficial to start early treatment with MTX or baricitinib, a more rapidly acting drug with a broader mechanism of action, compared to waiting for spontaneous remission with symptomatic therapy in patients with UA., Methods: The I CEA is a multicenter single-blind (independent assessor) randomized clinical trial with a 3-month interventional and 9-month observational follow-up period. The study includes patients with early (< 1 year symptom duration) DMARD-naïve undifferentiated arthritis. Patients with an increased risk of AEs with baricitinib treatment are excluded. Participants are randomized 1:1:1 to (1) symptom relief with NSAIDs and a single injection of glucocorticoids and (waiting for spontaneous remission); (2) methotrexate and a single injection of glucocorticoids, and NSAIDs are optional; and (3) baricitinib and a single injection of glucocorticoids and NSAIDs are optional. During the observational follow-up period, patients are treated in shared decision with their rheumatologist. The primary outcome will be the change in DAS at 3 months. Secondary outcomes include radiographic progression, physical functioning, patient-reported outcomes, cost utilities, safety, progression to classifiable RA, and disease activity over time., Discussion: The 12-month I CEA trial studies early treatment of patients with UA with methotrexate, baricitinib, or NSAIDs. The study initially had a more complex design. Emerging safety warnings about baricitinib necessitated adjustment of the trial protocol including more extensive exclusion criteria. The number of included patients was lower than initially planned, supported by an updated sample size calculation., Trial Registration: Dutch trial register NL73202.058.20, EudraCT 2019-004359-35, registered 10-06-2020. Protocol version 1Q, 06-05-2024., Competing Interests: Declarations Ethics approval and consent to participate The study is carried out in compliance with the recommendations of the Declaration of Helsinki, GCP, and in accordance with local guidelines, regulations, and acts. The medical ethical committee of the Leiden University Medical Center (reference P20.027) and all other participating hospitals approved the trial. Patients give informed consent before they are randomized in the study. Competing interests SAB has received funding from Pfizer (payments made to the LUMC) and speaker fees from Benecke.FvG has received consulting fees from, Abbvie, ASAS, BMS, Galapagos, Janssen, Lilly, Novartis, Pfizer, and UCB with all payments made to the LUMC.RB received research grants from Galapagos and Sanofi and consulting fees from Abbvie, Galapagos, Janssen, Pfizer, and UCB.JavdP, LvO, IS, PdJ, HV, SB, YGR: none., (© 2024. The Author(s).)

Background: About 80% of children with steroid-sensitive nephrotic syndrome (SSNS) have relapses. Of these children, half will relapse frequently, and are at risk of adverse effects from corticosteroids. While non-corticosteroid immunosuppressive medications prolong periods of remission, they have significant potential adverse effects. Currently, there is no consensus about the most appropriate second-line agent in children with frequently relapsing SSNS. In addition, these medications could be used with corticosteroids in the initial episode of SSNS to prolong the period of remission. This is the fifth update of a review first published in 2001 and updated in 2005, 2008, 2013 and 2020., Objectives: To evaluate the benefits and harms of non-corticosteroid immunosuppressive medications in SSNS in children with a relapsing course of SSNS and in children with their first episode of nephrotic syndrome., Search Methods: We searched the Cochrane Kidney and Transplant Register of Studies up to October 2024 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Registry Platform (ICTRP) Search Portal and ClinicalTrials.gov., Selection Criteria: Randomised controlled trials (RCTs) or quasi-RCTs were included if they involved children with SSNS and compared non-corticosteroid immunosuppressive medications with placebo, corticosteroids or no treatment; different non-corticosteroid immunosuppressive medications, or different doses, durations or routes of administration of the same non-corticosteroid immunosuppressive medication., Data Collection and Analysis: Two authors independently assessed study eligibility, risk of bias and extracted data from the included studies. Statistical analyses were performed using a random-effects model and results expressed as risk ratio (RR) for dichotomous outcomes or mean difference (MD) for continuous outcomes with 95% confidence intervals (CI). Confidence in the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach., Main Results: We identified 58 studies (122 reports) randomising 3720 children. Half were multicentre studies, and most studies were undertaken in South and East Asia (28 studies) and Europe (20 studies). The numbers of children randomised ranged from 14 to 211. Risk of bias assessment indicated that 32 and 33 studies were at low risk of bias for sequence generation and allocation concealment, respectively. Eleven studies were at low risk of performance bias and 13 were at low risk of detection bias. Forty-eight and 36 studies were at low risk of incomplete and selective reporting, respectively. Rituximab with or without prednisone compared with placebo with or without prednisone probably reduces the number of children experiencing relapse at six months (5 studies, 182 children: RR 0.22, 95% CI 0.11 to 0.43) and 12 months (3 studies, 108 children: RR 0.38, 95% CI 0.13 to 1.09) (moderate certainty), may increase the number with severe infusion reactions (4 studies, 162 children: RR 5.21, 95% CI 1.19 to 22.89; low certainty), but not severe infection or arthropathy (low certainty). Rituximab compared with tacrolimus probably reduces the risk of relapse at 12 months (4 studies, 238 children: RR 0.64, 95% CI 0.42 to 0.96) and may reduce the risk of relapse when compared with low dose mycophenolate mofetil (MMF) (1 study, 30 children: RR 0.17, 95% CI 0.04 to 0.62). Rituximab followed by MMF for 500 days reduces the risk of relapse compared with rituximab followed by placebo for 500 days (1 study, 78 children: RR 0.29, 95% CI 0.13 to 0.63; high certainty). Rituximab probably does not differ from ofatumumab in the riisk of relapse and 12 months (1 study, 140 children: RR 1.03, 95% CI 0.75 to 1.41; moderate certainty) or in adverse events. MMF and levamisole (1 study, 149 children: RR 0.90, 95% CI 0.70 to 1.16) may have similar effects on the number of children who relapse at 12 months (low certainty). Cyclosporin compared with MMF may reduce the risk of relapse at 12 months (3 studies, 114 children: RR 1.57, 95% CI 1.08 to 2.30) (low certainty). Levamisole compared with steroids or placebo may reduce the number of children with relapse during treatment (8 studies, 474 children: RR 0.52, 95% CI 0.33 to 0.82) (low certainty). Preliminary data from single studies indicate that levamisole and prednisone compared with prednisone alone may delay the onset of relapse after the initial episode of SSNS and that levamisole compared with increasing prednisone administration from alternate day to daily at the onset of infection may reduce the risk of relapse with infection (low certainty). Cyclosporin compared with prednisone may reduce the number of children who relapse (1 study, 104 children: RR 0.33, 95% CI 0.13 to 0.83) (low certainty). Alkylating agents compared with cyclosporin may make little or no difference to the risk of relapse during cyclosporin treatment (2 studies, 95 children: RR 0.91, 95% CI 0.55 to 1.48) (low certainty evidence) but may reduce the risk of relapse at 12 to 24 months (2 studies, 95 children: RR 0.51, 95% CI 0.35 to 0.74) (low certainty). Alkylating agents (cyclophosphamide and chlorambucil) compared with prednisone probably reduce the number of children who experience relapse at six to 12 months (6 studies, 202 children: RR 0.44, 95% CI 0.32 to 0.60) and at 12 to 24 months (4 studies, 59 children: RR 0.20, 95% CI 0.09 to 0.46) (moderate certainty)., Authors' Conclusions: New studies incorporated in this review update indicate that rituximab compared with prednisone, tacrolimus, or MMF is a valuable additional agent for managing children with relapsing SSNS. Comparative studies of CNIs, MMF, and levamisole suggest that CNIs may be more effective than MMF and that levamisole may be similar in efficacy to MMF. Important new studies suggest that MMF prolongs remission following rituximab, that levamisole may prevent infection-related relapse more effectively than changing from alternate-day to daily prednisone and that levamisole and prednisone compared with prednisone alone may prolong the time to first relapse. There are currently 23 ongoing studies which should improve our understanding of how to treat children with frequently relapsing SSNS., (Copyright © 2024 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Background: Oral mucositis affects about 20% of children undergoing high-dose methotrexate (HDMTX) for acute lymphoblastic leukemia (ALL), despite existing management strategies. Personalized HDMTX dosing, adjusted by pharmacokinetics and leukemia risk, has reduced mucositis incidence, but variations still occur with similar 24-h methotrexate levels., Methods: This retrospective study investigated risk factors for oral mucositis under individualized methotrexate protocols. Data from patients with ≥ Grade 2 oral mucositis (CTCAE v4.0) were analyzed from the St. Jude Children's Research Hospital total 16 trial. A 1:1 case-control matching method considered age, sex, risk classification, immunophenotype, and methotrexate course. McNemar's, Bowker's symmetry, and Wilcoxon signed-rank tests were used for statistical analyses. Risk factors for recurrent mucositis were identified in a case-only analysis., Results: The study found significant associations between methotrexate-induced mucositis and new-onset skin rashes (p = 0.0027), fever (p = 0.0016), neutropenic fever (p = 0.0008), lower absolute neutrophil count (p < 0.0001), acute kidney injury (AKI) (p = 0.0164), delayed methotrexate clearance (p = 0.0133), and higher 42-h methotrexate levels (p = 0.0179). In the standard/high-risk group, mercaptopurine dose was also linked to mucositis (p = 0.0495). Multivariable analysis showed that skin rashes (OR 6.5, p = 0.0016), fever (OR 2.8, p = 0.009), and neutropenia (OR 2.3, p = 0.0106) were independent risk factors for mucositis. Female sex (OR 7.12, p = 0.015) and AKI (OR 3.819, p = 0.037) were associated with recurrent mucositis., Conclusions: Fever, skin rashes, AKI, delayed methotrexate clearance, and higher 42-h methotrexate levels were key risk factors for HDMTX-induced oral mucositis. Skin rashes, fever, and neutropenia were independent predictors, while female sex and AKI were linked to recurrent mucositis., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

Introduction: Methotrexate polyglutamates (MTXPGs) are intracellular metabolites of methotrexate (MTX) that play a critical role in the drug's activity, influencing both its efficacy and toxicity. As the exact implications of MTXPGs in these processes remain a subject of debate, a comprehensive review of MTXPGs could provide valuable insights for clinicians and pharmacists, potentially minimizing adverse reactions and enhancing therapeutic outcomes., Areas Covered: A comprehensive search of relevant literature was conducted in PubMed and Web of Science databases, including studies from their inception to April 2024. Eligible studies included reviews, clinical trials, and real-world analyses. Additional manual searches and citation reviews were also performed. This review aims to explore MTXPGs with a primary focus on their pharmacokinetics, analytical methods, determinants of drug exposure, and their correlation with MTX efficacy and toxicity., Expert Opinion: MTXPGs have not yet garnered significant attention in clinical practice. However, multiple studies have demonstrated a relationship between MTXPGs and the efficacy and toxicity of MTX, suggesting a potential avenue for personalized treatment strategies. Future research should aim to further validate and refine this correlation. Additionally, attention should also be directed toward other metabolites of MTX, which may hold clinical significance.

MTX is an effective and widely used immunomodulatory drug for rheumatoid diseases. MTX osteopathy is a very rare and specific side effect, characterized by stress fractures at multiple locations in the lower extremity, hampering the patient's mobility by pain and loss of function. In clinical practice, osteoporosis and MTX osteopathy are repeatedly confused and a comparative workup is needed to clarity it's specifics. Furthermore, specific treatment options for MTX osteopathy need to be established. We compared patients suffering from MTX osteopathy to patients with osteoporosis (OPO). Patients underwent an extensive clinical workup including blood sampling, bone mineral density measurements, high-resolution peripheral quantitative computed tomography and muscular performance testing. Furthermore, treatment regimes in MTX osteopathy were compared with respect to regain of mobility and pain reduction. 83 patients with MTX osteopathy and 89 with OPO were included. Patients with MTX osteopathy did exhibit fractures predominantly at the lower extremity and pain scores were significantly higher (MTX: 6.75 ± 1.86 vs. OPO: 3.62 ± 2.95, p < 0.0001). MTX-caused mobility restriction was successfully reduced by treatment only if MTX was discontinued (pre-treatment: 2.16 ± 1.19 vs. post-treatment: 1.04 ± 0.87, p < 0.0001). Most mobility gain was achieved by involving anabolic treatment (anabolic: 2.1 ± 1.02 vs. antiresorptive: 1.09 ± 0.94, p < 0.05). In summary, MTX osteopathy is characterized by distinct lower extremity stress fractures leading to severe pain and immobility. Discontinuation of MTX is essential to enable treatment success and involving anabolic treatment seems to be more effectively in mobility regain as antiresorptive treatment alone., (© 2024. The Author(s).)

Objective: To know the perception of nurses about the management and exposure of methotrexate in primary care nursing staff of the Orihuela Health Department., Material and Method: This is a descriptive qualitative study carried out through semi-structured interviews with a sample of 15 intentionally selected nurses., Results: The participants expressed concern about the handling and exposure of methotrexate, which allowed them to perceive training as the greatest concern in the study unit. A main category called "knowing" was established, which encompasses all the reflections about the nurse's performance during the process of handling and exposure of cytostatics. From this main category, the following subcategories are developed: lack of knowledge, demand for training, personal protective equipment, cytostatic residues, exposure and ventilation., Conclusion: Our study shows that it is necessary to accredit and reaccredit the professional skills of nurses to carry out the management of methotrexate correctly, facilitating the use of instruments to standardize variability and seeking strategies to update knowledge and skills., (Copyright © 2024 Sociedad Española de Médicos de Atención Primaria (SEMERGEN). Publicado por Elsevier España, S.L.U. All rights reserved.)

Background and Objective: Erosions of the skin and mucous membranes with epidermal dysmaturation are a known side effect of cytostatic chemotherapy regimens and can also be observed during low-dose methotrexate (MTX) therapy. The study aimed to delineate the clinical and histopathological alterations., Patients and Methods: A database search of the archive for dermatopathology was conducted, identifying 22 patients who developed epidermal dysmaturation on low-dose MTX. Clinical and laboratory changes, along with an array of histologic parameters were analyzed and statistically evaluated using SPSS., Results: Patients were predominantly female with a mean age of 69.1 years. The main indications were psoriasis vulgaris and rheumatoid arthritis. Clinically, patients mostly presented erosive plaques at the injection site, on mucosal surfaces, and disseminated lesions. Most patients showed normal laboratory values. Histopathologically, key findings included enlarged keratinocytes with pale cytoplasm and enlarged nuclei with prominent nucleoli, along with the degeneration of the basal layer. Consistent observations in the dermal compartment included infiltration of neutrophilic granulocytes, lymphocytes, and histiocytes., Conclusions: This study proposes clinicopathological criteria for the diagnosis of MTX-associated skin toxicity, aiming to increase awareness among clinicians and pathologists for early diagnosis. Early recognition can prevent potentially life-threatening progression., (© 2024 The Author(s). Journal der Deutschen Dermatologischen Gesellschaft published by John Wiley & Sons Ltd on behalf of Deutsche Dermatologische Gesellschaft.)

Methotrexate (MTX) is a folic acid reductase inhibitor that manages various malignancies as well as immune-mediated inflammatory chronic diseases. Despite being frequently prescribed, MTX's severe multiple toxicities can occasionally limit its therapeutic potential. Intestinal toxicity is a severe adverse effect associated with the administration of MTX, and patients are significantly burdened by MTX-provoked intestinal mucositis. However, the mechanism of such intestinal toxicity is not entirely understood, mechanistic studies demonstrated oxidative stress and inflammatory reactions as key factors that lead to the development of MTX-induced intestinal injury. Besides, MTX causes intestinal cells to express pro-inflammatory cytokines like interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), which activate nuclear factor-kappa B (NF-κB). This is followed by the activation of the Janus kinase/signal transducer and activator of the transcription3 (JAK/STAT3) signaling pathway. Moreover, because of its dual anti-inflammatory and antioxidative properties, nuclear factor erythroid-2-related factor 2/heme oxygenase-1 (Nrf2/HO-1) has been considered a critical signaling pathway that counteracts oxidative stress in MTX-induced intestinal injury. Several agents have potential protective effects in counteracting MTX-provoked intestinal injury such as omega-3 polyunsaturated fatty acids, taurine, umbelliferone, vinpocetine, perindopril, rutin, hesperidin, lycopene, quercetin, apocynin, lactobacillus, berberine, zinc, and nifuroxazide. This review aims to summarize the potential redox molecular mechanisms of MTX-induced intestinal injury and how they can be alleviated. In conclusion, studying these molecular pathways might open the way for early alleviation of the intestinal damage and the development of various agent plans to attenuate MTX-mediated intestinal injury., (© 2024. The Author(s).)

Objectives: Methotrexate (MTX) is the most used drug to treat children and adults with arthritis and its use is burdened by adverse effects. The MTX intolerance severity score (MISS) was developed in English to identify patients who are intolerant to MTX. The aim of this study was to translate and validate the MISS in Italian., Methods: The Italian version of the MISS was developed following the "guidelines for process of cross-cultural adaptation of self-reported measures". The Italian version of the MISS was validated in 125 patients with juvenile idiopathic arthritis (JIA) followed at the Rheumatology Unit of Bambino Gesù Children Hospital. We assessed the construct validity and calculated the internal consistency of the Italian MISS. We performed ROC analysis to assess the overall performance of the Italian MISS., Results: We translated and adapted the MISS to the Italian language. The Italian MISS showed a very good internal consistency as shown by a Cronbach α of 0.87 (95% CI, 0.84-0.90) and a composite reliability of 0.89 (95% CI, 0.83-0.91).The Cohen's κ was 0.81 (95% CI, 0.71-0.91), suggesting a very good construct validity. The ROC analysis showed an area under the curve (AUC) of 0.97 (95% CI, 0.93-0.99). A threshold of 6 to define intolerant patients, showed a sensitivity of 98.3% and specificity of 81.2%., Conclusions: We developed the Italian version of the MISS and showed its validity and reliability to identify patients intolerant to MTX in clinical practice and in a research setting.

The optimal treatment strategy for newly diagnosed primary central nervous system lymphoma (PCNSL) has yet to be established, especially in the elderly. In the current study, we conducted a phase II study to evaluate the efficacy and safety of rituximab plus high-dose MTX followed by rituximab plus cytarabine in patients aged ≥60 years newly diagnosed with PCNSL. Patients received an induction treatment of high-dose methotrexate plus rituximab followed by two cycles of a consolidation treatment of cytarabine plus rituximab. The primary end-point was a 2-year progression-free survival (PFS) rate. A total of 35 patients were recruited, and their median age was 73 (range: 60-81). After induction treatment, the complete and partial responses (PRs) were 56% and 20% respectively. Twenty-six patients proceeded to the consolidation treatment; the complete and PRs were 59% and 9% respectively. After a median follow-up duration of 36.0 months, the 2-year PFS rate was 58.7%. Treatment was generally well-tolerated as only three patients were withdrawn from the study due to toxicity, and no treatment-related mortality was reported. The 2-year overall survival rate was 77.9%. The current study may suggest the feasibility of administering high-dose MTX plus cytarabine in PCNSL patients aged ≥60 years and the potential role of additive rituximab., (© 2024 British Society for Haematology and John Wiley & Sons Ltd.)

Several noninvasive liver fibrosis tests have been developed and appear to predict the severity of fibrosis, possibly replacing invasive liver biopsy as a monitoring tool. 1 The fibrosis-4 (FIB-4) score originally was proposed to help assess liver fibrosis in patients with human immunodeficiency virus and hepatitis C virus co-infection. 1 FIB-4 has been used widely to monitor the severity of liver fibrosis, especially in patients with nonalcoholic fatty liver disease, 2 now termed metabolic dysfunction-associated steatotic liver disease (MASLD). 3 ., (Copyright © 2024. Published by Elsevier Inc.)

Background: Methotrexate (MTX) intolerance in juvenile idiopathic arthritis (JIA) frequently leads to discontinuation due to anticipatory and associative gastrointestinal symptoms. Eye Movement Desensitization and Reprocessing (EMDR) has successfully been used in MTX intolerance, with lasting effects but frequently diminishing efficacy over time. BLAST (bi-lateral alternating stimulation tactile) wristbands utilize a similar process to EMDR. The aim of this study was to determine if utilization of BLAST wristbands could improve and prolong the effect of EMDR on patients with MTX intolerance., Methods: Consecutive patients admitted to the German Center for Pediatric and Adolescent Rheumatology with JIA and signs of MTX intolerance from October 2016 until March 2024 were included in this study. Treatment was performed using an adapted 8 phase EMDR protocol implementing BAST wristbands. Initial patients were treated with EMDR, subsequent patients additionally with BLAST wristbands. Health-related quality of live was determined using the PedsQL. Measurements of MISS (Methotrexate Intolerance Severity Score) and PedsQL were taken at 4 time points: directly before and after (MISS only) treatment, as well as 4 and 12 months after treatment. Changes in MISS and PedsQL were compared using descriptive statistics and repeated measures ANOVA., Results: 87 patients with MTX intolerance were included, 53 in group 1 without BLAST wristbands and 34 in group 2 which were concurrently treated with BLAST wristbands. All patients reported marked improvement of MTX intolerance symptoms (mean MISS score group 1: 15.0 ± 5.5 before treatment, 1.3 ± 1.5 after treatment, group 2: 16.8 ± 5.6 and 2.5 ± 2.5, respectively). After 4 and 12 months, MISS in group 1 was 8.1 ± 7.1 and 8.7 ± 8.4, and in group 2: 7.1 ± 6.3 and 6.5 ± 5.7. A repeated measures ANOVA showed a significant difference between the MISS results over time (F(3,114) = 64.6, p < 0.001), and also demonstrated a significant difference of the PedsQL results between the two groups over time (F(2,64) = 8.9, p < 0.001)., Conclusion: Treatment with Eye Movement Desensitization and Reprocessing (EMDR) could present an effective treatment of MTX intolerance, and using BLAST wristbands, further potential improvement is possible., (© 2024. The Author(s).)

A 79-year-old woman with psoriasis presented to the emergency department with new-onset eruptions on the trunk, extremities, and oral mucosa for 8-9 days. For psoriasis, she had been taking 15 mg of methotrexate weekly for over 18 years, and had discontinued folic acid a few months prior to this.

Objective: To report long-term safety and tolerability of olokizumab (OKZ) in combination with methotrexate (MTX) in subjects with active rheumatoid arthritis (RA), using pooled data from three randomised clinical trials (RCT) followed by open-label extension (OLE) study., Methods: Cumulative data from three phase 3 core trials and their OLE were analysed. Safety variables assessed included treatment-emergent adverse events (AEs), serious AEs (SAEs), AEs of special interest and laboratory results. Efficacy assessments included ACR20/50/70 responses, Disease Activity Score 28 (C-reactive protein) <3.2, CDAI remission and low disease activity (LDA), SDAI remission and LDA, HAQ-DI decrease of 0.22 unit and Boolean 2.0 remission., Results: A total of 2304 patients received OKZ in combination with MTX either once every 2 weeks or once every 4 weeks. Event rates per 100 patient-years in OKZ every 2 weeks and OKZ every 4 weeks, respectively, were 9.57 and 9.13 for SAEs; 2.95 and 2.34 for serious infections; 0.09 and 0.05 for gastrointestinal perforations; 0.58 and 0.83 for major adverse cardiovascular events; and 0.45 and 0.50 for malignancies. No increase in the rate of any AE was observed over 106 weeks of treatment. The evaluation of laboratory variables demonstrated the expected changes, like neutropenia, elevation of liver enzymes and blood lipids. Clinical response rates remained stable during the OLE., Conclusion: The long-term safety and tolerability of OKZ in combination with MTX remained stable. The efficacy of OKZ was maintained through week 106. These findings support OKZ as a treatment option for patients with active RA., Competing Interests: Competing interests: The analysis was funded by JSC R-Pharm. EF: research grants from BMS, Eli Lilly, Novartis, Roche; consulting fees from Abbvie, BMS, Eli Lilly, Gilead Sciences, Galapagos, Novartis, Roche, Sanofi, Sobi; speakers’ bureau for Abbvie, BMS, Eli Lilly, Gilead Sciences, Galapagos, Medac, Novartis, Roche, Sanofi, Sobi; RF: Consultant for AbbVie, Arthrosi, BMS, Galvani, Genentech, Gilead, GSK, InventisBio, Janssen, Eli Lilly, Novartis, Pfizer, Proviant, Recor, UCB, Vyne; Clinical Study grants: AbbVie, Acceleron, Arthrosi, Biosplice, BMS, Cugene, Flexion, Galvani, Gilead, GSK, Horizon, Idorsia, Janssen, LG Chem, Eli Lilly, Novartis, Pfizer, Proviant, Sankyo, UCB, Viela. SF: consulting fees from ICON and PPD contract research organisations, shareholder of Pfizer, INC stocks, consulting fees from R-Pharm; EK: employee of R-Pharm, with no R-Pharm stock; ML: research grants from Amgen, Biogen, UCB, Sun Pharmaceuticals, Abbvie, Pfizer, Novartis, Lilly, GSK, R-Pharm; EN: speakers’ bureau for AbbVie, Eli Lilly, Janssen, Novartis, Pfizer; DB, SG, SK and MS: employee of R-Pharm, with no R-Pharm stock; JS: Editor-in-Chief of ARD, research grants from Abbvie, Astra-Zeneca, Lilly; consulting fees from Abbvie, Galapagos/Gilead, Novartis-Sandoz, BMS, Samsung, Sanofi, Chugai, R-Pharma, Lilly; speakers’ bureau for Samsung, Lilly, R-Pharm, Chugai, MSD, Janssen, Novartis-Sandoz; RF: consulting fees from AbbVie, BMS, Gilead, Galvani, GSK, Janssen, Eli Lilly, Novartis, Pfizer, R-Pharm, UCB; speakers bureaus for AbbVie; Pfizer; R-Pharm. Disclosure forms provided by the authors are available in the full text of this article., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ on behalf of EULAR.)

High-dose methotrexate (HDMTX) is used in the treatment of a range of adult and childhood cancers. Although HDMTX can provide effective anti-tumor activity with an acceptable safety profile for most patients, delayed methotrexate elimination (DME) develops in a minority of patients receiving HDMTX and may be accompanied by renal dysfunction and potentially life-threatening toxicity. A panel of European physicians with experience in the use of HDMTX as well as of glucarpidase convened to develop a series of consensus statements to provide practical guidance on the prevention and treatment of DME, including the use of glucarpidase. Robust implementation of supportive measures including hyperhydration and urine alkalinization emerged as critical in order to reduce the risk of DME with HDMTX treatment, with leucovorin rescue critical in reducing the risk of DME complications. Early recognition of DME is important to promptly implement appropriate treatment including, intensified hydration, high-dose leucovorin and, when appropriate, glucarpidase., (© 2024. The Author(s).)

Objectives: To evaluate the risk of liver fibrosis and associated factors with the non-invasive fibrosis score-4 (FIB-4) index in patients with inflammatory arthritis using methotrexate (MTX)., Methods: Patients with rheumatoid arthritis (RA) and psoriatic arthritis (PsA) who were followed up in the rheumatology outpatient clinic, who were on methotrexate only and for whom FIB-4 index was could be calculated at methotrexate initiation and follow-up were included. The FIB-4 index was calculated according to the following formula: age (years) × AST(IU/L)/(platelet count(10 (9)/L) × √ALT(IU/L)). The patients' demographics, comorbidities, other treatments, cumulative MTX dose, and reasons for MTX cessation were assessed. For the multivariate analysis, possible factors associated with intermediate-high risk FIB-4 index at last visit were determined., Results: A total of 107 patients were enrolled in the study, of whom 82 (76.6%) had RA and 25 (23.4%) had PsA. At the initiation of MTX, 24 (22.4%) patients had intermediate-high risk FIB-4 index. Comorbidities and the rate of ≥3-4 Charlson comorbidity index were more common in patients with intermediate-high risk FIB-4 index. A total of 37 (34.5%) patients had intermediate-high risk FIB-4 index at the last visit after median 3.6 (0.3-22.06) years follow-up. The median cumulative MTX dose was 2550 mg (1050-13.991). Cumulative MTX dose [OR 1.18 (1.01-1.33), p = .03] and diabetes mellitus [OR 4.60 (1.74-12.50), p = .002] were associated factors with intermediate-high risk FIB-4 index. The concomitant use of hydroxychloroquine (HCQ) was found to be a low-risk factor for FIB-4 index [OR 0.28 (0.10-0.78) p = .015]., Conclusion: The FIB-4 index is a non-invasive method that can be used in daily rheumatology practice for the evaluation and follow-up of patients who will use methotrexate. Comorbidities and cumulative MTX dose seem to be related with the risk of liver fibrosis. Concomitant use of HCQ with MTX may reduce the risk of liver fibrosis., (© 2024 The Author(s). International Journal of Rheumatic Diseases published by Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)

Objective: To assess the effect of pretreatment with omega-3 alone or in combination with vitamin C on hepatotoxicity raised by methotrexate., Method: The experimental study was conducted at the animal house of the Iraqi Centre of Cancer Research and Medical Genetics and the Department of Pharmacology, College of Medicine, Al-Mustansiriyah University, Baghdad, Iraq, from November 2020 to July 2021, and comprised Swiss albino mice who were divided into 5 groups. Group A was treated with normal saline, group B was injected with methotrexate 20mg/kg intraperitoneally, group C was pretreated with omega 3 100mg/kg, group D was pretreated with vitamin C 100mg/kg, and group E was pretreated with concomitant vitamin C and omega 3 100mg/kg. The intervention lasted 9 days in each group, and were injected with methotrexate on day 10. The mice were sacrificed under chloroform anaesthesia after 48 hours. Blood sample was taken for biochemical examination. One part of liver was preserved in formalin 10% for histopathological study., Results: Of the 35 mice, there were 7(20%) in each of the 5 groups. There was a significant increase in malondialdehyde and lactate dehydrogenase levels and a decrease in the superoxide dismutase and glutathione (p<0.05)., Conclusions: Pretreatment with omega-3 and vitamin C ameliorated the hepatotoxicity induced by methotrexate due to strong antioxidant, anti-inflammatory and anti-apoptotic effects.

Objective: To examine the effect of using vitamin C and niclosamide together on liver damage caused by methotrexate., Methods: The study was conducted at the Pharmacology Department and the Iraqi Center for Cancer and Medical Genetics Research, College of Medicine, Mustansiriya University, Baghdad, Iraq, from November 2020 to July 2021, and comprised albino mice who were randomly assigned to 5 groups. Group 1 comprised controls, groups 2 to 5 was received methotrexate, niclosamide 70mg/kg/day, vitamin C 100mg/kg/day, and a combination of niclosamide and vitamin C, respectively. Mice in groups 3, 4 and 5 also received an intraperitoneal injection of methotrexate 20mg/kg to induce hepatotoxicity. After 48 hours of the injection, the mice were sacrificed under chloroform anaesthesia. Cardiac blood samples were drawn for biochemical examination. The liver, after being washed, was divided into two parts; one part was taken for histological examination, and the other was preserved in formalin 10% for histopathological analyses. Data was analysed using SPSS 16., Results: Of the 35 mice, there were 7(20%) in each of the 5 groups. The overall age ranged between 9-12 weeks and weight between 18-38gm. The results show significant hepatoprotection ( p-value <0.05) produced by both niclosamide and Vitamin C separately, reflected by a decrease in ALP, ALT, and LDH, while the combination of (niclosamide and Vitamin C) showed no additive effect (p>0.05) on enhancement of liver function., Conclusions: Niclosamide alone was found to be superior than in combination with vitamin C for treating methotrexate-induced liver damage.

Background: Gastrointestinal intolerance is common in rheumatoid arthritis (RA) patients using methotrexate and may lead to treatment discontinuation., Aim: To study the prevalence of gastrointestinal symptoms in a sample of RA methotrexate users as well as its possible association with clinical and epidemiological variables., Methods: Cross-sectional study of 192 patients with gastrointestinal symptoms using the MISS (methotrexate intolerance severity score). Clinical and epidemiological variables were collected through chart review and direct questioning. Patients' adherence to methotrexate was evaluated through Moriski-Green-Levin questionnaire., Results: The prevalence of gastrointestinal complaints was high with 55.7% of the sample classified as intolerant. Nausea and pain after drug ingestion were the most common reported complaints. This intolerance was associated with afro-descendant background (p=0.02); presence of associated fibromyalgia (p=0.04), concomitant use of glucocorticoids (p=0.03) and Jak inhibitors (0.03). A tendency towards association with leflunomide use was observed (p=0.06). Logistic regression was used to test drug associations with methotrexate intolerance, and showed that glucocorticoid use was independently associated with methotrexate intolerance OR=1.85; 95% CI=1.01-3.44; p=0.04. Route of administration, presence of previous gastric complaints, age and methotrexate dose did not interfere with MISS. MISS results were associated with moderate adherence to the drug., Conclusions: There is a high rate of methotrexate intolerance that is more common in afro-descendants, those with associated fibromyalgia, glucocorticoid and Jak inhibitors users., (Copyright © 2024 Sociedad España de Reumatología (SER), Colegio Mexicano de Reumatología (CMR) and Elsevier España, S.L.U. All rights reserved.)

Abstract: Methotrexate is one of the most frequently used medications for the treatment of rheumatic diseases. Although initially developed for use as chemotherapy for both solid and hematologic malignancies, it was used as early as the 1960s with success for rheumatoid arthritis (RA) and psoriatic arthritis, ultimately being approved by the US Food and Drug Administration for the treatment of RA in 1988. Beyond RA and psoriatic arthritis, methotrexate is used in the treatment of systemic lupus erythematosus, idiopathic inflammatory myopathies, and other inflammatory conditions. Methotrexate is cytotoxic to the trophoblast and has been used to treat both ectopic pregnancy and gestational trophoblastic neoplasia, leading to studies in the early 1990s that showed it was effective and safe for early abortion in combination with prostaglandin E1 analog misoprostol. Methotrexate is also a teratogen, causing serious birth defects in 6%-10% of patients taking it while pregnant. Additionally, women are more likely to be affected by both RA at SLE, as compared with males, thus worsening the burden of these adverse effects. Both methotrexate's history of use as an abortifacient and its teratogenic properties make its use more complicated in the current era of abortion policy in the United States following the Dobbs v. Jackson Women's Health Organization ruling. Recently published data suggest that this ruling has affected both provider perspectives and patient experiences as it relates to methotrexate use. In the post-Dobbs era, the role of the rheumatologist as it relates to patients' sexual and reproductive health is likely to expand., Competing Interests: The authors declare no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Interstitial lung disease (ILD) poses a serious threat in patients with rheumatoid arthritis (RA). However, the impact of cornerstone drugs, including methotrexate (MTX) and TNF inhibitor, on RA-associated ILD (RA-ILD) remains controversial., Methods: Using an SKG mouse model and single-cell transcriptomics, we investigated the effects of MTX and TNF blockade on ILD., Findings: Our study revealed that MTX exacerbates pulmonary inflammation by promoting immune cell infiltration, Th17 activation, and fibrosis. In contrast, TNF inhibitor ameliorates these features and inhibits ILD progression. Analysis of data from a human RA-ILD cohort revealed that patients with ILD progression had persistently higher systemic inflammation than those without progression, particularly among the subgroup undergoing MTX treatment., Interpretation: These findings highlight the need for personalized therapeutic approaches in RA-ILD, given the divergent outcomes of MTX and TNF inhibitor., Funding: This work was funded by GENINUS Inc., and the National Research Foundation of Korea, and Seoul National University Hospital., Competing Interests: Declaration of interests Dr. Sparks has received research support from Bristol Myers Squibb and Boehringer Ingelheim unrelated to this work. He has performed consultancy for AbbVie, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Gilead, Inova Diagnostics, Janssen, Optum, Pfizer, ReCor, Sobi, and UCB unrelated to this work., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Introduction: Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease that primarily affects middle-aged individuals but is increasingly prevalent among the elderly due to longer life expectancies. Treating elderly onset RA (EORA) is challenging for clinicians because of unique disease characteristics, comorbidities, polypharmacy, age-related physiological changes, and limited studies on the safety and efficacy of biological therapies in this population. This review aims to evaluate the use of various biological therapies in elderly RA patients., Areas Covered: This narrative review examines various aspects of RA in the elderly using published literature, randomized control trials, meta-analyses, and recommendations from the National Institute for Health and Care Excellence (NICE) and The European Alliance of Associations for Rheumatology (EULAR)., Expert Opinion: In EORA patients, the initiation of biological therapy is often delayed. Methotrexate remains the first-line treatment for both EORA and young onset RA (YORA). The combination of methotrexate and biological treatment shows comparable safety and efficacy in both EORA and YORA, except for rituximab, which is less effective in patients over 75. For elderly RA patients, biological (b-) disease-modifying antirheumatic drugs (DMARDs) are preferred as the first advanced therapy over targeted synthetic (ts-) DMARDs due to their superior safety profile.

Background: Head-to-head studies are important to select the optimal treatment in terms of efficacy and side effect profiles when several drugs are available., Aim of the Work: This article describes all studies comparing the use of disease-modifying antirheumatic drugs (DMARD) in rheumatoid arthritis (RA) in head-to-head studies or in which a DMARD was at least included in an active comparison arm., Results: A total of 23 studies comparing DMARDs were identified. These included comparisons of Janus kinase (JAK) inhibitors with methotrexate and with adalimumab as well as the oral surveillance study., Discussion: There are already an exceptionally large number of head-to-head studies in RA, both for comparisons of efficacy and safety of DMARDs. Nevertheless, more such comparative studies are needed, for example to clarify whether adverse events of tofacitinib observed in the oral surveillance study are specific to the JAK 1/JAK 3 inhibitor or are a class effect of all JAK inhibitors., (© 2024. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

High-dose methotrexate (HD-MTX) is used in the treatment of children with central nervous system (CNS) tumors; however, toxicity information is limited. We characterized toxicities following 102 administrations of HD-MTX (4.6-13.5 g/m 2 ) infused over 4 or 24 h in 38 children with a CNS tumor before 6 years of age (2010-2020). Delayed clearance of methotrexate occurred following 24% of infusions. Common Terminology Criteria for Adverse Events v5 grade 2-3 mucositis was observed in 47% of individuals, Grade 4 neutropenia in 76%, and grade 3-4 thrombocytopenia in 58%. No neurotoxicity was observed. HD-MTX can be safely used with supportive care and monitoring., (© 2024 Wiley Periodicals LLC.)

Introduction: Methotrexate (MTX) is a folate antagonist used as an immunosuppressant in a number of conditions, including rheumatoid arthritis (RA). Low-dose MTX (MTX-LD) is associated with a risk of haematological, hepatic, gastrointestinal and pulmonary toxicity, which may up until now have limited its use., State of the Art: In RA, data from retrospective cohorts have reported a possible excess risk of methotrexate toxicity in cases of underlying interstitial lung disease (ILD). However, recent prospective and retrospective multicentre studies have found no such increased risk, and have reassuringly concluded that MTX-LD can be prescribed in cases of RA-associated ILD (RA-ILD)., Perspectives and Conclusions: Current recommendations are not to delay the introduction of MTX in patients with RA at risk of developing ILD or in the presence of RA-ILD with mild to moderate respiratory impairment., (Copyright © 2024 SPLF. Published by Elsevier Masson SAS. All rights reserved.)

Background: Methotrexate is an essential medicine used to treat childhood malignancies including acute lymphoblastic leukemia. Neurotoxicity manifesting as leukoencephalopathy is an important adverse effect of methotrexate. Methotrexate-induced leukoencephalopathy classically demonstrates sub-acute-onset neurological manifestations that include learning disability, progressive dementia, drowsiness, seizures, ataxia, and hemiparesis. These are rare in children and are generally reported following intrathecal or intravenous use of methotrexate. In contrast, acute onset neurotoxicity with oral use of methotrexate is very rare. We report a 10-year-old boy presenting with acute onset limb weakness and neurological signs due to methotrexate-induced leukoencephalopathy following oral methotrexate., Case Presentation: A 10-year-old Sri Lankan boy presented with fever and headache for 5 days and difficulty in walking for 2 days. He was unable to stand unaided on admission, and his parents complained of repetitive, involuntary extension movements involving the right upper limb. He is a child diagnosed with acute lymphoblastic leukemia who was on treatment for a relapse with daily oral dexamethasone and mercaptopurine, weekly oral methotrexate and folinic acid, and once every two weeks intrathecal vincristine. On examination, he had dystonic movements of the right upper limb and hypotonia and reduced muscle power (grade 3/5) of the left upper and lower limbs proximally and distally. The muscle power of the right side was grade 4 (out of 5). Tendon reflexes were diminished in all four limbs, and the plantar response was flexor bilaterally. The child had dysmetria and intension tremors on both sides. T2-weighted magnetic resonance imaging of the brain revealed symmetrical high signal intensities with diffusion restriction involving bilateral putamen, subcortical areas, and deep white matter, suggesting treatment-related neurotoxicity due to methotrexate-induced leukoencephalopathy. Oral methotrexate was discontinued. He showed gradual improvement in limb weakness and other neurological signs following treatment with intravenous folinic acid, aminophylline, dexamethasone, and oral dextromethorphan., Conclusion: This case report describes a patient with rapidly progressing methotrexate-induced leukoencephalopathy following oral methotrexate. It highlights that the risk of neurotoxicity persists even with the oral use of methotrexate; therefore, the prescribers should be vigilant of this uncommon side effect., (© 2024. The Author(s).)

Background: There is a growing trend to include non-randomised studies of interventions (NRSIs) in rare events meta-analyses of randomised controlled trials (RCTs) to complement the evidence from the latter. An important consideration when combining RCTs and NRSIs is how to address potential bias and down-weighting of NRSIs in the pooled estimates. The aim of this study is to explore the use of a power prior approach in a Bayesian framework for integrating RCTs and NRSIs to assess the effect of rare events., Methods: We proposed a method of specifying the down-weighting factor based on judgments of the relative magnitude (no information, and low, moderate, serious and critical risk of bias) of the overall risk of bias for each NRSI using the ROBINS-I tool. The methods were illustrated using two meta-analyses, with particular interest in the risk of diabetic ketoacidosis (DKA) in patients using sodium/glucose cotransporter-2 (SGLT-2) inhibitors compared with active comparators, and the association between low-dose methotrexate exposure and melanoma., Results: No significant results were observed for these two analyses when the data from RCTs only were pooled (risk of DKA: OR = 0.82, 95% confidence interval (CI): 0.25-2.69; risk of melanoma: OR = 1.94, 95%CI: 0.72-5.27). When RCTs and NRSIs were directly combined without distinction in the same meta-analysis, both meta-analyses showed significant results (risk of DKA: OR = 1.50, 95%CI: 1.11-2.03; risk of melanoma: OR = 1.16, 95%CI: 1.08-1.24). Using Bayesian analysis to account for NRSI bias, there was a 90% probability of an increased risk of DKA in users receiving SGLT-2 inhibitors and an 91% probability of an increased risk of melanoma in patients using low-dose methotrexate., Conclusions: Our study showed that including NRSIs in a meta-analysis of RCTs for rare events could increase the certainty and comprehensiveness of the evidence. The estimates obtained from NRSIs are generally considered to be biased, and the possible influence of NRSIs on the certainty of the combined evidence needs to be carefully investigated., (© 2024. The Author(s).)

The use of methotrexate in clinical practice has expanded significantly in recent years, as an effective chemotherapeutic agent as well as disease-modifying treatment for conditions such as rheumatoid arthritis, psoriasis and Crohn's disease. It is also used as a steroid-sparing agent for a range of inflammatory diseases of the central and peripheral nervous systems. Clinical neurologists must, therefore, know how to start and uptitrate methotrexate, its monitoring requirements and its potential toxicities. This review aims first to explore the evidence base for using methotrexate in various neurological diseases and second to discuss important practicalities around its use, ensuring its safe application and appropriate monitoring., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: High-dose methotrexate (HDMTX) use can be limited by the development of acute kidney injury (AKI). Early AKI detection is paramount to prevent further renal injury and irreversible toxicities. This study sought to determine whether early elimination patterns of MTX would be useful as a biomarker of AKI in HDMTX treatment., Methods: This retrospective cohort study included two sites that collected ≥2 MTX levels within 16 h from completion of MTX infusion. Early levels were tagged and MTX elimination half-life (t ½ ) were calculated from combinations of two of three different early time periods. Receiver operating characteristic (ROC) curves were synthesized for each elimination t ½ (biomarker) with respect to AKI and delayed methotrexate elimination (DME); the biomarker with the highest area under the ROC curve (AUC) was tested in a multiple variable logistic regression model., Results: Data from 169 patients who received a total of 556 courses of HDMTX were analyzed. ROC analysis revealed MTX elimination t ½ calculated from the second and third time periods had the highest AUC for AKI at 0.62 (interquartile range [IQR] 0.56-0.69) and DME at 0.86 (IQR 0.73-1.00). After adjusting for age, sex, dose (mg/m 2 ), infusion duration, HDMTX course, and baseline estimated glomerular filtration rate, it remained significant for AKI with an OR of 1.29 and 95% confidence interval of 1.03-1.65., Conclusion: Early MTX elimination t ½ measured within 16 h of infusion completion was significantly associated with the development of AKI and serves as an early clearance biomarker that may identify patients who benefit from increased hydration, augmented leucovorin rescue, and glucarpidase administration., (© 2024 Resonance, Inc and The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

Objective: To explore the efficacy and safety of combination therapy with methotrexate (MTX) plus hydroxychloroquine (HCQ) vs. MTX monotherapy in patients with rheumatoid arthritis (RA)., Methods: Sixty patients without prior RA treatments were randomly allocated in a 1:1 ratio to two groups: one receiving MTX plus HCQ, and the other receiving MTX monotherapy. We conducted a comparative analysis before and after the 12-week trial, evaluating the visual analogue scale (VAS), the disease activity score in 28 joints (DAS), serum inflammatory factor (including serum C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), interleukin 6 (IL-6), tumor necrosis factor-alpha (TNF-α), as well as the outcome of the World Health Organization Quality of Life Brief Version questionnaire (WHOQOL-BREF) and the treatment-emergent adverse events (TEAEs) for all the participants in the study., Results: At the 12th week of the trial, a more remarkable decrease in pain score (VAS), disease activity score (DAS), and serum inflammatory factor levels could be noticed in individuals on the combination therapy. The quality of life score was as well found to be higher in the MTX + HCQ group than the MTX monotherapy group. The incidence of adverse reactions in the MTX + HCQ and the MTX monotherapy groups were 10.00% and 6.67%, respectively. However, no statistical significance could be observed (p > .05)., Conclusion: In our study, both the MTX + HCQ combination therapy and MTX monotherapy demonstrated improvements in symptoms, conditions and quality of life for patients with RA. Notably, the combination therapy could achieve better outcomes across all indices compared to MTX monotherapy, highlighting its potential as the optimal first-line treatment for RA. © 2024 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd., (© 2024 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)

Background: Treatments for osteoarthritis (OA) are limited. Previous small studies suggest that the antirheumatic drug methotrexate may be a potential treatment for OA pain., Objective: To assess symptomatic benefits of methotrexate in knee OA (KOA)., Design: A multicenter, randomized, double-blind, placebo-controlled trial done between 13 June 2014 and 13 October 2017. (ISRCTN77854383; EudraCT: 2013-001689-41)., Setting: 15 secondary care musculoskeletal clinics in the United Kingdom., Participants: A total of 207 participants with symptomatic, radiographic KOA and knee pain (severity ≥4 out of 10) on most days in the past 3 months with inadequate response to current medication were approached for inclusion., Intervention: Participants were randomly assigned 1:1 to oral methotrexate once weekly (6-week escalation 10 to 25 mg) or matched placebo over 12 months and continued usual analgesia., Measurements: The primary end point was average knee pain (numerical rating scale [NRS] 0 to 10) at 6 months, with 12-month follow-up to assess longer-term response. Secondary end points included knee stiffness and function outcomes and adverse events (AEs)., Results: A total of 155 participants (64% women; mean age, 60.9 years; 50% Kellgren-Lawrence grade 3 to 4) were randomly assigned to methotrexate ( n  = 77) or placebo ( n  = 78). Follow-up was 86% ( n  = 134; methotrexate: 66, placebo: 68) at 6 months. Mean knee pain decreased from 6.4 (SD, 1.80) at baseline to 5.1 (SD, 2.32) at 6 months in the methotrexate group and from 6.8 (SD, 1.62) to 6.2 (SD, 2.30) in the placebo group. The primary intention-to-treat analysis showed a statistically significant pain reduction of 0.79 NRS points in favor of methotrexate (95% CI, 0.08 to 1.51; P  = 0.030). There were also statistically significant treatment group differences in favor of methotrexate at 6 months for Western Ontario and McMaster Universities Osteoarthritis Index stiffness (0.60 points [CI, 0.01 to 1.18]; P  = 0.045) and function (5.01 points [CI, 1.29 to 8.74]; P  = 0.008). Treatment adherence analysis supported a dose-response effect. Four unrelated serious AEs were reported (methotrexate: 2, placebo: 2)., Limitation: Not permitting oral methotrexate to be changed to subcutaneous delivery for intolerance., Conclusion: Oral methotrexate added to usual medications demonstrated statistically significant reduction in KOA pain, stiffness, and function at 6 months., Primary Funding Source: Versus Arthritis., Competing Interests: Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M24-0303.

Methotrexate is a critical component of curative chemotherapy for pediatric acute lymphoblastic leukemia (ALL), but is associated with neurotoxicity. Information on long-term outcomes following an acute neurotoxic event is limited. Therefore, this report compares neurocognitive performance more than 12 months post diagnosis (mean = 4 years) between ALL patients with (n = 25) and without (n = 146) a history of acute neurotoxicity. Compared to children with no documented on-treatment neurotoxic event, children who experienced a neurotoxic event during treatment exhibited poorer performance on measures of fine motor function (p = .02) and attention (p = .02). Children with ALL who experience acute neurotoxicity may be candidates for early neuropsychological screening and intervention., (© 2024 Wiley Periodicals LLC.)

Purpose: High-dose methotrexate (HDMTX) is integral in treating hematologic malignancies but carries risks of severe toxicities due to prolonged MTX exposure. However, knowledge of delayed MTX excretion is primarily derived from pediatric and adolescent cohorts, with the reported predictors being presented as rough dichotomous values. This study aimed to identify risk factors for delayed MTX excretion exclusively in adult patients with hematologic malignancies and develop a more applicable predictive nomogram based on continuous clinical and laboratory variables., Methods: 517 HDMTX cycles in 194 patients were retrospectively analyzed. Delayed MTX excretion was defined as either MTX concentration ≥ 1.0 µmol/L at 48 h or ≥ 0.1 µmol/L at 72 h after HDMTX initiation. Multivariate logistic regression analysis was used to construct the nomogram internally validated with the bootstrap method., Results: Delayed MTX excretion was observed in 24.0% of cycles. Six significant predictors were identified: relapsed/refractory disease (Odds ratio [OR] 2.03), fewer HDMTX cycles (OR 0.771), treatment intent (OR 2.13), lower albumin (OR 0.563) and creatinine clearance levels (OR 0.993), and increased γ-glutamyl transpeptidase levels (OR 1.004, all P < 0.05). These were incorporated into a web-based nomogram as continuous variables with good prediction accuracy (area under the curve, 0.73) and without significant overfitting. Delayed MTX excretion increased risks of developing acute kidney injury, even solely at the 72 h timepoint (OR 2.57, P = 0.025), without providing any benefit of clinical outcomes., Conclusion: This study comprehensively characterized MTX elimination failure following HDMTX in adult patients and could pave the way for individualized risk prediction., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Methotrexate, an immunosuppressant used for the treatment of inflammatory bowel disease (IBD) for over 30 years, remains underused compared to thiopurines., Aims: To review the efficacy, safety, optimal dosing and delivery regimens of methotrexate in adults with IBD., Methods: We conducted a systematic review of studies involving patients with IBD treated with methotrexate from inception to August 2023. All studies were included from the MEDLINE database via PubMed., Results: For Crohn's disease, we included eight randomised controlled trials (RCTs) and 17 observational studies. Parenteral methotrexate effectively increased remission rates in steroid-dependent patients at 25 mg/week for 16 weeks and at 15 mg/week for maintenance. Methotrexate can be used in combination with anti-tumour necrosis factor (TNF) agents to reduce immunogenicity. Data comparing thiopurines and methotrexate remain scarce. For ulcerative colitis (UC), we included five RCTs and 10 observational studies were included; there was no evidence to support the use of methotrexate in (UC). We extracted safety data from 17 studies; mild-to-moderate adverse effects were common. The incidence of liver fibrosis or cirrhosis was low., Conclusion: Methotrexate is effective at inducing and maintaining remission in steroid-refractory Crohn's disease and can reduce anti-TNF-induced immunogenicity when used in combination therapy. Data regarding tolerance and safety are reassuring. These findings challenge preconceived ideas on methotrexate and suggest that it is a valid first-line conventional option for the treatment of mild-to-moderate Crohn's disease., (© 2024 John Wiley & Sons Ltd.)

Objectives: To compare the efficacy and safety of dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (dd-MVAC) with gemcitabine-based regimens for neoadjuvant chemotherapy (NAC) in muscle-invasive bladder cancer (MIBC) patients treated in Japan., Methods: Data for MIBC patients who received NAC-dd-MVAC followed by a radical cystectomy from June 2019 to May 2023 performed at our hospital were analyzed. For comparisons, data for MIBC patients who received NAC gemcitabine and cisplatin (GC) or gemcitabine and carboplatin (GCarbo) therapy between January 2010 and March 2019 were also obtained. Rates of ypT1N0 or less, progression-free survival (PFS), overall survival (OS), and NAC adverse effects were compared between the GC/GCarbo and dd-MVAC regimens., Results: Results for 32 patients who received dd-MVAC and 30 who received GC/GCarbo NAC therapy were analyzed. ypT1N0 or less was noted in 40.7% of the dd-MVAC and 40.0% of the GC/GCarbo groups, while ypT0N0 rates were 25% and 10%, respectively, with no statistical differences noted. However, Kaplan-Meier analysis of the total cohort demonstrated that dd-MVAC was associated with significantly better PFS and OS rates than GG/GCarbo (hazard ratios: 0.33, p = 0.0237, and 0.23, p = 0.0127, respectively). Propensity-matched models also showed similar results for both PFS and OS. Adverse effects of dd-MVAC were acceptable and the incidence of hematologic toxicity was lower as compared with GC/GCarbo therapy., Conclusion: The present study is the first to show that dd-MVAC as NAC can provide better survival as compared with a gemcitabine-based regimen for patients with MIBC treated in Japan., (© 2024 The Japanese Urological Association.)

Objective: To identify risk factors for readmission following methotrexate treatment for tubal pregnancy., Methods: A retrospective study undertaken in two tertiary medical centers, including all individuals with medically treated tubal pregnancy (N = 511), between December 2009 and June 2021. Individuals with and without readmission following methotrexate treatment were compared. The primary outcome was the readmission rate. Secondary outcomes included the rate of post-discharge gynecological emergency department visits, tubal rupture rate, and the eventual need for surgical treatment., Results: Readmission following methotrexate treatment occurred in 224/511 patients (43.8%). Most readmissions were due to abdominal pain or suspicion of treatment failure. Readmitted individuals were more likely to have a history of pelvic inflammatory disease and pretreatment serum human chorionic gonadotropin (hCG) >2000 mIU/mL. Both factors remained significantly associated with higher readmission rates in a logistic regression analysis (adjusted odds ratio [OR] 6.28, 95% confidence interval [CI] 1.30-30.45, and adjusted OR 2.73, 95% CI 1.83-4.07, respectively) after adjustment for age, endometriosis, tubal pathology, abdominal pain, and presence of yolk sac or embryo at diagnosis. A dose-dependent association was observed between pretreatment serum hCG levels and readmission rate (P < 0.001). Pretreatment hCG levels were also associated with tubal rupture and the eventual need for surgical treatment (P < 0.001 for both). A prediction model using hCG was not sufficiently accurate to predict readmission risk., Conclusion: Readmission following methotrexate treatment for tubal pregnancy was independently associated with previous pelvic inflammatory disease and pretreatment serum hCG levels. The latter was also associated with surgical intervention rate., (© 2024 International Federation of Gynecology and Obstetrics.)

Purpose: Psoriasis, affecting approximately 2% of the world's population, often necessitates systemic treatments, with methotrexate (MTX) as a cornerstone therapy. Despite documented systemic side effects of MTX, concerns about its impact on male reproductive health persist. We aim to investigate low-dose MTX effect on hormonal, cellular and functional ability of male reproductive system., Materials and Methods: Our prospective study on 40 male psoriasis patients receiving low-dose MTX (<15mg/week) comprehensively investigates its effects on erectile function, sex hormones, and spermiogram parameters., Results: After six months of MTX treatment, a significant decline in erectile function ( p  < 0.001) decreased total testosterone levels (p = 0.03) were observed. No significant reduction in sperm count was noted after six months of MTX treatment., Conclusions: Our study highlights a significant decline in erectile function following low-dose MTX therapy, warranting further investigation into this potential side effect. While reassuring for sperm quantity and quality, the findings emphasise the necessity for larger cohorts and longer follow-up times to validate results and comprehend the complex interactions between MTX and male sexual health.

Juvenile idiopathic arthritis is the most common rheumatic disorder in childhood and adolescence posing a significant threat of short-term and long-term disability if left untreated. Methotrexate is a folic acid analog with various immunomodulatory properties. It has demonstrated significant efficacy for the treatment of juvenile idiopathic arthritis, often considered the preferred first-line disease-modifying anti-rheumatic drug given as monotherapy or in combination with biological drugs. Despite this, there is a considerable risk for treatment disruptions owing to the high prevalence of methotrexate intolerance, with symptoms such as nausea, stomach ache, vomiting, and behavioral symptoms. Many different risk factors for the intolerance have been proposed including gender, age, disease activity, treatment duration, dosing and administration, and genetic and psychological factors. As the studies have shown contradictory results, many questions are left unanswered. Therefore, a consensus regarding outcome measures and reporting is crucial. In this review, we describe the identification and assessment of methotrexate intolerance and evaluate potential risk factors, genetic associations as well as management strategies., (© 2024. The Author(s).)

Background: Delayed excretion of high-dose methotrexate (HD-MTX) in pediatric acute lymphoblastic leukemia (ALL) can result in significant morbidity. While methotrexate is primarily renally excreted, HD-MTX may overwhelm renal excretion and increase reliance on fecal elimination. This study evaluated the association between laxative use for constipation and delayed excretion of HD-MTX., Methods: This multisite chart review included pediatric patients with ALL (2010-2020) who received HD-MTX (5 g/m 2 ). Delayed excretion was defined as a serum MTX concentration greater than 0.4 µM at Hour 48. We identified use of laxative medications after each HD-MTX infusion, with receipt of two or more doses considered a proxy for constipation. Multilevel logistic regression models evaluated associations between clinical factors and delayed HD-MTX excretion to account for multiple MTX cycles per individual., Results: A total of 533 eligible patients received 1875 HD-MTX infusions. Patients were mostly male (59.8%), Hispanic (56.7%), with a median age of 9.5 years. Delayed excretion was observed following 42.7% of HD-MTX infusions, and patients received two or more laxative doses during 19.9% of infusions. Independent of other factors, individuals who received two or more laxative doses were nearly 60% (odds ratio 1.58; 95% confidence interval: 1.19-2.09; p = .002) more likely to experience delayed excretion compared to those receiving fewer than two laxative doses., Conclusion: Receipt of at least two laxative doses was independently associated with delayed methotrexate excretion in pediatric patients with ALL. Future prospective studies are needed to confirm the secondary effects of constipation and confirm the association with constipation and identify clinical benefits that optimize drug excretion., (© 2024 The Author(s). Pediatric Blood & Cancer published by Wiley Periodicals LLC.)

Severe intestinal mucositis (IM) increases the risk of bloodstream infections (BSI) and inflammatory toxicity during acute lymphoblastic leukaemia (ALL) induction treatment. However, the implications of IM in subsequent ALL therapy phases after achieving remission remain unknown. This study investigated the relationship between IM (measured by plasma citrulline and the chemokine CCL20) and the development of BSI and systemic inflammation (reflected by C-reactive protein, CRP) in children with ALL during high-dose methotrexate (HDMTX) treatment, an important part of ALL consolidation therapy. The study compared patients treated according to the NOPHO ALL 2008 protocol (n = 52) and the ALLTogether1 protocol (n = 42), both with identical HDMTX procedures but different scheduling. One week post-HDMTX, citrulline dropped to median levels of 14.5 and 16.9 μM for patients treated according to the NOPHO ALL 2008 and ALLTogether1 protocols, respectively (p = 0.11). In a protocol and neutrophil count-adjusted analysis, hypocitrullinaemia (<10 μmol/L) was associated with increased odds of BSI within 3 weeks from HDMTX (OR = 26.2, p = 0.0074). Patients treated according to the NOPHO ALL 2008 protocol exhibited increased mucosal- and systemic inflammation post-HDMTX compared to patients treated according to ALLTogether1, with increased CCL20 (14.6 vs. 3.7 pg/mL, p < 0.0001) and CRP levels (10.0 vs. 1.0 mg/L, p < 0.0001). Both citrulline and CCL20 correlated with CRP for these patients (r s  = -0.44, p = 0.0016 and r s  = 0.35, p = 0.016, respectively). These results suggest that hypocitrullinaemia following HDMTX increases the risk of BSI, confirming previous observations from more intensive treatments. Moreover, these data indicate that the patients' vulnerability to mucositis and inflammatory toxicity after chemotherapy varies with treatment protocol., (© 2024 The Author(s). International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Introduction: The most frequent adverse events (AEs) of methotrexate (MTX) are gastrointestinal symptoms and hepatotoxicity, which can affect its adherence, leading to reduced effectiveness. The SLCO1B1 gene codes for a liver protein (OATP1B1) responsible for drug transportation. Genetic variations within the SLCO1B1 gene locus impact drug transport, leading to altered pharmacokinetic profiles, delayed MTX clearance, and increased risk of toxicity. This study aimed to determine the association between single nucleotide polymorphisms (SNPs) in the SLCO1B1 gene (rs4149056, rs2306283) with the development of AEs in patients with juvenile idiopathic arthritis (JIA) treated with MTX., Method: We performed an observational retrospective study to analyze the relationship between SNPs in the SLCO1B1 gene and the development of AEs in pediatric patients treated with MTX for JIA., Results: Thirty patients with JIA were included, 22 females (73.3%), with a median age of 11 years (IQR 8.3-15). The most frequent JIA subtype was rheumatoid factor-positive polyarthritis (36.7%). Twenty patients (66.7%) reported AEs. The *1B haplotype was the most frequent in this group (53.3%) and conferred a higher risk of developing AEs (OR = 3.89, 95% CI = 1.23 -12.29, p = 0.03)., Conclusions: Patients with the allele *1B may benefit from lower doses of MTX. SLCO1B1 genotyping is a promising technique to identify patients at higher risk of AEs during treatment with MTX, thus requiring dose optimization., Competing Interests: Declarations. Disclosures: None., (© 2024. The Author(s), under exclusive licence to International League of Associations for Rheumatology (ILAR).)

Background: Safety of dupilumab in atopic dermatitis (AD) was investigated in randomized controlled trials (RCT). However, head-to-head trials comparing with conventional systemic drugs are lacking and large real-world data on the long-term safety profile as compared are scarce., Objective: To compare long-term safety profile of dupilumab with conventional systemic drugs used in the management of moderate to severe AD., Methods: Data from electronic health records of AD patients treated with either dupilumab, azathioprine, Cyclosporine A, mycophenolate mofetil, methotrexate, or oral glucocorticoids were retrieved from the TriNetX US Collaborative Network . Risks of adverse events and new onset of type-2-inflammatory diseases within 5 years after treatment initiation was investigated., Results: 5 propensity-matched cohorts, up to 18,708 individuals per cohort, were created. Dupilumab treatment displayed reduced risk for diseases of the circulatory, the upper respiratory, and the musculoskeletal system, infections, and type 2 diseases as compared to all other treatment options. In contrast risk for conjunctivitis was increased in dupilumab treated patients as compared to mycophenolate mofetil and methotrexate., Conclusion: Here presented data indicates that treatment with dupilumab for AD has reduced risk for adverse effects of conventional systemic drugs and thus might be safer. Obtained data should be verified in prospective studies.

Purpose: High-dose methotrexate (HDMTX) therapy is an important component in treatment regimens for acute lymphoblastic leukemia (ALL). Courses are associated with a risk of renal injury, delayed elimination, and increased systemic toxicity. Recently hypoalbuminemia has been recognized as yet another risk factor., Methods: To examine the impact of serum albumin we reviewed 325 HDMTX 5 g/m2 courses in a cohort of 51 children treated on the NOPHO ALL 2008 protocol, dividing the courses into four groups with different levels of baseline albumin (A < 25 g/L, B 25-29 g/L, C 30-34 g/L and D ≥ 35 g/L)., Results: Hypoalbuminemia was present in 51% of the courses, mostly in the early phases of chemotherapy while asparaginase therapy is ongoing, and especially if given less than 2 weeks after a dose (78%). Hypoalbuminemia had a significant impact on the end-of-infusion serum MTX, depending on the degree of hypoalbuminemia: MTX > 150 µM was seen in 37%, 32%, 20% and 8% in groups A to D. Serum albumin < 30 g/L was significantly associated with low MTX clearance < 10 L/h/1.73m2 (78% vs. 36%) and high AUC ≥ 1000 µM*h (44% vs. 31%). The frequency of rising creatinine or prolonged elimination was not increased, but the risk of stomatitis was significantly higher (42% vs. 19%)., Conclusion: Low serum albumin is caused by concurrent asparaginase therapy and has a clinically significant impact on MTX disposition. Guidelines for administering HDMTX may need adjustment if serum albumin < 30 g/L, and, if possible, HDMTX courses should not be scheduled soon after asparaginase doses., Competing Interests: Declarations Conflicts of interest The authors declare no competing interests., (© 2024. The Author(s).)

Dose-limiting toxicities (DLTs) are severe adverse effects that define the maximum tolerated dose of a cancer drug. In addition to the specific mechanisms of each drug, common contributing factors include inflammation, apoptosis, ion imbalances, and tissue-specific enzyme deficiencies. Among various DLTs are bleomycin-induced pulmonary fibrosis, doxorubicin-induced cardiomyopathy, cisplatin-induced nephrotoxicity, methotrexate-induced hepatotoxicity, vincristine-induced neurotoxicity, paclitaxel-induced peripheral neuropathy, and irinotecan, which elicits severe diarrhea. Currently, specific treatments beyond dose reduction are lacking for most toxicities. Further research on cellular and molecular pathways is imperative to improve their management. This review synthesizes preclinical and clinical data on the pharmacological mechanisms underlying DLTs and explores possible treatment approaches. A comprehensive perspective reveals knowledge gaps and emphasizes the need for future studies to develop more targeted strategies for mitigating these dose-dependent adverse effects. This could allow the safer administration of fully efficacious doses to maximize patient survival.