Background Real-world comparative evidence on systemic agents, phototherapy, and biologics for atopic dermatitis (AD) remains limited. Objective To compare 24-week effectiveness and safety of methotrexate (MTX), cyclosporine, narrowband ultraviolet B (NB-UVB) phototherapy, upadacitinib, and dupilumab in adults with AD. Methods In this multicenter retrospective cohort (N = 1000; 200 per monotherapy group) across Saudi Arabia, SCORAD was extracted at baseline and mapped to prespecified weeks 2, 6, 12, and 24. Confounding was addressed using a multinomial propensity score (baseline SCORAD, age, sex, nationality) with overlap weighting; balance was assessed using Max |SMD|. Longitudinal change from baseline (ΔSCORAD) was analyzed using overlap-weighted generalized estimating equations with a treatment-by-time interaction, reporting adjusted marginal mean ΔSCORAD (95% CI). Results Unadjusted 24-week improvement was highest with dupilumab (75.8%) and upadacitinib (74.1%) (p < 0.001). In overlap-weighted models, both were associated with the largest week-24 improvements (ΔSCORAD −27.04 and −26.68). NB-UVB and methotrexate were intermediate, whereas cyclosporine had smaller sustained improvement. Upadacitinib had the highest recorded adverse-event frequency (68.5%), whereas dupilumab had the lowest (9%). Conclusion Dupilumab and upadacitinib were associated with larger 24-week SCORAD improvements than conventional systemic therapies and NB-UVB within this stratified analytic cohort. Results are associative and may be affected by residual confounding.

Objectives: The evidence for treating rheumatoid arthritis (RA) with a treat-to-target (T2T) approach was examined for clinical outcomes. Methods: Since August 2010, RA treatment has implemented the T2T strategy, aiming to achieve a simplified disease activity index (SDAI). The SDAI, Health Assessment Questionnaire Disability Index (HAQ), and pain score (PS-VAS) were monitored. The relationships between these clinical outcomes and variables, including changes in medication, were investigated. Results: Over a 15-year follow-up of 764 RA patients, the total duration was divided into two periods for each outcome. In the First period, the average dose of methotrexate (MTX) increased (p &lt; 0.001). At the same time, glucocorticoids use (GCs) decreased (p &lt; 0.001), and biologic and targeted synthetic disease-modifying anti-rheumatic drugs (bDMARDs and tsDMARDs) use increased (p &lt; 0.01). Consequently, the mean SDAI score declined (p &lt; 0.001), which was attributed to an increase in MTX dose and a decrease in GCs use, However, HAQ scores increased (p &lt; 0.01), and PS-VAS remain stable. In the Second period, the average MTX dose decreased despite stable SDAI and decreasing HAQ scores and PS-VAS (p &lt; 0.01), which was attributed to an increase in the use of tsDMARDs, particularly baricitinib, upadacitinib, and filgotinib (p &lt; 0.01). Overall, the average age increased (p &lt; 0.001), while SDAI scores dropped (p &lt; 0.001), and HAQ scores and PS-VAS decreased (p &lt; 0.01). Conclusions: Clinical outcomes stayed stable with changes in medication use under the T2T approach.

Clinical trials have demonstrated the efficacy of sarilumab in preventing radiographic progression. This study investigated the structural remission rate and factors associated with radiographic progression in patients with rheumatoid arthritis (RA) treated with sarilumab in clinical practice. Of 114 patients treated with sarilumab across four centers, 59 with radiographic assessments at baseline and Week 52 were included. Radiographic progression was assessed using the van der Heijde-modified Total Sharp score (mTSS). Patients were divided into methotrexate (MTX) + and MTX - groups; the structural remission rate (ΔmTSS ≤ 0.5) and associated factors were analyzed. The median age was 69.0years, median disease duration 10.0years, mean disease activity score 28-erythrocyte sedimentation rate 4.94, and median modified Health Assessment Questionnaire 0.5, with no differences between groups. Baseline median erosion score was 21.0, joint space narrowing score was 22.0, and mTSS was 37.0. At Week 52, the mean changes were: erosion 0.33, joint space narrowing score 0.18, and mTSS 0.51, with a structural remission rate of 78.0%, 82.4% for the MTX + group, and 76.2% for the MTX - group. The mean change in joint space narrowing score was higher in the MTX - group (0.42) than in the MTX + group (- 0.20) (p = 0.038). Baseline glucocorticoid (GC) use was associated with radiographic progression (odds ratio, 13.1; 95% confidence interval, 2.51-68.9; p = 0.002). Sarilumab was associated with limited radiographic progression in patients with RA in clinical practice. Associations with MTX use and baseline GC exposure should be interpreted cautiously given the observational design. Key Points • This study reports the structural remission rate and factors associated with radiographic progression in patients with rheumatoid arthritis treated with sarilumab in clinical practice. • The structural remission rate for sarilumab was 78.0%. The change in the joint space narrowing score was significantly higher in the MTX- group (0.42 ± 1.34) compared with the MTX + group (- 0.20 ± 1.22). • Glucocorticoid use was associated with radiographic progression at 52weeks (odds ratio, 13.1).

Redox, inflammatory, and ferroptosis pathway modulation by methotrexate and dexamethasone in primary human RPE cells under basal and acute H₂O₂-induced oxidative stress: An in vitro study.

Effect of methotrexate in preventing retinal detachment after proliferative vitreoretinopathy surgery: A systematic review and meta-analysis.

Methotrexate (MTX) remains a cornerstone therapy for chronic inflammatory diseases (e.g. , rheumatoid arthritis, psoriasis). However, long-standing concerns about MTX hepatotoxicity - especially liver fibrosis - have historically led to conservative monitoring and routine invasive liver biopsies at predefined cumulative dose thresholds. These practices often prompted early discontinuation of MTX therapy. These concerns originated from early liver biopsy studies in high-dose MTX patients that did not adequately account for metabolic risk factors. Emerging evidence indicates that advanced fibrosis is rare in MTX-treated patients and usually attributable to coexisting metabolic comorbidities (e.g. , obesity, insulin resistance) rather than the cumulative MTX dose itself. Moreover, noninvasive fibrosis assessment modalities and recent large cohort studies demonstrate that MTX at standard doses with folate supplementation seldom drives fibrogenesis independently. This review reappraises MTX-related fibrosis risk in light of contemporary data and highlights a shift from dose-driven biopsy protocols to risk-based, noninvasive monitoring strategies. Recognizing that MTX is less hepatotoxic than historically assumed can prevent unnecessary drug discontinuation and refocus management on modifiable metabolic risk factors.

Methotrexate(MTX) is widely used in rheumatology practice for rheumatoid arthritis and many other conditions, including psoriatic arthritis, autoimmune connective tissue diseases, sarcoidosis, and vasculitis. The most common adverse effects of MTX include nausea, fatigue, dizziness, headache, stomatitis and abdominal pain. Serious adverse effects include hepatotoxicity, pulmonary toxicity, nephrotoxicity, myelosuppression and increased risk of lymphoproliferative disorders. In our review of the literature, case reports of sexual dysfunction have beeen reported during MTX therapy. We report here one case of sexual dysfunction during MTX therapy.

Objectives Rheumatoid arthritis (RA) is an autoimmune disease whose treatment has evolved with the introduction of disease-modifying antirheumatic drugs and biological agents such as ritu­ximab (RTX). The objective of this study was to evaluate the efficacy, safety, and treatment adherence of RTX used as monotherapy and in combination with methotrexate (MTX) or leflu­nomide (LFN) in patients with RA refractory to conventional therapy. Material and methods A prospective cohort study was conducted including 157 patients, divided into 3 groups: RTX monotherapy (&lt;i&gt;n&lt;/i&gt; = 48), RTX + MTX (&lt;i&gt;n&lt;/i&gt; = 66), and RTX + LFN (&lt;i&gt;n&lt;/i&gt; = 43). Efficacy, safety, and adherence were evaluated at weeks 1, 24, and 48 using the Health Assessment Questionnaire (HAQ), Disease Activity Score in 28 joints (DAS28), American College of Rheumatology 70% response (ACR70), and Treat-to-Target (T2T) criteria. Ethical approval was obtained from the local institutional ethics committee. Results All 3 therapeutic regimens demonstrated comparable clinical efficacy, with no statistically significant differences in disease activity scores. Adverse events were more frequent in the RTX + LFN group, although not statistically significant. Treatment adherence was highest in the RTX monothe­rapy group (100%). Conclusions No significant differences in efficacy or safety were found among the 3 study groups; However, treatment adherence was significantly higher in the RTX monotherapy group (100%).

The most common autoimmune illness in both developed and under developed countries is rheumatoid arthritis (RA). In the past, RA could not be effectively treated with any existing strategies. However, new medications and therapeutic approaches have been created to combat this condition in the present day as a result of advancements in drug delivery science. Numerous advancements have been made in the therapy formulations for RA that are currently on the market in the last few years. One well-known medication for the treatment of RA is methotrexate (MTX). However, most current treatment formulations have several adverse effects and are unable to completely alleviate all RA symptoms. Combination therapy for the treatment of RA may be more successful than MTX therapy alone in addressing such problems. We discovered that MTX plus infliximab (INF), golimumab (GOL), leflunomide (LEF), folic acid (FA), and azathioprine was more successful than MTX alone because it had less adverse effects and a lower risk of RA relapses. MTX monotherapy has been shown to be less effective than combinations with one or more drugs. We examined the many injectable treatments for RA, focusing on thermo-responsive targeted drug delivery systems as cutting-edge means of delivering MTX, either alone or in conjunction with other treatments. Thermo-responsive in situ hydrogel-based injectables in latest drug delivery systems have the potential to address many of the challenges related to RA treatment and therapy.

A combinational approach to antimicrobial design emerges from a nanoemulsified nanoplatform from the union of two Egyptian essential oils-orange peel and clove-whose distinct chemistries were revealed by GC-MS. Orange EO is dominated by D-limonene (63.25%), with supporting alkyl-benzenes (22.92%) and β-myrcene (1.41%), while clove EO centers on Eugenol (36.20%), Caryophyllene (19.30%), Eugenol acetate (18.71%), along with alkyl-benzenes (11.86%) and humulene (2.41%). The chemical consonance between Eugenol and Limonene hints at a cooperative assembly: their lipophilic profiles enable the formation of nanoemulsified nanoparticles from their emulsion blend, potentially amplifying bioavailability and multi-target action. Biologically, Eugenol/Limonene demonstrates tangible antimicrobial activity. In a direct DHFR inhibition assay, the nanoformulation inhibits DHFR with an IC50 of 8075 ± 0.96μg/mL, while the benchmark drug methotrexate (MTX) shows far stronger inhibition ( IC50 = 0.81 ± 0.07μg/mL). Across pathogenic strains, the nanoemulsion exhibits broad antibacterial reach, producing inhibition zones of 24.0-29.0mm and delivering bactericidal effects with MICs of 8.0-32.0μg/mL and MBCs of 64.0-512.0μg/mL. Explorations into in vivo-like tissue responses reveal nuanced outcomes. The nano-treated cohort shows dramatic reductions in bacterial load, yet also manifests airway changes consistent with bronchiolar irritation and alveolar remodelling, signalling both therapeutic potential and safety considerations. Histological comparisons indicate that nanoparticle-treated groups preserve some alveolar integrity, with Type II pneumocytes and lamellar bodies present. Overall, the study underscores the promise of combining EO components to enhance antimicrobial performance via nanostructured carriers, while highlighting the delicate balance between efficacy and pulmonary safety.

Methotrexate (MTX) is the anchor conventional synthetic disease-modifying antirheumatic drug (csDMARD) in rheumatoid arthritis. Postmarketing safety patterns may differ between MTX monotherapy and MTX-based dual-csDMARD combinations. This study aimed to compare disproportionality signals for MTX alone versus MTX combined with hydroxychloroquine, leflunomide, or sulfasalazine and comparison with drug information safety profiles. A retrospective disproportionality study was conducted using a spontaneous reporting database across 2016Q1 to 2025Q2. Groups were MTX only (MTX as primary suspect) and MTX + hydroxychloroquine, leflunomide, or sulfasalazine (two drug reports with one primary suspect and one secondary suspect). Reporting odds ratios (RORs) were estimated at system organ class (SOC) and preferred term (PT) levels. Significant PTs were checked against drug information safety profiles. Time-to-onset (TTO) was summarized. A total of 148,315 reports were eligible. SOC signals were modest for MTX only, and highest for infections and infestations (ROR = 1.77) and blood and lymphatic disorders (ROR = 1.77). Combination cohorts showed strong musculoskeletal signals (ROR 8.13 to 9.64) and investigations (ROR = 3.25 to 3.72). Selected PT RORs included mucosal inflammation = 12.47, bone marrow failure = 12.83, and B-cell lymphoma = 13.94 in MTX only. Chondropathy reached 19.16 in MTX + leflunomide. Lip blister reached 17.02 and compartment syndrome 17.56 in MTX + sulfasalazine. Early TTO was seen for vomiting (median 22days; 67% within 30days) and mucosal inflammation (median 14days; 58% within 30days) in MTX only. Drug ineffective was delayed across groups, up to 1422days in MTX + hydroxychloroquine. Strict exposure signal detection identified regimen-specific SOC, PT, and TTO patterns. Several significant PTs were not captured in drug information profiles and warrant follow-up.

To assess the predictive value of hematologic and biochemical inflammatory indices for methotrexate (MTX) treatment outcomes in tubal ectopic pregnancy (TEP) and to develop machine learning (ML) models for individualized risk stratification. This retrospective cohort included 293 hemodynamically stable TEP patients who were treated with a single dose of MTX between January 2019 and December 2023. Demographic, clinical, ultrasonographic, and laboratory data were analyzed. Inflammatory indices-including neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio, systemic immune-inflammation index, systemic inflammation response index (SIRI), aggregate index of systemic inflammation (AISI), and fibrinogen-to-albumin ratio (FAR)-were calculated. Outcomes were categorized as single-dose MTX success, requirement for additional MTX, or surgery. Predictive accuracy of five supervised ML algorithms was evaluated using receiver operating characteristic analysis. Single-dose MTX was successful in 65.5% of patients; 18.4% required an additional dose, and 16.0% underwent surgery. AISI had the highest predictive accuracy for surgery [area under the curve (AUC)=0.929], followed by SIRI (AUC=0.899) and FAR (AUC=0.847). NLR best predicted the need for additional MTX (AUC=0.675). Naïve Bayes achieved the highest performance for surgical prediction (accuracy=98.3%, AUC=0.998), while random forest and gradient boosting were most effective in predicting the need for additional MTX (accuracy=83.1%, AUC=0.884-0.896). Feature importance analyses consistently ranked AISI, SIRI, and FAR as top predictors. AISI, SIRI, and FAR are strong predictors of MTX failure and surgical intervention in TEP. Combining these biomarkers with ML models markedly improves predictive performance and supports a personalized approach to TEP management. Multicenter prospective validation is needed before clinical application.

Methotrexate (MTX) is used in treating several malignancies. However, MTX neurotoxicity remains a significant clinical side effect, leading to cell division malformation, and neurogenesis impairment. Chrysin, a flavonoid compound found in natural products, demonstrates various biological characteristics, including neuroprotective and antioxidant properties. The purpose of this study was to investigate the ameliorative effect of chrysin on oxidative damage and neurogenesis impairment caused by MTX. Male Sprague-Dawley rats were randomly divided into four groups, including the vehicle, MTX (75 mg/kg), chrysin (10 mg/kg), and chrysin+MTX groups. Chrysin was orally administered for 15 days. MTX was administered intravenously on days 8 and 15. The hippocampal neural stem cells were evaluated using sex determining region Y-box 2 (sox2) and nestin immunofluorescence staining. Antioxidant enzyme expression and the levels of oxidative stress marker were assessed. Additionally, the expressions of nuclear factor erythroid 2-related factor 2 (Nrf2), brain-derived neurotrophic factor (BDNF), cAMP-response element binding (CREB), and phosphorylated CREB (pCREB) were evaluated using Western blotting. Results showed that MTX significantly decreased the activity of antioxidant enzymes and produced oxidative stress. MTX also impaired neurogenesis, evidenced by decreased sox2 and nestin-positive cells and decreased expression of Nrf2, BDNF, CREB, and pCREB in the hippocampus and prefrontal cortex. However, chrysin significantly reversed the effects of MTX on these parameters. In conclusion, chrysin exhibits neuroprotective effects against MTX-induced neurogenesis impairment by upregulating antioxidant enzyme activity, reducing oxidative stress, and improving protein expression related to neurogenesis.

Juvenile idiopathic arthritis (JIA) used to be a joint-destroying disease, but thanks to modern treatment strategies and medications, many patients with JIA today reach inactive disease. However, once disease remission is achieved, there is a lack of knowledge and recommendations regarding maintenance therapy. Drug-free remission is the ultimate goal in JIA, but withdrawal of medications increases the risk of disease flare. Clinical approaches vary widely, underscoring a need for knowledge about maintenance treatment strategies that allow for safe tapering and withdrawal of medications in JIA patients in sustained remission. The MOVE-JIA study is a randomized, controlled trial with the primary objective to compare the effect of two different treatment withdrawal strategies, to a stable dose of methotrexate (MTX) and tumor necrosis factor inhibitors (TNFi), based on the risk of flares in children and adolescents with JIA with sustained inactive disease. A key secondary objective is the proportion of children with disease flare compared between the two withdrawal groups. In this investigator-initiated multicenter, randomized, 3-grouped, parallel, open-label, noninferiority trial, treating physicians at seven Norwegian pediatric rheumatology hospital centers will include 150 patients with JIA. Key eligibility criteria are as follows: Fulfilment of the International League of Associations for Rheumatology (ILAR) classification criteria for non-systemic JIA, inactive disease for ≥ 12months documented at a minimum of 2 consecutive visits, and no active uveitis for ≥ 24months under treatment with stable doses of MTX and TNFi. They will be randomized in a 1:1:1 ratio to (A) stable treatment, (B) methotrexate withdrawal, or (C) TNFi withdrawal. Randomization will be stratified for JIA subtype and study center. For patients in group B and C who are still in remission after 12months, a new randomization will be performed for complete medication withdrawal for the next 12months. After 24months, medication adjustments will be done with shared decision-making. The primary endpoint is the rate of disease flare compared between the drug withdrawal groups and the stable treatment group between baseline and 12months follow-up. The key secondary endpoint is the proportion with disease flare compared between the two withdrawal groups. Incidence and severity of adverse events will be monitored. The results from the MOVE-JIA trial will present an evidence-based treatment strategy for JIA patients with inactive disease. The trial will also give us knowledge about regaining disease remission after flares and possibilities of drug-free remission. All outcomes from the trial will provide a scientific basis for optimized JIA care and result in new treatment recommendations. EU CT 2024-512017-12-00. Registered on October 24th, 2024; ClinicalTrials.gov NCT06653634. Registered on October 24th, 2024. URL: Study Details | NCT06653634 | Optimizing Treatment for Patients With Juvenile Idiopathic Arthritis in Sustained Remission: The MOVE-JIA Trial | ClinicalTrials.gov. Date of first recruitment: October 24th, 2024.

Abstract Background: Granulomatous mastitis (GM) is a rare, benign inflammatory breast condition primarily affecting parous, reproductive-aged women. However, Hispanic and African American women are disproportionately affected. As GM can mimic malignant breast disease, it remains a diagnostic and therapeutic challenge, especially in the absence of standardized treatment guidelines. Methods: A single-institution, retrospective review of all cases of GM sequentially captured from January 2024 to March 2025 at a minority-serving breast clinic. A total of 4 patients were included in the study. Results: All four patients initially presented with breast pain, swelling, and masses concerning for malignancy based on clinical findings and imaging. Biopsies in each case confirmed granulomatous mastitis without evidence of malignancy. Antibiotics and steroids provided partial or temporary relief in three patients, but recurrent or persistent disease led to the application of disease-modifying antirheumatic drug therapy with methotrexate (MTX). Notably, all patients had a negative rheumatologic workup. Conclusions: This series illustrates the varied clinical spectrum of GM and underscores the importance of a timely biopsy to differentiate it from carcinoma, particularly in women of color. Notably, our case series suggests that early MTX initiation can be valuable, particularly in patients with persistent or recurrent disease despite antibiotics and corticosteroids, which could reduce morbidity and avoid prolonged surgical interventions. Prospective studies are needed to further clarify the role of early MTX in GM management and to establish standardized treatment protocols. Citation Format: A. M. Otieno, D. Dewar, T. Haroun, Q. Chu, S. Nagel, M. Tee, R. Williams. Case Series on Early Methotrexate Use in Reducing Morbidity in Granulomatous Mastitis [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS5-06-06.

Hepatorenal toxicity is one of the most life-threatening adverse effects of methotrexate (MTX). The present study investigated the potential protective effects of glutamine (GLU), glycine (GLY), methionine (MET), and leucine (LEU) in MTX-induced hepatorenal toxicity in vitro and in vivo. Freshly isolated hepatocytes and renal slices of rats were used to investigate the effect of these amino acids in vitro, while male Sprague-Dawley rats were used to evaluate their effects in vivo. Rats were assigned into 6 equal groups: a negative control, MTX (20mg/kg/day, i.p., 3days), MTX + (GLU 25mg/kg/day i.p., 6days), MTX + (GLY 0.5 gm/kg/day, i.p., 3days), MTX + (MET 1mg/kg/day, i.p., 6days) and MTX + LEU (50mg/kg/day, i.p., 6days). These amino acids showed enhanced viability of liver and kidney cells assessed by trypan blue exclusion and lactate dehydrogenase leakage tests, respectively. Besides, pre-incubation of suspended hepatocytes or renal slices with GLU (25mM and 10mM, respectively), GLY (25mM and 5mM, respectively), MET (12.5mM and 5mM, respectively) or LEU (25mM and 10mM, respectively), 30min before MTX, significantly down-regulated caspase-3 and TNF-α levels as compared with MTX-intoxicated groups. MTX-induced hepatorenal toxicity was manifested by increasing liver and kidney enzymes, oxidative stress and severe histopathological alterations. Amino acids pre-treatment abrogated MTX-induced alteration in hepatorenal toxicity indices as evidenced by amelioration in oxidative stress, inflammatory mediators, and histopathological changes. Amino acids may serve as a promising adjuvant therapy with MTX as it may ameliorate its hepatorenal toxicity through antioxidant, anti-inflammatory and anti-apoptotic mechanisms.

The anoikis signature in rheumatoid arthritis: Insights into methotrexate resistance and the complementary therapeutic role of triptolide.

Methotrexate (MTX), a common chemotherapeutic and immunosuppressive drug, is limited by dose-dependent nephrotoxicity mediated by oxidative stress, mitochondrial dysfunction, and apoptosis. L-carnitine (LCR), a mitochondrial cofactor with antioxidant and anti-apoptotic properties, may counteract these mechanisms. This study aims to determine whether LCR mitigates MTX-induced nephrotoxicity by rebalancing the BAX/BCL2 apoptotic axis and preserving renal compartment integrity (endothelial CD31, tubular cytokeratin, podocyte WT1). Twenty-four female Wistar rats were randomized into Control, MTX (20 mg/kg, i.p., Day 5), LCR (200 mg/kg/day, i.p., 10 days), and MTX + LCR groups (n = 6 each). Renal injury was assessed by serum creatinine, urea, BUN, histopathology, immunohistochemistry (CD31, cytokeratin, WT1), and RT-qPCR for BAX/BCL2. MTX impaired renal function, caused vascular hyperemia, hemorrhage, and tubular necrosis, increased CD31, cytokeratin, and BAX and decreased WT1 and BCL2. LCR co-treatment improved biochemical indices, reduced lesions, decreased CD31 and cytokeratin, partially restored WT1 and re-balanced apoptosis (BAX↓, BCL2↑). LCR disrupts oxidative stress, the mitochondrial apoptosis cascade, and preserves endothelial, tubular, and podocyte integrity in MTX nephrotoxicity.

To provide evidence from randomized controlled trials (RCTs) for large-vessel vasculitis (LVV), including Takayasu arteritis (TAK) and giant cell arteritis (GCA), to inform the forthcoming 2026 Japanese Circulation Society (JCS) clinical practice guideline. We drafted 4 and 7 clinical questions for TAK and GCA, respectively. A systematic review (SR) of RCTs was conducted using PubMed, CENTRAL, EMBASE, and the Japan Medical Abstracts Society through March 2024. Assessed with the GRADE approach, the certainty of evidence was very low for the most critical outcomes, low for some outcomes, and moderate for only 1 outcome. Evidence for TAK was limited. Tocilizumab (TCZ) resulted in a numerically lower relapse rate vs. placebo (risk ratio (RR) 0.73, 95% confidence interval (CI) 0.39-1.37) and was similar to adalimumab. No clear difference between mycophenolate mofetil (MMF) and methotrexate (MTX), or between abatacept (ABA) and placebo was observed. In GCA, TCZ reduced relapse (RR 0.29, 95% CI 0.09-0.98) and increased remission (RR 3.56, 95% CI 2.29-5.54) over placebo at 52 weeks. Tumor necrosis factor inhibitor, ABA, and MTX showed no benefit in cranial GCA. Serious adverse events were comparable between treatment groups. Geographic variation and differences in entry criteria were noted. This SR was comprehensive synthesis of evidence from RCTs for LVV therapies to support the 2026 JCS guideline.

Methotrexate (MTX)-induced pulmonary toxicity severely limits its clinical use and effective preventive strategies are lacking. This study evaluated the protective effects of agomelatine (AGO), a melatonergic antidepressant, against MTX-induced lung injury, focusing on its dual-pathway action targeting both immune cell infiltration and apoptotic signaling. Thirty-two female Wistar rats were assigned to: Control, AGO (20 mg/kg/day, p.o., 7 days), MTX (single i.p. dose, 20 mg/kg), and MTX + AGO groups. Lung tissues were examined by histopathology, immunohistochemistry (CD45+, CD68+), and RT-qPCR (BAX, BCL2). MTX administration caused marked pulmonary damage (histopathological score: 2.75 ± 0.25, p < 0.001), significant infiltration of CD45+ leukocytes and CD68+ macrophages and an elevated BAX/BCL2 ratio (3.5 ± 0.4 vs. 1.0 ± 0.2 in Control, p < 0.001). AGO cotreatment significantly ameliorated these alterations via its dual activity, lowering the histopathological score (1.25 ± 0.25, p < 0.01), reducing CD45+/CD68 immunopositivity, and restoring the BAX/BCL2 ratio toward cell survival (1.4 ± 0.3, p < 0.01 vs. MTX). These findings provide integrated immunohistochemical and molecular evidence supporting the concurrent modulation of immune cell infiltration and apoptotic signaling by AGO in MTX-induced lung injury. Given its established clinical use and favorable safety profile, AGO may represent a potential adjunctive candidate to reduce the risk of MTX-related pulmonary complications, through concurrent targeting of immune and apoptotic pathways.