Methotrexate Treatment Research Articles

Associations of gender with sexual functioning, loneliness, depression, fatigue and physical function amongst patients suffering from rheumatoid arthritis with a particular focus on methotrexate usage

There is a lack of knowledge regarding methotrexate (MTX) usage in patients with rheumatoid arthritis (RA) and its possible links with gender, disease characterization and sexual functioning, loneliness, fatigue and depression. We, therefore, investigated the associations of gender with physical function, fatigue, depression, loneliness and sexual functioning with a particular focus on MTX usage. A cross-sectional study design was used. Inclusion criteria were RA diagnosis, age above 18 years and available data on MTX treatment 1 year after diagnosis. Data consisted of responses from validated questionnaires regarding physical function, fatigue, depression, loneliness and sexual functioning combined with evaluations from medical records. Data were analysed with linear regression models comparing numerical outcome measures between male and female patients and between MTX users and MTX non-users. Amongst 286 patients with RA (69 men and 217 women), 67.8% were MTX users 1 year after diagnosis. Comparing women and men, both overall and within subgroups of MTX usage, we found significantly more adverse outcomes for women than men in physical functioning at diagnosis and in sexual function, depression, fatigue and physical functioning at enrolment in the study. Gender differences were also present when comparing MTX users with MTX non-users divided by gender. There were only significant differences in the HAQ and loneliness scores when comparing MTX users with MTX non-users. Women with RA had more negative outcomes measured by the selected PROMs compared to men with RA, both overall and in subgroups of users and non-users of MTX. These findings call for sharpened attention to the importance of gender in the treatment and care of patients with RA, as well as in future clinical research.

Metabolomic Alterations in Methotrexate Treatment of Moderate-to-Severe Psoriasis.

BACKGROUND Aberrant lipid metabolism alterations in skin tissue, blood, or urine have been implicated in psoriasis. Here, we examined lipid metabolites related to psoriasis and their association with the age of disease onset. MATERIAL AND METHODS Differences in lipid metabolites before and after methotrexate (MTX) treatment were evaluated. The discovery cohort and validation cohort consisted of 50 and 46 patients, respectively, with moderate-to-severe psoriasis. After MTX treatment, the patients were divided into response (Psoriasis Area and Severity Index [PASI] 75 and above) and non-response (PASI below 75) groups, blood was collected for serum metabolomics, and multivariate statistical analysis was performed. RESULTS We detected 1546 lipid metabolites. The proportion of the top 3 metabolites was as follows: triglycerides (TG, 34.8%), phospholipids (PE, 14.5%), phosphatidylcholine (PC, 12.4%); diglycerides (DG) (16: 1/18: 1), and DG (18: 1/18: 1) showed strong positive correlations with onset age. There were marked changes in TG (16: 0/18: 0/20: 0), TG (18: 0/18: 0/22: 0), TG (14: 0/18: 0/22: 0), TG (14: 0/20: 0/20: 0), lysophosphatidylcholine (LPC) (16: 0/0: 0), LPC (18: 0/0: 0), LPC (14: 0/0: 0), and LPC (18: 1/0: 0) levels before and after 12 weeks of MTX treatment. The glycerophospholipid metabolic pathway was implicated in psoriasis development. Of the 96 recruited patients, 35% were MTX responders and 65% non-responders. PE (34: 4) and PE (38: 1) levels were significantly different between the groups. Obvious differences in lipid metabolism were found between early-onset (<40 years) and late-onset (≥40 years) psoriasis. Significant changes in serum lipid profile before and after MTX treatment were observed. CONCLUSIONS The specific lipid level changes in responders may serve as an index for MTX treatment efficacy evaluation.

Pulse azathioprine and low-dose methotrexate vs. standard-dose methotrexate in treatment of patients with moderate-to-severe psoriasis: a randomized controlled trial.

Psoriasis is a common chronic, immune-mediated inflammatory skin disease. Despite the availability of several systemic therapeutic agents, treatment of psoriasis remains a challenge because of the associated adverse effects and/or the financial burden of these medications, given the chronicity of the disease. We aimed to compare the efficacy and safety of combined pulse azathioprine (AZA) and low-dose methotrexate (MTX) vs. a conventional dose of MTX in patients with chronic plaque psoriasis. In this randomized controlled trial, 67 patients with moderate-to-severe plaque psoriasis were randomized into two groups, receiving either combined pulse AZA (300 mg weekly dose) and low-dose MTX (10 mg weekly) or conventional-dose MTX (0.3 mg kg-1 per week) for 16 weeks. Patients were assessed for treatment response using the Psoriasis Area and Severity Index (PASI) score and for the development of any adverse effects at weeks 12 and 16, and for a further 3 months after stopping treatment. A statistically significantly higher proportion of the patients receiving combined pulse AZA and low-dose MTX achieved ≥ 90% improvement in PASI and 100% improvement (PASI 100) at week 12, and PASI 100 at week 16, compared with those receiving the conventional dose of MTX as monotherapy. No serious adverse events were reported during the entire study period in the two groups. Combination therapy using pulse AZA and low-dose MTX can be an efficacious treatment for moderate-to-severe plaque psoriasis, with a relatively good safety profile.

Evaluation of the parameters in predicting single-dose methotrexate therapy success for ectopic pregnancy.

Methotrexate has demonstrated efficacy in treating ectopic pregnancies. This study explores factors influencing treatment success, focusing on laboratory and ultrasonographic findings, particularly the day 4 to day 1 β-hCG level ratio. Retrospective cohort study was conducted within patients diagnosed with tubal ectopic pregnancy. Patients' characteristics, ultrasound findings, laboratory data, and β-hCG levels (days 1, 4, 7), and operation findings were reviewed. Women's characteristics were investigated who were treated with single dose of MTX (50 mg/m2 ). Patients who were performed surgery after MTX treatment were identified as MTX treatment failure. Among 439 women, 259 underwent surgery due to acute symptoms. Of those treated with MTX, 143 experienced treatment success, while 37 underwent surgery after MTX (MTX failure). Comparative analysis revealed significant differences in β-hCG levels on admission (1128 and 4125 mIU/mL) and the day 4 to day 1 β-hCG ratio (0.91 and 1.25). The overall MTX success rate was 79%, reaching 93% and 89% for β-hCG levels <1000 mIU/mL and <2000 mIU/mL, respectively. Success dropped to 50% with levels exceeding 5000 mIU/mL. ROC analysis identified a crucial 2255 mIU/mL cut-off for β-hCG (sensitivity 70.3% and specificity 68.5%) and a day 4 to day 1 β-hCG ratio of 95.5% (sensitivity 84.7%, specificity 72.5%, positive predictive value 75.4%) for predicting MTX success. Establishing a β-hCG cutoff can reduce hospital stay. The day 4 to day 1 β-hCG ratio holds promise as a widely applicable predictor for MTX success or for determining MTX administration on day 4.

Treatment modalities for granulomatous mastitis, seeking the most appropriate treatment with the least recurrence rate: a systematic review and meta-analysis

BackgroundGranulomatous mastitis (GM) is a rare, benign, inflammatory breast disease with an unknown etiology that predominantly affects women of reproductive age. The definitive treatment of GM is currently controversial; an appropriate therapeutic strategy has yet to be identified, and the disease’s high recurrence rate remains. This study aims to determine the recurrence rate for each GM treatment strategy to identify the most appropriate treatment modality.MethodsThe search for relevant articles was undertaken using three international databases, including Medline, Scopus, and Web of Science. Articles published in English until the end of 2021 evaluating the recurrence rate of GM were included. Using Stata 13.0, the pooled incidence and 95% confidence interval (CI) for the recurrence rate were determined.ResultsSixty-five eligible studies were included in our study. The recurrence rates of systemic steroid use, topical steroid use, antibiotic use, methotrexate use, observation, drainage, excision, antibiotic use and surgery, steroid use and surgery, antibiotic and steroid use, methotrexate and steroid use were 24% (95% CI: 21–27%), 11% (95% CI: 6–21%), 18% (95% CI: 14–22%), 13% (95% CI: 7–22%), 11% (95% CI: 7–17%), 65% (95% CI: 50–78%), 13% (95% CI: 10–16%), 23% (95% CI: 14–36%), 7% (95% CI: 5–11%), 11% (95% CI: 6–18%), and 4% (95% CI: 2–8%), respectively. Drainage had the highest recurrence rate, while combined methotrexate and steroid treatment had the lowest rate.ConclusionThe optimal treatment strategy for GM depends on the disease’s severity, consequences, and the patient's features. The study results indicate that combination therapy is preferable for minimizing the risk of relapse and reducing treatment complications.

Prevalence of overweight and obesity, and associated risk factors in an axial spondyloarthritis cohort

Background. Overweight and obesity are more common in axial spondyloarthritis (axSpA) cohorts than in the general population. The purpose of this study wase to assess the prevalence of overweight in patients with axSpA depending on sex and to identify axSpA-related factors, which are positively associated with body weight (BW). Materials and methods. Study design: a retrospective single-institution case series. Data source: medical records of patients with axSpA. Nutritional status was categorized by body mass index (BMI) according to WHO criteria. Results. The data of 142 patients with axSpA (78.2 % men) were analyzed. Weight was positively associated with: height (p &lt; 0.0001), BASMI ≥ 4 (p &lt; 0.0001), methotrexate treatment (p &lt; 0.000) and cumulative glucocorticoids (GCs) dose ≥ 1.45 g (p = 0.01), with the relative importance (RI) of each factor of 100, 59, 61, and 24.8 %. The strength of the association between BW and BASMI was attenuated under the influence of the following confounders: gender (23.7 %), age (20.7 %), height (12.9 %) and strengthened under by the influence of BASDAI ≥ 7 (by 13.7 %) and the duration of GCs therapy (by 11.1 %). Height was negatively associated with female gender (p &lt; 0.0001) and back pain intensity (p &lt; 0.04). The developed regression models for body weight and height explained, respectively, 57.8 and 54 % of the variations parameters of patients with axSpA. Conclusions. Prevalence of overweight in the study sample of Ukrainian axSpA patients is lower than in cohorts outside of Ukraine, but still significant positive association of BW with spinal mobility limitation, exposure to MTX and high cumulative dose of GCs provides preliminary evidence their role in pathological weight gain.

Comparison of effectiveness of methotrexate in patients with late-onset versus younger-onset rheumatoid arthritis: Real-world data from an inception cohort in Japan (NICER-J).

To compare the effectiveness of methotrexate (MTX) as initial therapy in patients with late-onset and younger-onset rheumatoid arthritis (LORA and YORA). Of 114 patients with YORA and 96 patients with LORA, defined as RA occurring at ≥65 years of age, enrolled in a multicentre RA inception cohort study, 71 and 66 patients who had been followed up to 6 months after starting MTX treatment were included in this study. Proportions of patients on MTX treatment at 6 months were 96% and 92% in the YORA and LORA groups, respectively. Despite lower doses of MTX in the LORA group compared with the YORA group, no significant difference was observed in clinical disease activity index scores between the two groups throughout the follow-up period. The proportion of patients in clinical disease activity index remission at 6 months was 35% in both groups. Logistic regression analysis revealed that knee joint involvement and high Health Assessment Questionnaire-Disability Index were significant negative predictors of achieving clinical disease activity index remission at 6 months in the LORA group. Observations up to 6 months revealed that the effectiveness of MTX administered based on rheumatologist discretion in patients with LORA is comparable to that in patients with YORA in clinical settings.

Methotrexate treatment strategies for rheumatoid arthritis: a scoping review on doses and administration routes

BackgroundTo describe the evidence of methotrexate (MTX) initiation strategies in patients with rheumatoid arthritis (RA) and, in the case of non-responders, analyse the efficacy and safety of route and dose optimisation.MethodsWe conducted a comprehensive scoping review of randomised controlled trials according to PRISMA Scoping Reviews Checklist and the framework proposed by Arksey and O’Malley. PubMed, EMBASE, and Cochrane were searched without language restriction, and hand searches of relevant articles were examined.ResultsWe identified 1,367 potentially eligible studies, of which 12 were selected based on the titles and abstracts and then on the full-length articles. In naïve-MTX patients, a linear dose-response relationship for starting dose was found between 5 mg/m2/week (7.5–10 mg/week) and 10 mg/m2/week (15–22 mg/week), without toxicity correlation. A higher initial dose of MTX (25 mg vs. 15 mg) was more effective, resulting in fewer dose increases due to ineffectiveness and more dose reductions due to higher remission rates. There was also a trend towards increased gastrointestinal toxicity. Comparing different routes of administration of MTX, subcutaneous MTX showed a statistically higher ACR20 response (85%) in comparison with oral MTX (77%) (p < 0.05). The clinical efficacy and safety of accelerated and conventional start MTX regimens were comparable between 7.5 and 15 mg with a 2,5 mg dose increase every two weeks. In RA patients who have failed the initial treatment with MTX, the stepwise increase in MTX doses is associated with a higher ACR20 response and sustained remission rate than other strategies. In MTX non-responders, optimisation to SC MTX was associated with improvements in ACR20 and ACR50 rates with similar toxicity between groups. In the early RA patients subgroup, SC MTX showed higher ACR20 response rates than oral MTX, and intensive oral methods have a much higher sustained remission rate, shorter mean time to remission, and better clinical disease activity measures than conventional treatments.ConclusionsHigher starting doses of MTX and initial subcutaneous MTX made better performance in improving the ACR20 response, although the clinical effectiveness and safety of other MTX start regimens are comparable. This scoping review provides evidence in support of optimising MTX treatment in terms of route and dose prior to concluding that MTX treatment in RA patients has failed.

Changes in Inflammatory Cytokines in Responders and Non-Responders to TNFα Inhibitor and IL-17A Inhibitor: A Study Examining Psoriatic Arthritis Patients.

This study aimed to examine the changes in biomarker levels in responders and non-responders to tumor necrosis factor alpha inhibitor (TNFi) and interleukin-17A inhibitor (IL-17Ai) in psoriatic arthritis (PsA) patients over a 4-month period after treatment initiation. A total of 68 PsA patients initiating either TNFi, IL-17Ai, or methotrexate treatment were included. Blood plasma and clinical outcome measures were collected adjacent to treatment initiation and after four months. A commercially available multiplex immunoassay was included to evaluate 54 biomarkers. Mean changes were used to evaluate change over time. A statistically significant decrease in pro-inflammatory cytokines IL-6 (log-transformed mean change -0.97, 95%CI -4.30; 2.37, [p = 0.032]) and an increase in anti-inflammatory IL-10 (0.38, 95%CI 1.74; 2.50 [p = 0.010]) were seen in TNFi responders. Meanwhile, a statistically significant increase in the target cytokine IL-17A was seen in both IL-17Ai responders (2.49, 95%CI -1.84; 6.85 [p = 0.031]) and non-responders (2.48, 95%CI -1.46; 6.41 [p = 0.001]). This study demonstrated differing changes in cytokine levels when comparing treatment responders and non-responders, highlighting the need to improve the understanding of the different immune response mechanisms explaining different responses to medical treatment in PsA patients.

Involvement of the ABCB1 C3435T Variant but Not the MTHFR C677T or MTHFR A1298C Variant in High-Dose Methotrexate-Induced Toxicity in Pediatric Acute Lymphoblastic Leukemia Patients in China.

It remains unclear whether the MTHFR C677T, MTHFR A1298C and ABCB1 C3435T genetic variants are associated with methotrexate (MTX) elimination delay and high-dose MTX (HD-MTX) toxicities in the treatment of pediatric acute lymphoblastic leukemia (ALL). The aim of our study was to analyze the potential predictive role of MTHFR C677T, MTHFR A1298C and ABCB1 C3435T in toxicities and the relationship between these variants and MTX elimination delay during HD-MTX therapy in pediatric ALL patients. We conducted a retrospective study on ALL patients receiving HD-MTX treatment with available MTHFR C677T, MTHFR A1298C and ABCB1 C3435T genotype and 44-h plasma MTX levels. Logistic regression analyses and chi-square tests were used to assess the relationship between the variants and HD-MTX toxicities and MTX elimination delay. Genotype frequencies were in Hardy-Weinberg equilibrium. MTX elimination delay did not significantly differ between MTHFR C677T and MTHFR A1298C or ABCB1 C3435T. Leukopenia (P=0.028), neutropenia (P=0.034) and oral mucositis (P=0.023) were 6.444-fold, 4.978-fold and 9.643-fold increased, respectively, in ABCB1 C3435T homozygous genotype (TT) patients compared to wild-type (CC) patients. No significant association was found between the toxicities investigated and MTHFR C677T or MTHFR A1298C. This study showed that the ABCB1 C3435T homozygous allele genotype (TT) is associated with increased MTX-related toxicities (leukopenia, neutropenia and oral mucositis). These results may help to distinguish pediatric ALL patients with a relatively high risk of MTX-related toxicities before HD-MTX infusion and optimize MTX treatment.

Association of the rs1801133 and rs1801131 polymorphisms in the MTHFR gene and the adverse drug reaction of methotrexate treatment in a sample of Iraqi rheumatoid arthritis patients

Background: Methotrexate is one of the mainstays for treating rheumatoid arthritis (RA) with a wide range of adverse drug reactions, however, it’s the relationship between adverse drug reactions and genetic polymorphism remains to be highlighted, and there is a lack of studies concerning Arabic Iraqi population regarding this aspect. Objective: Evaluate the association between genetic mutations in the MTHFR gene in SNPs (rs1801133G&amp;gt;A and rs1801131T&amp;gt;G) on the adverse drug reaction for RA Iraqi patients. Methods: An observational study, that involved 95 Iraqi RA patients with established RA. Patients were divided according to the occurrence of adverse drug reactions. A polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was being utilized for MTHFR variants (rs1801133 and rs1801131). The Macrogen Company (Korea) provided the forward and reverse primers in lyophilized form. All PCR procedures are carried out using a PCR thermal cycler (Germany). Results: The study included 95 patients with RA, with a mean age of 43.1 ± 10.6 years, most of the patients were female (85.3%), about 35.8% were smokers, most of the patients had disease low activity (45.2%), followed by moderate (41.1%), high (9.5%), and remission (4.2%). No significant association between individual genetic polymorphism with adverse drug reactions. AG haplotype for rs1801133 rs1801131 polymorphism is associated with reducing the risk of overall adverse drug reactions, meanwhile, GT haplotype for rs1801133, and rs1801131 polymorphism were marginally associated with increased risk of adverse drug reactions. Conclusion: In conclusion, we have successfully found a panel of pharmacogenetic indicators that have the potential to be valuable in predicting the response to methotrexate treatment in patients with rheumatoid arthritis. Haplotypes for rs1801133 rs1801131 polymorphism are associated with reducing or increasing the risk of MTX adverse drug reactions. It is very important to evaluate patients’ haplotypes before starting the therapy program so that we can expect the treatment outcome with the most suitable dose and most tolerable one at the same time.

Exploring candidate biomarkers for rheumatoid arthritis through cardiovascular and cardiometabolic serum proteome profiling.

RA patients are at higher risk of cardiovascular disease, influenced by therapies. Studying their cardiovascular and cardiometabolic proteome can unveil biomarkers and insights into related biological pathways. This study included two cohorts of RA patients: newly diagnosed individuals (n=25) and those with established RA (disease duration >25 years, n=25). Both cohorts were age and sex-matched with a control group (n=25). Additionally, a longitudinal investigation was conducted on a cohort of 25 RA patients treated with methotrexate and another cohort of 25 RA patients treated with tofacitinib for 6 months. Clinical and analytical variables were recorded, and serum profiling of 184 proteins was performed using the Olink technology platform. RA patients exhibited elevated levels of 75 proteins that might be associated with cardiovascular disease. In addition, 24 proteins were increased in RA patients with established disease. Twenty proteins were commonly altered in both cohorts of RA patients. Among these, elevated levels of CTSL1, SORT1, SAA4, TNFRSF10A, ST6GAL1 and CCL18 discriminated RA patients and HDs with high specificity and sensitivity. Methotrexate treatment significantly reduced the levels of 13 proteins, while tofacitinib therapy modulated the expression of 10 proteins. These reductions were associated with a decrease in DAS28. Baseline levels of SAA4 and high levels of BNP were associated to the non-response to methotrexate. Changes in IL6 levels were specifically linked to the response to methotrexate. Regarding tofacitinib, differences in baseline levels of LOX1 and CNDP1 were noted between non-responder and responder RA patients. In addition, response to tofacitinib correlated with changes in SAA4 and TIMD4 levels. In summary, this study pinpoints molecular changes linked to cardiovascular disease in RA and proposes candidate protein biomarkers for distinguishing RA patients from healthy individuals. It also highlights how methotrexate and tofacitinib impact these proteins, with distinct alterations corresponding to each drug's response, identifying potential candidates, as SAA4, for the response to these therapies.

Seasonal and Treatment-Related Variation in 25-Hydroxy Vitamin D Concentration in Patients with Rheumatoid Arthritis.

Background/Objectives: 25-hydroxy vitamin D (25-OH-D) is a fat-soluble compound that plays many essential functions, including bone formation, neuromuscular functions, and prevention of osteoporosis and inflammation. Recent data indicate that its metabolites are associated with rheumatoid arthritis (RA) progression and neuropathic pain in RA patients. We aimed to assess the effect of RA pharmacotherapy and seasonal variation on serum levels of 25-OH-D in RA patients who received treatment with methotrexate (MTX) or leflunomide (LEF) for at least one year. Methods: This study is a retrospective analysis of data collected from 101 patients with RA who received treatment for at least one year. All of them have supplemented 25-OH-D (2000 IU daily) for at least one year. Results: We observed a significant seasonal variation in 25-OH-D concentration (p = 0.004). Moreover, there were significant differences (p = 0.03) between LEF (50.63 ± 17.73 ng/mL) and MTX (34.73 ± 14.04 ng/mL) treatment groups, but only for the summer population. A correlation was observed between 25-OH-D and RA duration-once again, in the summer population (the whole group-r = -0.64; treatment subgroups-r = -0.82 for LEF and -0.61 for MTX). Deficiency of 25-OH-D (below 20 ng/mL) was confirmed in 28.7% of patients, while 18.8% had suboptimal 25-OH-D levels (20-30 ng/mL). Conclusions: Our results showed that both RA pharmacotherapy and seasonal variation affect the serum levels of 25-OH-D in patients with active RA.

The impact of folate pathway variants on the outcome of methotrexate therapy in rheumatoid arthritis patients.

There are currently no validated criteria that entirely explain or predict response to methotrexate (MTX) treatment in rheumatoid arthritis (RA). We tried to identify the connection between three variants (RFC1 G80A (rs1051266), TYMS 2R/3R (rs34743033), and ATIC C347G (rs2372536)) in the folate pathway of MTX metabolism and the response to MTX monotherapy in a cohort of RA cases. A prospective study on 100 RA patients on MTX monotherapy was performed. Disease activity was measured at the start of treatment and 6months after treatment with MTX. The patients were then split into two groups: those who responded to the treatment and those who did not. The molecular genetic study for the RFC1 (G80A) variant was employed via the PCR-restriction fragment length polymorphism (PCR-RFLP) technique, the ATIC (C347G) variant was performed using TaqMan allelic discrimination real-time PCR, and the tandem repeat sequences of TYMS (2R/3R) were amplified by conventional PCR and detected by agarose gel electrophoresis. The genotype distribution of RFC-1 (G80A) showed significant variations among non-responders and responders in the recessive genetic model. A significant difference was found in TYMS (2R/3R) in the dominant and heterozygous genetic models. However, ATIC (C347G) genotype frequency did not exhibit substantial link with drug response in all genetic models. Furthermore, the genotype and allele rates of the analyzed variants did not show any significant association with adverse events in all genetic models. The 80AA genotype of RFC-1 G80A and the 2R/3R or 3R/3R genotypes of TYMS 2R/3R are more vulnerable to the good consequences of MTX therapy. Key Points • Current recommendations support the gold standard role of MTX as a first-line monotherapy for RA patients. However, up to 40% of RA patients do not respond or exhibit partial response to MTX. • Persistent disease activity due to treatment unresponsiveness will affect the long-term outcomes in RA patients. • We aimed, through molecular genetic study, to identify the connection between three variants in the folate pathway of MTX metabolism and the response to methotrexate monotherapy in a cohort of RA patients.

Drug-drug interaction assessment based on a large-scale spontaneous reporting system for hepato- and renal-toxicity, and thrombocytopenia with concomitant low-dose methotrexate and analgesics use

BackgroundMethotrexate (MTX) is the cornerstone of rheumatoid arthritis (RA) treatment and is highly effective with low-dose intermittent administration. MTX is occasionally used in combination with non-steroidal anti-inflammatory drugs (NSAIDs) and acetaminophen (APAP)/paracetamol for pain or inflammation control. With MTX treatment, the side effects, such as hepatotoxicity, renal failure, and myelosuppression should be considered. These are also seen with analgesics treatment.MethodsWe used a large spontaneously reported adverse event database (FAERS [JAPIC AERS]) to analyze whether the reporting of adverse events increased upon MTX and analgesic therapy in patients with RA.ResultsAfter identifying RA cases, the crude reporting odds ratios (cRORs) for hepatotoxicity, renal failure, and thrombocytopenia associated with the use of MTX, APAP, or NSAIDs were calculated by disproportionality analysis, which revealed significantly higher cRORs for these events. No analgesics showed consistent positive signals for drug-drug interaction (DDI) with concomitant low-dose MTX analyzed using four algorithms for DDI interaction (the Ω shrinkage measure, additive or multiplicative, and combination risk ratio models). However, in renal failure and thrombocytopenia, loxoprofen (Ω025 = 0.08) and piroxicam (Ω025 = 0.46), and ibuprofen (Ω025 = 0.74) and ketorolac (Ω025 = 3.52), respectively, showed positive signals in the Ω shrinkage measure model, and no consistency was found among adverse events or NSAIDs.ConclusionsStudies using spontaneous reporting systems have limitations such as reporting bias or lack of patient background; however, the results of our comprehensive analysis support the results of previous clinical or epidemiological studies. This study also demonstrated the usefulness of FAERS for DDI assessment.

TWEAK levels in psoriatic patients treated with narrowband ultraviolet B and methotrexate.

Psoriasis is an autoimmune disease which has an effect on the joints and skin. Tumor Necrosis Factor-Like Weak Inducer of Apoptosis (TWEAK) is a multi-functional cytokine which regulates the cellular processes and has been related to a variation of conditions. To measure the level of serum TWEAK in psoriatic diseased persons and its relationship to the PASI score pre- and post-therapy with narrowband ultraviolet B phototherapy (NB-UVB) and methotrexate (MTX). This randomized controlled trial was conducted on 40 patients and 20 healthy persons as controls. Patient Group was randomly subdivided to two groups. The 1st group consisted of 20 patients who received NB-UVB treatment. The 2nd group included 20 MTX-treated candidates. Blood samples were drawn from patients in order to detect serum TWEAK levels using ELISA. The research was registered on Clinical Trials Registration: RCT approval numbers: NCT0481191. The mean PASI score percent improvement after 12 weeks of treatment was higher in the MTX group (90%) than NB-UVB group (60%). The serum TWEAK level at baseline was 60.47 ± 12.6 pg/mL in NB-UVB group and 54.69 ± 21.7 pg/mL in MTX group which reduced to 24.93 ± 17.6 pg/mL and 32.13 ± 23.6 pg/mL, respectively (p < 0.001), after 12 weeks of treatment. There was a positive correlation between the serum levels of TWEAK and severity of PASI score (r = 0.399, p = 0.014). TWEAK grades in psoriasis are substantially higher than in controls. TWEAK levels were dramatically reduced during NB-UVB and MTX treatment. TWEAK may have a potential sign for psoriasis diagnosis and prognosis.

Efficacy of methotrexate treatment in extrauterine pregnancies and beta-human chorionic gonadotropin levels

Efficacy of methotrexate treatment in extrauterine pregnancies and beta-human chorionic gonadotropin levels

Intrathecal Methotrexate-Induced Lumbosacral Polyradiculopathy: A Case Report

BACKGROUND: Polyradiculopathy caused by intrathecal methotrexate (IT MTX) is a rare and serious complication of chemotherapy. The pathophysiology involved is likely due to a drug-induced folate deficiency and subsequent local immune reaction in the spinal cord. CASE REPORT: The authors present a 68-year-old woman with stage I breast cancer and stage III diffuse large B-cell lymphoma who developed low back pain after IT MTX treatment. Further workup revealed diffuse rope-like thickening of the cauda equina nerve roots with subtle linear low-level leptomeningeal enhancement on magnetic resonance imaging and severe primary axonal and motor polyneuropathy affecting the upper and lower extremities on electromyography/nerve conduction studies, likely a result of IT MTX toxicity. Treatment should emphasize conservative measures. Alternatively, intravenous immunoglobulin followed by intravenous methylprednisolone can be considered. CONCLUSIONS: Polyradiculopathy caused by IT MTX is a rare finding that can be treated. It would be beneficial to further study the effects of IT MTX and create treatment protocols for its adverse effects. KEY WORDS: Intrathecal methotrexate, polyradiculopathy, cauda equina, cancer, case report

Non-tubal ectopic pregnancy treatment experiences of a tertiary care center.

To evaluate the incidence, the risk factors, and the treatment outcomes of Non-tubal ectopic pregnancies (NTEP) treated in a tertiary care center. A total of 110 NTEP cases treated between 2014 and 2019 were included in the retrospective study. The study cohort was divided into 6 groups according to the pregnancy localization: 87 cesarean scar pregnancies (CSPs), 7 ovarian pregnancies, 6 interstitial pregnancies, 4 rudimentary horn pregnancies, 4 abdominal pregnancies, and 2 cervical pregnancies. One woman rejected all treatment modalities. Demographic characteristics, treatment modalities, and outcomes of each group were evaluated. In the study cohort, expectant management was performed in one (0.9%) woman. The methotrexate (MTX) treatment was administered in 29 (26.3%) women. Seventeen (15.4%) women underwent surgery, and 63 (57.2%) women underwent manual vacuum aspiration (MVA). A woman rejected all treatment modalities. Although 70.1% (n = 61) of CSPs were cured with MVA, 24.1% (n = 21) of them were treated with a single-dose MTX regimen in addition to MVA. The higher mean gestational sac size (33,9 ± 12,96mm vs. 17,34 ± 9,87mm), the higher mean gestational week (8,43 ± 1,16w vs. 6,66 ± 1,49w), the presence of fetal heartbeat (FHB) (90.5% vs. 26,2%) and the history of pelvic ınflammatory disease (PID) (38.1% vs. 6,6%) were found in the CSPs with MVA treatment failure (p < 0.05). The management of NTEPs should be individualized according to the clinical and ultrasonographic findings. The size of the ectopic pregnancy mass, the gestational week, the presence of FHB, and the PID history were the predictive factors for the failure of MVA in CSP cases.

External Evaluation of Population Pharmacokinetic Models for High-Dose Methotrexate in Adult Patients with Hematological Tumors.

Currently, numerous population pharmacokinetic (popPK) models for methotrexate (MTX) have been published for estimating PK parameters and variability. However, it is unclear whether the accuracy of these models is sufficient for clinical application. The aim of this study is to evaluate published models and assess their predictive performance according to the standards of scientific research. A total of 237 samples from 74 adult patients who underwent high-dose MTX (HDMTX) treatment at Shanghai Changzheng Hospital were collected. The software package NONMEM was used to perform an external evaluation for each model, including prediction-based diagnosis, simulation-based diagnosis, and Bayesian forecasting. The simulation-based diagnosis includes normalized prediction distribution error (NPDE) and visual predictive check (VPC). Following screening, 7 candidate models suitable for external validation were identified for comparison. However, none of these models exhibited excellent predictive performance. Bayesian simulation results indicated that the prediction precision and accuracy of all models significantly improved when incorporating prior concentration information. The published popPK models for MTX exhibit significant differences in their predictive performance, and none of the models were able to accurately predict MTX concentrations in our data set. Therefore, before adopting any model in clinical practice, extensive evaluation should be conducted.