Methotrexate Users Research Articles

Gastrointestinal symptoms in patients using methotrexate: A cross-sectional study in a sample with rheumatoid arthritis

BackgroundGastrointestinal intolerance is common in rheumatoid arthritis (RA) patients using methotrexate and may lead to treatment discontinuation. AimTo study the prevalence of gastrointestinal symptoms in a sample of RA methotrexate users as well as its possible association with clinical and epidemiological variables. MethodsCross-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. ResultsThe 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. ConclusionsThere is a high rate of methotrexate intolerance that is more common in afro-descendants, those with associated fibromyalgia, glucocorticoid and Jak inhibitors users.

Interstitial Lung Disease in Patients With Rheumatoid Arthritis or Psoriatic Arthritis Initiating Biologics and Controls: Data From 5 Nordic Registries.

Interstitial lung disease (ILD) is one of the most common pulmonary manifestations of rheumatoid arthritis (RA), but its prevalence has not been investigated in psoriatic arthritis (PsA). The role of methotrexate (MTX) in ILD development remains under debate. This study (1) compares the incidences of ILD in patients with RA or PsA initiating a first biologic disease-modifying antirheumatic drug (bDMARD) to that in the general population, and (2) investigates the role of MTX comedication on ILD incidence. Patients were identified in 5 rheumatology registries. Demographics, MTX use, and disease activity were retrieved. Matched subjects from the general population were available from 4 countries. Incidence of ILD during follow-up of up to 5 years was assessed through national patient registries. Subjects with prior ILD were excluded. Adjusted hazard ratios (HRs) were calculated for ILD incidence in patients vs the general population, and for MTX users vs nonusers. During follow-up of 29,478 patients with RA and 10,919 patients with PsA initiating a first bDMARD and 362,087 population subjects, 225, 23, and 251 cases of ILD were identified, respectively. HRs for ILD (vs population subjects) were 9.7 (95% CI 7.97-11.91) in RA and 4.4 (95% CI 2.83-6.97) in PsA. HRs for ILD with MTX comedication (vs nonuse) were 1.0 (95% CI 0.72-1.25) in RA and 0.9 (95% CI 0.38-2.05) in PsA. Among patients with RA and PsA initiating a bDMARD, the risk of ILD was higher than in the general population, and was highest in RA. MTX comedication was not a risk determinant for ILD.

Duration of Postvaccination Neutralizing Antibodies to SARS-CoV-2 and Medication Effects: Results from the Safety and Immunogenicity of COVID-19 Vaccination in Systemic Immune-Mediated Inflammatory Diseases Cohort Study.

In the face of the ongoing circulation of SARS-CoV-2, the durability of neutralization post-COVID-19 vaccination in immune-mediated inflammatory disease (IMID) is a key issue, as are the effects of medications. Adults (n = 112) with inflammatory bowel disease, psoriasis/psoriatic arthritis, rheumatoid arthritis, spondylarthritis, and systemic lupus were recruited from participating Canadian medical centers from 2021 to 2023. We focused on log-transformed neutralization (lentivirus methods) as a continuous outcome, with separate models for wild-type and Omicron strains BA.1 and BA.5. Compared with 30 to 120 days postvaccination, subsequent periods were associated with greater neutralization in unadjusted models for wild-type, BA.1, and BA.5 strains and against the BA.1 strain in adjusted models. Rituximab was associated with lower neutralization for the BA.1 strain in adjusted models, with a similar trend for BA.5. In methotrexate users, there were trends for less neutralization of BA.1 and BA.5 in all unadjusted models, whereas in adjusted models, there was significantly lower neutralization only for the wild type. Three or more doses and Omicron-specific vaccines were both independently associated with better neutralization ability for all three strains. A COVID-19 infection within six months before sampling was associated with higher neutralization of wild type and BA.1 in adjusted analyses. Anti-tumor necrosis factor agents were associated with lower neutralization ability for BA.5 in adjusted analyses. Neutralization responses in immunosuppressed individuals with IMID were durable over time and were augmented by more than three doses and Omicron-specific vaccines. Less neutralization was seen with certain medications. Our work clarifies the joint effects of vaccine history, infection, and medications on COVID-19 immunity.

Behçet's Disease Current Therapies: MTX- Imuran and Long-term Effect of VIT D and Colchicine (Multi Centric Cohort Study from Aseer Region, Saudi Arabia)

Background: Behçet's disease (BD) is a rare, chronic inflammatory disorder that recurs over time, impacting multiple systems, positioning it at the intersection of autoimmune and auto-inflammatory syndromes. BD is a unique clinical entity known for its diverse manifestations with recurring oral ulcers are the most common, followed by genital ulcers. This article aims to explore and emphasize the diverse medication approaches for treating our patients with Behçet's disease. Methods: A comprehensive retrospective analysis was conducted on medical records and data of patients under active care in rheumatology clinics, all of whom had a confirmed diagnosis of Behçet's disease looking for their different treatment options. We defined organ involvement severity to Mild (one organ), Moderate (2 organs) and sever is 3 and more organ involvement. Results: 111 patients, evenly distributed by gender, we analyzed therapy effects on Behçet's disease. Azathioprine and methotrexate users (54 and 13 patients, respectively) were typically aged 21-60. Colchicine use (78 patients) showed consistent results, with similar organ involvement severity. Comparatively, Vitamin D use (55 patients) showed similar age and gender distribution, with a quarter exhibiting severe organ involvement. However, neurological, gastrointestinal, and pulmonary symptoms showed no significant differences across these groups. Conclusion: In our study, we observed more sever disease in people taking MTX compared to Imuran. We also observed no morbidity or mortality benefit of vitamin D. Collaboration across disciplines is crucial for personalized treatment, considering organ involvement, age, gender, symptom intensity, and disease duration. Larger, prospective studies are needed to compare different Conventional Disease modifying agent and to consider mortality benefits of Colchicine in BD.

Association Between the Dose of Tofacitinib and Risk of Herpes Zoster in Patients With Rheumatoid Arthritis: Analysis of Japanese Adverse Drug Event Report Data.

Tofacitinib is one of the Janus kinase inhibitors approved for the treatment of rheumatoid arthritis. The major adverse event of this drug is herpes zoster, which can lead to death in severe cases. The risk of herpes zoster has been studied at 10 mg/day of tofacitinib; however, 5 mg/day, which is recommended in patients with chronic kidney disease, is unclear. To investigate whether 5 mg/day of tofacitinib reduced the risk of herpes zoster compared with 10 mg/day in rheumatoid arthritis patients. We analyzed the Japanese Adverse Drug Event Report Data (JADER) database and compared the frequency of herpes zoster in rheumatoid arthritis patients treated with tofacitinib 5 mg/day and 10 mg/day. Multivariable logistic regression analysis was performed to identify the risk factors for herpes zoster in tofacitinib users. A total of 812 tofacitinib users with rheumatoid arthritis were identified, including 131 with herpes zoster. Disproportionality for herpes zoster was observed between 5 mg/day and 10 mg/day (reporting odds ratio (OR): 0.68, 95% confidence interval (CI): 0.47-0.98, P = 0.045). Multivariable logistic regression analysisshowed that the risk of herpes zoster was significantly increased in female patients (OR: 1.87, 95% CI: 1.12-3.12, P = 0.016) and methotrexate users (OR: 1.69, 95% CI: 1.12-2.54, P = 0.013) and significantly decreased with tofacitinib 5 mg/day compared with 10 mg/day (OR: 0.62, 95% CI: 0.40-0.96, P = 0.032). We suggest that tofacitinib 5 mg/day may decrease the risk of herpes zoster compared with 10 mg/day in rheumatoid arthritis patients.

Increased risk of cardiovascular events under the treatments with Janus kinase inhibitors versus biological disease-modifying antirheumatic drugs in patients with rheumatoid arthritis: a retrospective longitudinal population-based study using the Japanese health insurance database

ObjectivesTo compare the risk of cardiovascular events among Janus kinase inhibitors (JAKIs), biological disease-modifying antirheumatic drugs (bDMARDs) (tumour necrosis factor inhibitors (TNFIs) and non-TNFIs) and methotrexate (MTX) in Japanese patients...

Urinary methotrexate dosage in rheumatoid arthritis, in patients treated for at least 6 months: a potential marker of adherence

ObjectivesNon-adherence to rheumatoid arthritis (RA) treatments must be identified. A methotrexate (MTX) urinary dosage (METU) was recently developed. The aim of our study was to assess adherence to MTX in...

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.

Use of transient elastography to assess hepatic steatosis and fibrosis in patients with juvenile idiopathic arthritis during methotrexate treatment

ObjectivesThis study aimed to assess the prevalence and identify predictors of hepatic steatosis and fibrosis in patients with juvenile idiopathic arthritis (JIA) during methotrexate treatment.MethodThis cross-sectional study included JIA patients who had received methotrexate for > 1 year. Laboratory data including liver chemistry and lipid profiles were collected. Liver stiffness measurements (LSM) and controlled attenuation parameters (CAP) were determined by transient elastography. Significant hepatic fibrosis was defined as LSM > 7 kilopascal (kPa), and hepatic steatosis was defined as CAP > 225 decibel/meter (dB/m). Logistic regression analysis was performed to identify predictors associated with hepatic steatosis and fibrosis.ResultsOf 60 patients, 66.7% were female, and the median age (IQR) was 12.8 (10.6–15.0) years. The median duration of methotrexate usage (IQR) was 45 (22–85) months, and the median cumulative dose of methotrexate (IQR) was 3768 (1806–6466) mg. The median LSM (IQR) and CAP (IQR) were 4.1 (3.4–4.6) kPa and 191.0 (170.3–223.8) dB/m, respectively. No patients had transient elastography-defined hepatic fibrosis, whereas 21.7% had hepatic steatosis. A body mass index Z-score > 1 (OR 5.71 [95%CI 1.31–24.98], p = 0.021) and higher cumulative dose of methotrexate (OR 1.02 [95%CI 1.00–1.04], p = 0.041) were associated with hepatic steatosis, whereas the cumulative dose of steroids was not (OR 1.00 [95%CI 1.00–1.01], p = 0.097).ConclusionsHepatic steatosis is common among JIA patients receiving methotrexate, but none had transient elastography-defined hepatic fibrosis. Overweight/obese JIA adolescents and patients with a high cumulative dose of methotrexate are at risk for hepatic steatosis.Key Points•Long-term low-dose methotrexate usage and the concomitant use of other DMARDs did not increase the risk of hepatic fibrosis in JIA patients.•The prevalence of hepatic steatosis in JIA patients receiving methotrexate was higher than in a healthy pediatric population.•Overweight/obesity and a higher cumulative dose of methotrexate were predictors of hepatic steatosis.

Low-Dose Methotrexate and Serious Adverse Events Among Older Adults With Chronic Kidney Disease

Low-dose methotrexate is used to treat rheumatoid arthritis and psoriasis. Due to its kidney elimination, better evidence is needed to inform its safety in adults with chronic kidney disease (CKD). To compare the 90-day risk of serious adverse events among adults with CKD who started low-dose methotrexate vs those who started hydroxychloroquine and to compare the risk of serious adverse events among adults with CKD starting 2 distinct doses of methotrexate vs those starting hydroxychloroquine. This retrospective, population-based, new-user cohort study was conducted in Ontario, Canada (2008-2021) using linked administrative health care data. Adults aged 66 years or older with CKD (defined as an estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m2 but not receiving dialysis) who started low-dose methotrexate (n = 2309) were matched 1:1 with those who started hydroxychloroquine. Low-dose methotrexate (5-35 mg/wk) vs hydroxychloroquine (200-400 mg/d). The primary outcome was a composite of serious adverse events: a hospital visit with myelosuppression, sepsis, pneumotoxic effects, or hepatotoxic effects within 90 days of starting the study drug. Prespecified subgroup analyses were conducted by eGFR category. Propensity score matching was used to balance comparison groups on indicators of baseline health. Risk ratios (RRs) were obtained using modified Poisson regression, and risk differences (RDs) using binomial regression. In a propensity score-matched cohort of 4618 adults with CKD (3192 [69%] women; median [IQR] age, 76 [71-82] years), the primary outcome was higher in patients who started low-dose methotrexate vs those who started hydroxychloroquine (82 of 2309 [3.55%] vs 40 of 2309 [1.73%]; RR, 2.05 (95% CI, 1.42-2.96); RD, 1.82% [95% CI, 0.91%-2.73%]). In subgroup analysis, the risks increased progressively at lower eGFR (eg, eGFR <45 mL/min/1.73 m2: RR, 2.79 [95% CI, 1.51-5.13]). In the secondary comparison with hydroxychloroquine, methotrexate users at 15 to 35 mg/wk had a higher risk of the primary outcome. In this cohort of 4618 older patients with CKD, the 90-day risk of serious adverse events was higher among those who started low-dose methotrexate than those who started hydroxychloroquine. If verified, these risks should be balanced against the benefits of low-dose methotrexate use.

Effectiveness and safety of filgotinib in rheumatoid arthritis: a real-life multicentre experience.

We investigated the effectiveness and safety of filgotinib in a real-life multicentre cohort of rheumatoid arthritis (RA) patients. RA patients were evaluated at baseline and after 12 and 24 weeks and were stratified based on previous treatments as biologic disease-modifying anti-rheumatic drug (bDMARD)-naive and bDMARD-insufficient responders (IR). Concomitant usage of methotrexate (MTX) and oral glucocorticoids (GC) was recorded. At each timepoint we recorded disease activity, laboratory parameters and adverse events. 126 patients were enrolled. 15.8% were bDMARD-naive (G0), while 84% were bDMARD-IR (G1). In G0, 45% of patients were in monotherapy (G2) and 55% were taken MTX (G3). In G1, 50% of patients were in monotherapy (G4) and 50% used MTX (G5).A significant reduction in all parameters at 12 weeks was observed; in the extension to 24 weeks the significant reduction was maintained for patient global assessment (PGA), examiner global assessment (EGA), visual analogue scale (VAS) pain, VAS fatigue, disease activity score (DAS)28- C-reactive protein (CRP) and CRP values. Filgotinib in monotherapy showed better outcomes in bDMARD-naive patients, with significant differences for patient reported outcomes (PROs) and DAS28-CRP. At 12 weeks, low disease activity (LDA) and remission were achieved in a percentage of 37.2 % and 10.7 % by simplified disease activity index (SDAI), 42.6 % and 5.7 % by clinical disease activity index (CDAI), 26.8 % and 25.2 % by DAS28-CRP, respectively. A significant decrease in steroid dose was evidenced in all patients. We observed a major adverse cardiovascular event in one patient and an increase in transaminase in another. No infections from Herpes Zoster were reported. Our real-world data confirm the effectiveness and safety of filgotinib in the management of RA, especially in bDMARD-naive patients.

Psoriasis/Psoriatic Arthritis Patients' Long-term Treatment Patterns and Adherence to Systemic Treatments Monitoring Recommendations.

Limited information exists regarding treatment of patients with psoriasis/psoriatic arthritis in primary care. The aim of this study is to assess treatment patterns, adherence, persistence, and compliance in newly diagnosed patients with psoriasis/psoriatic arthritis from 2012 to 2018 in Stockholm, Sweden. In addition, laboratory monitoring before initiation of treatment and at recommended intervals was quantified for patients prescribed methotrexate or biologics. A total of 51,639 individuals were included, with 39% initiating treatment with topical corticosteroids and < 5% receiving systemic treatment within 6 months post-diagnosis. During a median (interquartile range) follow-up of 7 (4-8) years, 18% of patients received systemic treatments at some point. Overall, 5-year persistence rates were 32%, 45% and 19% for methotrexate, biologics, and other systemic treatments, respectively. Pre-initiation laboratory tests, as recommended by guidelines, were performed in approximately 70% and 62% of methotrexate and biologics users, respectively. Follow-up monitoring at recommended time intervals occurred in 14-20% and 31-33% of patients prescribed methotrexate and biologics, respectively. These findings highlight gaps in the pharmacological care of patients with psoriasis/psoriatic arthritis, including suboptimal adherence/persistence and inadequate laboratory monitoring.

Prevalence of Methotrexate-Induced Lung Involvement in Psoriasis Patients

Background: Seventy five psoriasis patients who visited the Pakistani Institute of Medical Sciences in Islamabad from January 2021 to January 2022 were examined to assess the incidence of methotrexate-induced lung involvement. Long-term methotrexate therapy often results in lung involvement, which may present as pleuritis, pneumonia, fibrosis, and obliterative bronchiolitis. Clinical evaluations and case data were retrospectively reviewed. Out of the Seventy five individuals tested, the results indicate that 15 (15%) had mild to moderate lung involvement, while 4 (4%) had severe lung involvement. In 67% of the patients, there was no discernible lung involvement. The frequency of methotrexate-induced lung involvement at the Pakistani Institute of Medical Sciences is quite low, despite the fact that it is a possible side effect of long- term methotrexate usage for psoriasis patients. If long-term methotrexate usage raises the likelihood of lung involvement in psoriasis patients, further investigation is required. Objectives: Identifying the frequency of methotrexate-induced lung involvement in psoriasis patients seen at the Pakistani Institute of Medical Sciences in Islamabad from January 2021 to January 2022 is the goal of this research. Methods: Seventy five psoriasis patients who were seen between January 2021 and January 2022 at the Pakistani Institute of Medical Sciences (PIMS) in Islamabad were the subject of the research. Lung involvement was evaluated by a retrospective examination of the case files and clinical evaluation, which may have required pulmonary function tests, chest X-rays, or even chest CT scans. There was no discernible lung involvement, mild to moderate lung involvement, severe lung involvement, or no lung involvement at all. Results: Seventy-five individuals were examined; fifteen (15%) had mild to moderate lung involvement, four (4%) had severe lung involvement, and sixty-seven (67%) had no discernible lung involvement. Conclusion: According to the study's findings, although methotrexate-induced lung involvement is a possible side effect of long-term methotrexate usage for people with psoriasis, it is not very common at the Pakistani Institute of Medical Sciences. 67% of the individuals in the study had no observable lung involvement. If long-term methotrexate usage raises the likelihood of lung involvement in psoriasis patients, further investigation is required. Keyword: Methotrexate, Psoriasis, Lung Involvement, Prevalence, PIMS

Occurrence of adverse events associated with the initiation of methotrexate and biologics for the treatment of psoriasis in routine clinical practice

Background: Limited information exists on the risk of adverse events (AEs) attributed to methotrexate (MTX) and biologics for the treatment of psoriasis/psoriatic arthritis (PsA/PsO) in heterogeneous clinical practice and beyond the duration of clinical trials.Methods: An observational study of 6294 adults with incident PsA/PsO who initiated MTX or biologics in Stockholm from 2006-2021 was conducted. The risk of kidney, liver, hematological, serious infectious, and major gastrointestinal AEs was quantified and compared between therapies using incidence rates, absolute risks, and adjusted hazard ratios (HRs) from propensity-score weighted Cox regression.Results: Median follow-up was 4.3 (2–7) years. Users of MTX had a higher risk of anemia (HR 1.79 [95% CI, 1.48–2.16]), particularly mild-moderate anemias (1.93;1.49–2.50), and mild (1.46;1.03–2.06) and moderate-severe liver AEs (2.22;1.19–4.15) compared to biologics. Chronic kidney disease incidence did not differ between therapies (affecting 1.5% of the population in 5 years; HR:1.03;0.48–2.22). Acute kidney injury, serious infections, and major gastrointestinal AEs showed low absolute risks and no clinically meaningful differences between both therapies.Conclusion: The use of MTX for psoriasis patients in routine care was associated with a higher risk of anemia and liver AEs than biologics, but similar risks of kidney, serious infections, and major gastrointestinal AEs.

P046 A multinomial approach to prediction of methotrexate treatment response and discontinuation due to adverse events in rheumatoid arthritis

Abstract Background/Aims As recommended by the NICE guidelines, methotrexate (MTX) is typically prescribed as the first line therapy for patients with rheumatoid arthritis (RA). However, around 40% of patients do not respond to MTX at 6 months and around 80% experience adverse events (AEs). Our previous systematic review identified that clinical prediction models of MTX outcomes suffered from methodological limitations, including a lack of validation, suboptimal handling of missing data, and no consideration of competing risks, such as patients discontinuing due to adverse events (AEs). These shortcomings resulted in high risk of bias and should be addressed to aid the implementation of outcome prediction in clinical practice. Therefore, this study aimed to (i) develop a multinomial prediction model for estimating an individual’s risks of not achieving low disease activity (LDA) and discontinuing due to AEs at 6 months after starting MTX, using information observable at the starting point of treatment, (ii) update prognosis at 3 months, and (iii) internally validate these models to assess performance. Methods Data came from the national multi-centre (n = 38) Rheumatoid Arthritis Medication Study (RAMS), which recruited patients with a diagnosis of RA or undifferentiated polyarthritis starting MTX for the first time. We conducted a Patient and Public Involvement focus group with past and current MTX users, which informed our outcome choice of LDA (DAS28 ≤3.2). A multinomial logistic regression (MLR) was used to develop a prediction model that estimated the probabilities of three outcomes: 1) not in LDA, 2) achieved LDA, and 3) discontinued due to AEs. The updated model at 3 months was conditional on patients not having achieved LDA. Missing data was handled using multiple imputation and models were internally validated through bootstrapping. Calibration, discrimination, and variance explained was assessed to quantify model performance. Results A total of 1632 patients were included in the analysis. At 6 months, 756 (46%) patients achieved LDA, 730 (45%) were not in LDA, and 146 (9%) discontinued due to AEs. The updated model at 3 months included 1179 (72%) patients as they had not achieved LDA. For the LDA outcome pair, the c-statistic was 0.73 (0.70, 0.75), while it was 0.54 (0.49, 0.59) for the AEs outcome. The calibration slope was 0.99 (0.85, 1.12) and 0.74 (0.23, 1.23), respectively. Predictive performance at 3 months was similar to baseline. Conclusion Our MLR models handled outcomes of disease activity and AEs simultaneously. We were able to predict outcomes of LDA more accurately than AEs and performance was better in terms of calibration, which is crucial for the clinical utility of a prediction model. This modelling approach could provide more clinically useful and realistic predictions of MTX outcomes, as competing risks such as AEs have previously been ignored. Disclosure C.K. Gehringer: None. G.P. Martin: None. K.L. Hyrich: Honoraria; Abbvie. Grants/research support; BMS and Pfizer. S.M.M. Verstappen: None. J.C. Sergeant: None.

Aptamer/proximity hybridization-based label-free and highly sensitive colorimetric detection of methotrexate via polymerization/nicking recycling amplifications

Methotrexate (MTX) is one of the commonly used therapeutic drugs for treating various tumors and autoimmune diseases. However, high dose usage of MTX may cause severe side effects and the monitoring of MTX is therefore critical. By coupling a new MTX aptamer-based proximity hybridization with polymerization/nicking reaction (PNR) recycling amplifications, we develop here a sensitive and label-free colorimetric approach for MTX detection in diluted human serums. The MTX molecules can bind and switch the conformation of aptamers in the DNA duplex probes to initiate subsequent proximity hybridization-induced PNR recycling processes for the yield of a great deal of G-quadruplexes with the assistance of two single-stranded assistant DNA sequences. Hemin subsequently combines with these G-quadruplexes to produce lots of G-quadruplex/hemin horseradish peroxidase (HRP) mimicking DNAzymes, which then catalyze intensified color transition of the substrate solution to exhibit highly magnified UV–Vis absorption for label-free and ultrasensitive detection of MTX at concentration as low as 5.66 nM in the range of 10 nM to 1 μM. High selectivity of the developed method also enables it to monitor low levels of MTX in diluted serum samples, which offers such a method enormous potentials for convenient and highly sensitive detection of other small molecule drugs for various clinical applications.

Frequency of Helicobacter pylori in Patients With Rheumatoid Arthritis Whose Methotrexate Was Stopped Due to Gastrointestinal Intolerance.

The aims of this study were to compare the frequency of Helicobacter pylori between patients with rheumatoid arthritis (RA) with and without methotrexate (MTX)-related gastrointestinal system (GIS) intolerance, and to demonstrate the associated factors with such intolerance. The data of 9756 patients with RA who presented between January 2011 and December 2020 were evaluated. Methotrexate-related GIS intolerance was defined as the discontinuation of MTX owing to the dyspeptic symptoms despite supportive measures and was detected in 1742 (31.3%) patients among 5572 MTX users. A total of 390 patients with and without intolerance who had at least 1 gastroscopic evaluation were included in the final analyses. The demographic, clinical, laboratory, and pathologic characteristics of patients with and without MTX-related GIS intolerance were compared. To determine the associated factors with MTX-related GIS intolerance, logistic regression analysis was performed. Of 390 patients, 160 (41.0%) patients had MTX-related GIS intolerance. According to the pathology results, the presence of H. pylori , inflammation, and activity were significantly higher in patients with MTX-related GIS intolerance ( p < 0.001 for each comparison). In multivariable logistic regression analysis, the use of biologic disease-modifying antirheumatic drugs (DMARDs) or targeted synthetic DMARDs was found to be an independently associated factor for MTX-related GIS intolerance (odds ratio [OR], 3.03 for model 1; OR, 3.02 for model 2) in addition to H. pylori presence (OR, 9.13 for model 1; OR, 5.71 for model 2). In this study, we found that the presence of H. pylori and the use of biologic or targeted synthetic DMARDs were associated with MTX-related GIS intolerance.

No association between methotrexate and impaired bone mineral density in a cohort of patients with polymyalgia rheumatica, giant cell arteritis, granulomatosis with polyangiitis and other vasculitides—a cross-sectional analysis with dose–response analyses

ObjectiveTo investigate whether methotrexate (MTX) use is associated with bone mineral density (BMD) in patients with polymyalgia rheumatica (PMR) and various forms of vasculitis.MethodsRh-GIOP is a cohort study designed to evaluate bone health in patients with inflammatory rheumatic diseases. This cross-sectional analysis assessed the baseline visits of all patients with PMR or any kind of vasculitis. Following univariable analysis, multivariable linear regression analysis was performed. The lowest T-score of either the lumbar spine or the femur was chosen as the dependent variable to examine the relationship between MTX use and BMD. These analyses were adjusted for a variety of potential confounders, including age, sex, and glucocorticoid (GC) intake.ResultsOf 198 patients with PMR or vasculitis, 10 patients were excluded for very high GC dose (n = 6) or short disease duration (n = 4). The remaining 188 patients had the following diseases: PMR 37.2%, giant cell arteritis 25.0%, granulomatosis with polyangiitis 16.5%, followed by rarer diseases. The mean age was 68.0 ± 11.1 years, mean disease duration was 5.58 ± 6.39 years, and 19.7% had osteoporosis by dual x-ray absorptiometry (T-score ≤ −2.5). 23.4% were taking MTX at baseline with a mean dose of 13.2 mg/week (median: 15 mg/week). 38.6% of those used a subcutaneous preparation. MTX users had similar BMD compared to non-users (minimum T-scores −1.70 (± 0.86) versus −1.75 (± 0.91), respectively; p = 0.75). There was no statistically significant dose–response relationship: neither current nor cumulative dose were associated with BMD in unadjusted or adjusted models (current dose: slope −0.02; −0.14 to 0.09; p = 0.69; cumulative dose: slope −0.12; −0.28 to 0.05; p = 0.15).ConclusionIn the Rh-GIOP cohort, MTX is used in about a quarter of patients with PMR or vasculitis. It is not associated with BMD levels.

Risk of Infection in Children With Psoriasis Receiving Treatment With Ustekinumab, Etanercept, or Methotrexate Before and After Labeling Expansion

Psoriasis in children is increasingly treated with systemic medications, yet their risk of serious infection is not well characterized in clinical practice. Pediatric clinical trials for these medications were often small and placebo controlled. To estimate the 6-month rate of infections among children with psoriasis who started treatment with ustekinumab, etanercept, or methotrexate. This cohort study used insurance claims data from clinical practices across the US on children aged 17 years or younger with psoriasis who were receiving treatment with a topical medication for psoriasis and started new treatment with ustekinumab, etanercept, or methotrexate. The analysis was stratified by the time before pediatric labeling (2009-2015) and after pediatric approval (2016-2021). Patient follow-up started 1 day after initiating treatment and ended at 6 months. New treatment with ustekinumab, etanercept, and methotrexate. During follow-up, the frequency of inpatient serious infections and outpatient infections requiring treatment was compared. Event rates and rate ratios were estimated after propensity score decile stratification. After exclusions, we identified 2338 patients (1368 girls [57.8%]) who initiated new treatment with a targeted immunomodulating agent. In all, 379 patients started treatment with ustekinumab, 779 patients started treatment with etanercept, and 1180 patients started treatment with methotrexate from 2009 through 2021. The propensity score-adjusted incidence rate of serious infection was 18.4 per 1000 person-years (3 events) for ustekinumab users, 25.6 per 1000 person-years (9 events) for etanercept users, and 14.9 per 1000 person-years (8 events) for methotrexate users. The adjusted rate of outpatient infections was 254.9 per 1000 person-years (39 events) for ustekinumab users, 435.7 per 1000 person-years (139 events) for etanercept users, and 433.6 per 1000 person-years (209 events) for methotrexate users. The adjusted rate ratio of outpatient infections was 0.58 (95% CI, 0.41-0.83) for ustekinumab vs etanercept, 0.66 (95% CI, 0.48-0.91) for ustekinumab vs methotrexate, and 0.95 (95% CI, 0.75-1.21) for etanercept vs methotrexate. Rate ratios were similar during the off-label use era and after pediatric labeling. Among children with psoriasis who started treatment with immunomodulating agents, serious infections were infrequent. This cohort study suggests that there was no increase in the risk of outpatient infections for children who started treatment with ustekinumab compared with etanercept or methotrexate.

Distal Tibial Hemimelia in Fetal Methotrexate Syndrome: A Case Study and Literature Review

Methotrexate (MTX), a folate antagonist, is used in various fields, including malignancies and rheumatoid or inflammatory autoimmune diseases. MTX is used for the non-surgical treatment of ectopic pregnancies and the elective termination of pregnancy. The teratogenic effects of MTX have been recognized since the 1960s. Fetal methotrexate syndrome (FMS) was established based on the study of congenital anomalies. Generally, there is a risk of FMS when MTX is used between four and six weeks after conception. Here, we reviewed the literature regarding MTX usage and described a case of FMS that was born with a rare anomaly, such as tibial hemimelia, in a mother who had received MTX 4 months before conception for the management of an ectopic pregnancy.