Related Experiment Video
Updated: Dec 28, 2025
Minimal Erythema Dose MED Testing
Published on: May 28, 2013
Adverse Effects of Low-Dose Methotrexate: A Randomized Trial
Daniel H Solomon1, Robert J Glynn1, Elizabeth W Karlson1
1Brigham and Women's Hospital, Boston, Massachusetts (D.H.S., R.J.G., E.W.K., F.L., C.C., J.C., C.X., J.M., N.B., P.F.D., B.M.E., A.D.P., S.P.H., M.M., D.A.R., S.Y.R., A.R., J.A.S., J.S., D.H.S., S.K.T., K.M.V., N.P.P., P.M.R.).
Background:
Low-dose methotrexate (LD-MTX) is the most commonly used drug for systemic rheumatic diseases worldwide and is the recommended first-line agent for rheumatoid arthritis. Despite extensive clinical use for more than 30 years, few data on adverse event (AE) rates derive from randomized, placebo-controlled trials, where both causality and magnitude of risk can be inferred.
Objective:
To investigate AE rates, risk, and risk differences comparing LD-MTX versus placebo.
Design:
Prespecified secondary analyses of a double-blind, placebo-controlled, randomized trial. (ClinicalTrials.gov: NCT01594333).
Setting:
North America.
Participants:
Adults with known cardiovascular disease and diabetes or metabolic syndrome.
Intervention:
Random allocation to LD-MTX (≤20 mg/wk) or placebo. All participants received folic acid, 1 mg/d, 6 days per week.
Measurements:
Risks for specific AEs of interest, as well as for all AEs, were compared across treatment groups after blinded adjudication.
Results:
After an active run-in period, 6158 patients were enrolled and 4786 randomly assigned to a group; median follow-up was 23 months and median dosage 15 mg/wk. Among the randomly assigned participants, 81.2% were male, median age was 65.7 years, and median body mass index was 31.5 kg/m2. Of 2391 participants assigned to LD-MTX, 2080 (87.0%) had an AE of interest, compared with 1951 of 2395 (81.5%) assigned to placebo (hazard ratio [HR], 1.17 [95% CI, 1.10 to 1.25]). The relative hazards of gastrointestinal (HR, 1.91 [CI, 1.75 to 2.10]), pulmonary (HR, 1.52 [CI, 1.16 to 1.98]), infectious (HR, 1.15 [CI, 1.01 to 1.30]), and hematologic (HR, 1.15 [CI, 1.07 to 1.23]) AEs were elevated for LD-MTX versus placebo. With the exception of increased risk for skin cancer (HR, 2.05 [CI, 1.28 to 3.28]), the treatment groups did not differ in risk for other cancer or mucocutaneous, neuropsychiatric, or musculoskeletal AEs. Renal AEs were reduced in the LD-MTX group (HR, 0.85 [CI, 0.78 to 0.93]).
Limitation:
The trial was done in patients without rheumatic disease who tolerated LD-MTX during an active run-in period.
Conclusion:
Use of LD-MTX was associated with small to moderate elevations in risks for skin cancer and gastrointestinal, infectious, pulmonary, and hematologic AEs, whereas renal AEs were decreased.
Primary Funding Source:
National Institutes of Health.
Insights
Low-dose methotrexate (LD-MTX) use in patients with cardiovascular disease showed increased risks for gastrointestinal, pulmonary, infectious, and hematologic adverse events (AEs). However, renal AEs were decreased, and skin cancer risk was elevated.
Area of Science:
- Rheumatology and Pharmacology
- Cardiovascular Disease Research
- Clinical Trial Analysis
Background:
- Low-dose methotrexate (LD-MTX) is a primary treatment for systemic rheumatic diseases, including rheumatoid arthritis.
- Despite widespread use, robust data on adverse event (AE) rates from placebo-controlled trials are limited.
- Understanding LD-MTX risks is crucial for patient safety and treatment optimization.
Purpose of the Study:
- To quantify and compare adverse event (AE) rates and risks between LD-MTX and placebo.
- To identify specific AE profiles associated with LD-MTX in a high-risk population.
- To provide evidence-based insights into the safety of LD-MTX.
Main Methods:
- A double-blind, placebo-controlled, randomized trial (ClinicalTrials.gov: NCT01594333) was conducted in North America.
- Adult participants with cardiovascular disease and diabetes or metabolic syndrome were randomized to LD-MTX (≤20 mg/wk) or placebo, with all receiving folic acid.
- Adverse events were assessed through blinded adjudication, comparing risks between groups over a median follow-up of 23 months.
Main Results:
- Of 4786 participants, 87.0% on LD-MTX and 81.5% on placebo experienced an AE of interest.
- LD-MTX was associated with elevated risks for gastrointestinal (HR, 1.91), pulmonary (HR, 1.52), infectious (HR, 1.15), and hematologic (HR, 1.15) AEs.
- Increased skin cancer risk (HR, 2.05) was observed with LD-MTX, while renal AEs were reduced (HR, 0.85).
Conclusions:
- LD-MTX use in patients without rheumatic disease but with cardiovascular risk factors is linked to increased risks of certain AEs.
- The study highlights a need for careful monitoring of gastrointestinal, pulmonary, infectious, hematologic, and skin adverse events.
- Reduced renal AE risk with LD-MTX suggests potential benefits in specific patient populations, warranting further investigation.
More Related Videos
Related Concept Videos
01:29Therapeutic Drug Monitoring: Affecting Factors
01:29Drugs for Treatment of Crohn's Disease in IBD Using Immunomodulatory Agents
01:08Effect of Hepatic Disease on Pharmacokinetics: Dose Adjustments Due to Hepatic Impairment
01:15Bioavailability Study Design: Healthy Subjects Versus Patients
01:17Phase II Reactions: Methylation Reactions
The mechanism of methylation unfolds in two stages. The first stage sees a methyltransferase enzyme facilitating the transfer of a methyl group from S-adenosylmethionine (SAM) to the substrate, forming S-adenosylhomocysteine (SAH). The second stage involves further metabolism of SAH into homocysteine, which can be recycled...
01:16Therapeutic Drug Monitoring: Overview and Classification