Adverse Effects of Low-Dose Methotrexate: A Randomized Trial.
Journal
Annals of internal medicine
ISSN: 1539-3704
Titre abrégé: Ann Intern Med
Pays: United States
ID NLM: 0372351
Informations de publication
Date de publication:
17 03 2020
17 03 2020
Historique:
pubmed:
18
2
2020
medline:
4
9
2020
entrez:
18
2
2020
Statut:
ppublish
Résumé
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. To investigate AE rates, risk, and risk differences comparing LD-MTX versus placebo. Prespecified secondary analyses of a double-blind, placebo-controlled, randomized trial. (ClinicalTrials.gov: NCT01594333). North America. Adults with known cardiovascular disease and diabetes or metabolic syndrome. Random allocation to LD-MTX (≤20 mg/wk) or placebo. All participants received folic acid, 1 mg/d, 6 days per week. Risks for specific AEs of interest, as well as for all AEs, were compared across treatment groups after blinded adjudication. 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]). The trial was done in patients without rheumatic disease who tolerated LD-MTX during an active run-in period. 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. National Institutes of Health.
Sections du résumé
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.
Identifiants
pubmed: 32066146
pii: 2761423
doi: 10.7326/M19-3369
pmc: PMC7229518
mid: NIHMS1575779
doi:
Substances chimiques
Antirheumatic Agents
0
Placebos
0
Methotrexate
YL5FZ2Y5U1
Banques de données
ClinicalTrials.gov
['NCT01594333']
Types de publication
Journal Article
Randomized Controlled Trial
Research Support, N.I.H., Extramural
Video-Audio Media
Langues
eng
Sous-ensembles de citation
IM
Pagination
369-380Subventions
Organisme : NHLBI NIH HHS
ID : R01 HL119718
Pays : United States
Organisme : NHLBI NIH HHS
ID : U01 HL101389
Pays : United States
Organisme : NHLBI NIH HHS
ID : U01 HL101422
Pays : United States
Commentaires et corrections
Type : CommentIn
Type : CommentIn
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