{"doi":"10.1002/acr2.11187","title":"Adverse Effects of Low‐Dose Methotrexate in a Randomized Double‐Blind Placebo‐Controlled Trial: Adjudicated Hematologic and Skin Cancer Outcomes in the Cardiovascular Inflammation Reduction Trial","abstract":"OBJECTIVE: Low-dose methotrexate (LD-MTX), a cornerstone in the treatment of rheumatoid arthritis, is associated with a moderately increased risk of anemia, leukopenia, and skin cancers, but the risks of myelosuppression and malignancy during LD-MTX use remain incompletely described. We examined the risks of cytopenias and skin cancers among patients taking LD-MTX versus placebo in a large randomized controlled trial (RCT). METHODS: We prespecified secondary analyses of a double-blind, placebo-controlled RCT that included adults with known cardiovascular disease and diabetes or metabolic syndrome in the United States and Canada. Subjects were randomly allocated to LD-MTX (20 mg/week maximum) or placebo. All subjects received folic acid (1 mg daily for 6days/week). We assessed the frequency of blindly adjudicated hematologic and malignant adverse events (AEs). RESULTS: A total of 2391 subjects were randomized to LD-MTX (mean dosage 14.9 mg/week), and 2395 were randomized to placebo. During follow-up, in the LD-MTX arm, simultaneous two-line cytopenias (n = 92 [3.9%]) or pancytopenia (n = 13 [0.54%]) were infrequent. Pancytopenia developed as soon as 4 months and as late as 3.5 years after beginning LD-MTX, though the latter subject had been recently diagnosed with multiple myeloma. Overall skin cancer risk was increased in users of LD-MTX compared with users of placebo, which driven largely by a statistically significant increased risk of squamous cell skin cancer (hazard ratio [HR] 3.31; 95% confidence interval [CI] 1.63-6.71). Melanoma was increased in LD-MTX, but this was not statistically significant (HR 2.33; 95% CI 0.60-9.01). CONCLUSIONS: Among subjects using LD-MTX, simultaneous two-line cytopenias and pancytopenia were uncommon. We found more cases of skin cancer, particularly squamous cell carcinomas, in the LD-MTX arm than the placebo arm.","journal":"ACR Open Rheumatology","year":2020,"id":99544,"datarank":0.515098080672772,"base_score":3.4339872044851463,"endowment":3.4339872044851463,"self_citation_contribution":0.515098080672772,"citation_network_contribution":0.0,"self_endowment_contribution":0.515098080672772,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":30,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9607,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":481411,"name":"Nancy Berliner","orcid":"0000-0001-7502-6895","position":1,"is_corresponding":false},{"id":32996,"name":"Nina P. Paynter","orcid":"0000-0003-3376-3867","position":2,"is_corresponding":false},{"id":45776,"name":"Robert J. Glynn","orcid":"0000-0002-0697-8996","position":3,"is_corresponding":false},{"id":78549,"name":"Jean MacFadyen","orcid":null,"position":4,"is_corresponding":false},{"id":491114,"name":"J Colls","orcid":null,"position":5,"is_corresponding":false},{"id":490016,"name":"Fengxin Lu","orcid":"0000-0002-9357-311X","position":6,"is_corresponding":false},{"id":391214,"name":"Chang Xu","orcid":"0000-0002-5524-4550","position":7,"is_corresponding":false},{"id":21979,"name":"Paul M. Ridker","orcid":"0000-0003-1249-4522","position":8,"is_corresponding":false},{"id":391215,"name":"Daniel H. Solomon","orcid":"0000-0001-8202-5428","position":9,"is_corresponding":false},{"id":490015,"name":"Kathleen M.M. Vanni","orcid":"0000-0003-0839-9661","position":0,"is_corresponding":true}],"reference_count":16,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-18T22:38:09.754371Z","pmid":"33201596","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}