PMID- 33201596 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20220113 IS - 2578-5745 (Electronic) IS - 2578-5745 (Linking) VI - 2 IP - 12 DP - 2020 Dec TI - 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. PG - 697-704 LID - 10.1002/acr2.11187 [doi] AB - 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. CI - (c) 2020 The Authors. ACR Open Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology. FAU - Vanni, Kathleen M M AU - Vanni KMM AUID- ORCID: 0000-0003-0839-9661 AD - Brigham and Women's Hospital, Boston, Massachusetts. FAU - Berliner, Nancy AU - Berliner N AUID- ORCID: 0000-0001-7502-6895 AD - Brigham and Women's Hospital, Boston, Massachusetts. FAU - Paynter, Nina P AU - Paynter NP AD - Brigham and Women's Hospital, Boston, Massachusetts. FAU - Glynn, Robert J AU - Glynn RJ AD - Brigham and Women's Hospital, Boston, Massachusetts. FAU - MacFadyen, Jean AU - MacFadyen J AD - Brigham and Women's Hospital, Boston, Massachusetts. FAU - Colls, Joshua AU - Colls J AD - Brigham and Women's Hospital, Boston, Massachusetts. FAU - Lu, Fengxin AU - Lu F AD - Brigham and Women's Hospital, Boston, Massachusetts. FAU - Xu, Chang AU - Xu C AD - Brigham and Women's Hospital, Boston, Massachusetts. FAU - Ridker, Paul M AU - Ridker PM AD - Brigham and Women's Hospital, Boston, Massachusetts. FAU - Solomon, Daniel H AU - Solomon DH AUID- ORCID: 0000-0001-8202-5428 AD - Brigham and Women's Hospital, Boston, Massachusetts. LA - eng GR - R01 HL119718/HL/NHLBI NIH HHS/United States GR - NIH R01 HL119718/NH/NIH HHS/United States GR - NIH U01 HL101422/NH/NIH HHS/United States GR - NIH U01 HL101389/NH/NIH HHS/United States PT - Journal Article DEP - 20201117 PL - United States TA - ACR Open Rheumatol JT - ACR open rheumatology JID - 101740025 PMC - PMC7738806 EDAT- 2020/11/18 06:00 MHDA- 2020/11/18 06:01 PMCR- 2020/11/17 CRDT- 2020/11/17 12:19 PHST- 2020/05/08 00:00 [received] PHST- 2020/09/16 00:00 [accepted] PHST- 2020/11/18 06:00 [pubmed] PHST- 2020/11/18 06:01 [medline] PHST- 2020/11/17 12:19 [entrez] PHST- 2020/11/17 00:00 [pmc-release] AID - ACR211187 [pii] AID - 10.1002/acr2.11187 [doi] PST - ppublish SO - ACR Open Rheumatol. 2020 Dec;2(12):697-704. doi: 10.1002/acr2.11187. Epub 2020 Nov 17.