Daniel H. Solomon, MD; Robert J. Glynn, PhD; Elizabeth W. Karlson, MD; Fengxin Lu, MD; Cassandra Corrigan, BA; Josh Colls, BA; Chang Xu, MS; Jean MacFadyen, BA; Medha Barbhaiya, MD; Nancy Berliner, MD; Paul F. Dellaripa, MD; Brendan M. Everett, MD; Aruna D. Pradhan, MD; Sarah P. Hammond, MD; Meredith Murray, BA; Deepak A. Rao, MD; Susan Y. Ritter, MD; Anna Rutherford, MD; Jeffrey A. Sparks, MD; Jackie Stratton, BA; Dong H. Suh, BS; Sara K. Tedeschi, MD; Kathleen M.M. Vanni, BA; Nina P. Paynter, PhD *; Paul M Ridker, MD *

Grant Support: By grants NIH R01 HL119718, NIH U01 HL101422, and U01 HL101389 from the National Institutes of Health (NIH).

Disclosures: Dr. Solomon reports grants from the National Heart, Lung, and Blood Institute (NHLBI) during the conduct of the study; grants from Amgen, AbbVie, Janssen, Corrona, and Pfizer outside the submitted work; and receipt of royalties for writing a chapter on nonsteroidal anti-inflammatory drugs in UpToDate. Dr. Glynn reports grants from NHLBI during the conduct of the study and grants from AstraZeneca, Kowa, Pfizer, and Novartis outside the submitted work. Ms. MacFadyen reports grants from NHLBI during the conduct of the study. Dr. Everett reports grants from NHLBI during the conduct of the study and personal fees from Novartis, Amgen, Merck, Roche Diagnostics, Amarin, and Novartis outside the submitted work. Dr. Pradhan reports grants from the NIH during the conduct of the study. Dr. Hammond reports research support from Merck and AiCuris outside the submitted work. Dr. Rao reports personal fees from Amgen, Pfizer, Janssen, Merck, Scipher Medicine, GlaxoSmithKline, and Bristol-Myers Squibb and grants from Merck and Celgene outside the submitted work. Dr. Ritter reports grants from the NIH during the conduct of the study. Dr. Sparks reports grants from Amgen and Bristol-Myers Squibb and personal fees from Bristol-Myers Squibb, Optum, Janssen, and Gilead outside the submitted work. Dr. Ridker reports grants from NHLBI during the conduct of the study; grants from Novartis and Kowa outside the submitted work; and personal fees from Novartis, Inflazome, Corvidia, and CiVi Biopharma outside the submitted work. Authors not named here have disclosed no conflicts of interest. Disclosures can also be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M19-3369.

Editors' Disclosures: Christine Laine, MD, MPH, Editor in Chief, reports that her spouse has stock options/holdings with Targeted Diagnostics and Therapeutics. Darren B. Taichman, MD, PhD, Executive Editor, reports that he has no financial relationships or interests to disclose. Cynthia D. Mulrow, MD, MSc, Senior Deputy Editor, reports that she has no relationships or interests to disclose. Jaya K. Rao, MD, MHS, Deputy Editor, reports that she has stock holdings/options in Eli Lilly and Pfizer. Christina C. Wee, MD, MPH, Deputy Editor, reports employment with Beth Israel Deaconess Medical Center. Sankey V. Williams, MD, Deputy Editor, reports that he has no financial relationships or interests to disclose. Yu-Xiao Yang, MD, MSCE, Deputy Editor, reports that he has no financial relationships or interest to disclose.

Data Sharing Statement: The authors have indicated that they will not be sharing data. The data will be placed in the NIH BioLINCC on the agreed-upon date. This has been committed to as part of the NIH grant.



Corresponding Author: Daniel H. Solomon, MD, Division of Rheumatology, Inflammation, and Immunity, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115; e-mail, dsolomon@bwh.harvard.edu.

Current Author Addresses: Drs. Solomon, Glynn, Karlson, Lu, Berliner, Dellaripa, Everett, Pradhan, Hammond, Murray, Rao, Ritter, Rutherford, Sparks, Tedeschi, Paynter, and Ridker; Ms. Corrigan; Mr. Colls; Ms. Xu; Ms. MacFadyen; Ms. Stratton; Mr. Suh; and Ms. Vanni: Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115.

Author Contributions: Conception and design: D.H. Solomon, R.J. Glynn, E.W. Karlson, J. Colls, M. Barbhaiya, N.P. Paynter, P.M. Ridker.

Analysis and interpretation of the data: D.H. Solomon, R.J. Glynn, E.W. Karlson, J. Colls, C. Xu, J. MacFadyen, M. Barbhaiya, N. Berliner, P.F. Dellaripa, B.M. Everett, A. Rutherford, J.A. Sparks, D.H. Suh, N.P. Paynter, P.M. Ridker.

Critical revision of the article for important intellectual content: D.H. Solomon, R.J. Glynn, E.W. Karlson, B.M. Everett, A.D. Pradhan, S.P. Hammond, D.A. Rao, J.A. Sparks, D.H. Suh, S.K. Tedeschi, N.P. Paynter, P.M. Ridker.

Final approval of the article: D.H. Solomon, R.J. Glynn, E.W. Karlson, F. Lu, C. Corrigan, J. Colls, C. Xu, J. MacFadyen, M. Barbhaiya, N. Berliner, P.F. Dellaripa, B.M. Everett, A.D. Pradhan, S.P. Hammond, M. Murray, D.A. Rao, S.Y. Ritter, A. Rutherford, J.A. Sparks, J. Stratton, D.H. Suh, S.K. Tedeschi, K.M.M. Vanni, N.P. Paynter, P.M. Ridker.

Administrative, technical, or logistic support: D.H. Solomon, R.J. Glynn, J. Colls, J. MacFadyen, M. Murray, S.Y. Ritter, J.A. Sparks, J. Stratton, K.M.M. Vanni, N.P. Paynter, P.M. Ridker.

Collection and assembly of data: D.H. Solomon, R.J. Glynn, F. Lu, J. Colls, J. MacFadyen, M. Barbhaiya, P.F. Dellaripa, B.M. Everett, A.D. Pradhan, S.P. Hammond, M. Murray, D.A. Rao, S.Y. Ritter, J.A. Sparks, J. Stratton, D.H. Suh, S.K. Tedeschi, K.M.M. Vanni, N.P. Paynter, P.M. Ridker.

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.

Prespecified secondary analyses of a double-blind, placebo-controlled, randomized trial. (ClinicalTrials.gov: NCT01594333)

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.

Artificial Wreath

Solomon DH, Glynn RJ, Karlson EW, et al. Adverse Effects of Low-Dose Methotrexate: A Randomized Trial. Ann Intern Med. 2020;:. [Epub ahead of print 18 February 2020]. doi: https://doi.org/10.7326/M19-3369

Gastroenterology/Hepatology, Hematology/Oncology, Liver Disease, Pulmonary/Critical Care, Rheumatology.

Pageant Crowns, Bridal Crowns, Rhinestone Mask, Rhinestone Scepter - Crownsworld,https://www.crownsworldchina.com/