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Investigating changes in disease activity as a mediator of cardiovascular risk reduction with methotrexate use in rheumatoid arthritis
  1. Tate M Johnson1,2,
  2. Harlan R Sayles1,3,
  3. Joshua F Baker4,5,
  4. Michael D George4,5,
  5. Punyasha Roul1,
  6. Cheng Zheng3,
  7. Brian Sauer6,7,
  8. Katherine P Liao8,
  9. Daniel R Anderson9,
  10. Ted R Mikuls1,2,
  11. Bryant R England1,2
  1. 1Medicine & Research Service, VA Nebraska-Western Iowa Health Care System, Omaha, Nebraska, USA
  2. 2Department of Internal Medicine, Division of Rheumatology, University of Nebraska Medical Center, Omaha, Nebraska, USA
  3. 3Department of Biostatistics, University of Nebraska Medical Center, Omaha, Nebraska, USA
  4. 4Department of Medicine, Division of Rheumatology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
  5. 5Rheumatology, Corporal Michael J Crescenz VA Medical Center, Philadelphia, Pennsylvania, USA
  6. 6Rheumatology, VA Salt Lake City Health Care System, Salt Lake City, Utah, USA
  7. 7Department of Medicine, Division of Rheumatology, University of Utah Medical Center, Salt Lake City, Utah, USA
  8. 8Rheumatology, VA Boston Healthcare System, West Roxbury, Massachusetts, USA
  9. 9Department of Internal Medicine, Division of Cardiology, University of Nebraska Medical Center, Omaha, Nebraska, USA
  1. Correspondence to Dr Bryant R England, Medicine & Research Service, VA Nebraska-Western Iowa Health Care System, Omaha, Nebraska, USA; bryant.england{at}unmc.edu

Abstract

Objective Examine the association of methotrexate (MTX) use with cardiovascular disease (CVD) in rheumatoid arthritis (RA) using marginal structural models (MSM) and determine if CVD risk is mediated through modification of disease activity.

Methods We identified incident CVD events (coronary artery disease (CAD), stroke, heart failure (HF) hospitalisation, CVD death) within a multicentre, prospective cohort of US Veterans with RA. A 28-joint Disease Activity Score with C-reactive protein (DAS28-CRP) was collected at regular visits and medication exposures were determined by linking to pharmacy dispensing data. MSMs were used to estimate the treatment effect of MTX on risk of incident CVD, accounting for time-varying confounders between receiving MTX and CVD events. A mediation analysis was performed to estimate the indirect effects of methotrexate on CVD risk through modification of RA disease activity.

Results Among 2044 RA patients (90% male, mean age 63.9 years, baseline DAS28-CRP 3.6), there were 378 incident CVD events. Using MSM, MTX use was associated with a 24% reduced risk of composite CVD events (HR 0.76, 95% CI 0.58 to 0.99) including a 57% reduction in HF hospitalisations (HR 0.43, 95% CI 0.24 to 0.77). Individual associations with CAD, stroke and CVD death were not statistically significant. In mediation analyses, there was no evidence of indirect effects of MTX on CVD risk through disease activity modification (HR 1.03, 95% CI 0.80 to 1.32).

Conclusions MTX use in RA was associated with a reduced risk of CVD events, particularly HF-related hospitalisations. These associations were not mediated through reductions in RA disease activity, suggesting alternative MTX-related mechanisms may modify CVD risk in this population.

  • rheumatoid arthritis
  • methotrexate
  • cardiovascular disease

Data availability statement

Data are available on reasonable request from the VA Rheumatoid Arthritis Registry and Biorepository after obtaining the required ethical approval.

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Data availability statement

Data are available on reasonable request from the VA Rheumatoid Arthritis Registry and Biorepository after obtaining the required ethical approval.

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Footnotes

  • Handling editor Josef S Smolen

  • Contributors TMJ, TRM and BRE designed the study. TMJ, JFB, PR, BS, TRM and BRE were responsible for acquisition of data. TMJ, HRS, PR, CZ and BRE analysed the data. All authors were responsible for interpretation of the data and for drafting, revising and approving the final submitted manuscript.

  • Funding TMJ was supported by a Rheumatology Research Foundation Resident Research Preceptorship. TRM is supported by a VA Merit Award (BX004600) and grants from the Rheumatology Research Foundation and the National Institutes of Health: National Institute of General Medical Sciences (U54GM115458), National Institute on Alcohol Abuse and Alcoholism (R25AA020818) and National Institute of Arthritis and Musculoskeletal and Skin Diseases (2P50AR60772). BRE is supported by a Rheumatology Research Foundation Scientist Development Award and the VA (CX002203).

  • Disclaimer The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs or the United States government.

  • Competing interests MDG receives grant support from Bristol Myers Squibb for unrelated work.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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