Tumor Necrosis Factor-α Inhibitor Use and the Risk of Incident Hypertension in Patients with Rheumatoid Arthritis

Epidemiology. 2016 May;27(3):414-22. doi: 10.1097/EDE.0000000000000446.


Objective: To compare the risk of incident hypertension between initiators of tumor necrosis factor (TNF)-α inhibitors and initiators of nonbiologic disease modifying antirheumatic drugs (hereafter referred to as nonbiologics) in rheumatoid arthritis patients taking methotrexate monotherapy.

Methods: We conducted a cohort study using insurance claims data (2001-2012) from the US. We identified initiators of use of either TNF-α inhibitors or nonbiologics. Subsequent exposure to these agents was measured monthly in a time-varying manner. The outcome of interest was incident hypertension, defined by a diagnosis and a prescription for an antihypertensive drug. Marginal structural models estimated hazard ratios (HRs) adjusted for both baseline and time-varying confounders. To validate the primary analysis, we designed a verification analysis to evaluate a known association between leflunomide (a nonbiologic disease modifying agent) and hypertension.

Results: We identified 4,822 initiations of TNF-α inhibitor use and 2,400 of nonbiologic use. Crude incidence rates of hypertension per 1,000 person-years of follow-up were 36 (95% CI [confidence interval]: 32, 41) for the TNF-α inhibitor group and 42 (95% CI: 34, 51) for the nonbiologics group. The crude HR of TNF-α inhibitors versus nonbiologics for the risk of incident hypertension was 0.85 (95% CI: 0.67, 1.1). After adjusting for both baseline and time-varying covariates using marginal structural models, the HR was 0.95 (95% CI: 0.74, 1.2). In the verification analysis, the adjusted HR of incident hypertension was 2.3 (95% CI: 1.7, 3.0) in leflunomide initiators compared with methotrexate initiators.

Conclusion: Treatment with TNF-α inhibitors was not associated with a reduced risk of incident hypertension compared with nonbiologics in rheumatoid arthritis patients.See Video Abstract at http://links.lww.com/EDE/B36.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adalimumab / therapeutic use
  • Adult
  • Antibodies, Monoclonal / therapeutic use
  • Antirheumatic Agents / therapeutic use*
  • Arthritis, Rheumatoid / drug therapy*
  • Azathioprine / therapeutic use
  • Certolizumab Pegol / therapeutic use
  • Cohort Studies
  • Cyclophosphamide / therapeutic use
  • Etanercept / therapeutic use
  • Female
  • Humans
  • Hydroxychloroquine / therapeutic use
  • Hypertension / epidemiology*
  • Incidence
  • Infliximab / therapeutic use
  • Male
  • Methotrexate / therapeutic use
  • Middle Aged
  • Minocycline / therapeutic use
  • Penicillamine / therapeutic use
  • Proportional Hazards Models
  • Retrospective Studies
  • Risk Factors
  • Sulfasalazine / therapeutic use
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors*


  • Antibodies, Monoclonal
  • Antirheumatic Agents
  • Tumor Necrosis Factor-alpha
  • Sulfasalazine
  • Hydroxychloroquine
  • Cyclophosphamide
  • golimumab
  • Infliximab
  • Adalimumab
  • Minocycline
  • Penicillamine
  • Azathioprine
  • Etanercept
  • Certolizumab Pegol
  • Methotrexate