Impact of Smoking in Response to Tumor Necrosis Factor Inhibitors in Axial Spondyloarthritis: Methodologic Considerations for Longitudinal Observational Studies

Arthritis Care Res (Hoboken). 2020 Apr;72(4):591-599. doi: 10.1002/acr.23851. Epub 2020 Mar 12.


Objective: Observational data facilitate examination of treatment-effect heterogeneity, but the risk of bias is substantial. The present study was undertaken to highlight methodologic considerations through an analysis of whether smoking affects response to tumor necrosis factor inhibitors (TNFi) in axial spondyloarthritis (SpA).

Methods: We used longitudinal data from the British Society for Rheumatology Biologics Register for Ankylosing Spondylitis. Participants fulfilling the Assessment of SpondyloArthritis international Society criteria for axial SpA who started their first TNFi were eligible for analysis. In comparing the impact of smoking status, weighted generalized estimating equations were used to examine changes in several continuous outcome measures, including the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and the Ankylosing Spondylitis Disease Activity Score (ASDAS). Inverse probability weights were used to account for differences in baseline covariates and excluded participants. We separately assessed response in the first 3 months to account for nonrandom dropout.

Results: For 840 participants who started on TNFi, 1,641 assessments from 627 individuals were analyzed (69% male, mean age 46 years). A total of 33% were current smokers and 30% ex-smokers. Ex-smokers and current smokers had worse disease than never smokers at baseline. Accounting for these differences, response did not differ according to smoking status. Compared to never smokers, ex-smokers (β = -0.6, 95% confidence interval [95% CI] -1.4, 0.3) and current smokers (β = -0.4, 95% CI -1.1, 0.4) had a similar response according to the BASDAI and ASDAS (ex-smokers β = -0.1, 95% CI -0.5, 0.3; current smokers β = -0.01, 95% CI -0.4, 0.4) at 3 months.

Conclusion: TNFi response did not differ according to baseline smoking status in this UK cohort. Conflicting results from previous studies were likely due to methodologic differences. This analysis highlights potential sources of bias that should be addressed in future studies.

Publication types

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

MeSH terms

  • Adult
  • Antirheumatic Agents / therapeutic use*
  • Female
  • Humans
  • Longitudinal Studies
  • Male
  • Middle Aged
  • Registries
  • Severity of Illness Index
  • Smoking*
  • Spondylarthritis / diagnosis
  • Spondylarthritis / drug therapy*
  • Treatment Outcome
  • Tumor Necrosis Factor Inhibitors / therapeutic use*
  • United Kingdom


  • Antirheumatic Agents
  • Tumor Necrosis Factor Inhibitors