Table 4.

Key Methodologic Issues for Observational Studies of TNF Inhibitors and Cancer Risk

Methodologic Issue	Considerations
Outcome assessment	Must be consistent across subjects without respect to exposure; use of an external cancer “registry” linked to the study database is ideal; subject report is of unknown accuracy
TNF inhibitor exposure definition	Exposure should begin with the first dosage or after some defined “lag period”; exposure can end with the last dosage, extend until after some number of half-lives beyond last dosage, or continue indefinitely after the last dosage; secondary analyses can help test the above assumptions
Reference group selection	Reference exposure should be active treatment used in similar circumstances as a TNFi (versus the absence of a TNFi); reference exposure and the TNFi should both be initiators versus ongoing use
Concomitant treatment inclusion	Other immunosuppressive treatments must be included as covariates or exposures of interest
Confounder adjustment	Other comorbid conditions and proxies for rheumatic disease severity should be included as covariates