The comparative safety of first-line conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) used for the treatment of rheumatoid arthritis: protocol for a multi-database real-world cohort study

Study type

• Study type:
  Non-interventional study
• Scope of the study:
  Assessment of risk minimisation measure implementation or effectiveness

Non-interventional study

• Non-interventional study design:
  Cohort

Study drug and medical condition

• Anatomical Therapeutic Chemical (ATC) code:
  (P01BA02) hydroxychloroquine

  hydroxychloroquine

  (L04AX03) methotrexate

  methotrexate

  (L04AA13) leflunomide

  leflunomide

  (A07EC01) sulfasalazine

  sulfasalazine
• Medical condition to be studied:
  Rheumatoid arthritis

Population studied

• Age groups:
  Adults (18 to < 46 years)

  Adults (46 to < 65 years)

  Adults (65 to < 75 years)

  Adults (75 to < 85 years)

  Adults (85 years and over)
• Estimated number of subjects:
  300000

Study design details

• Main study objective:
  1. To assess the cardiovascular safety of MTX compared to LEF, HCQ, and SSZ2. To estimate the risk of infections associated with the use of MTX compared to LEF, HCQ, and SSZ3. To study the risk of cancer associated with the use of MTX compared to LEF, HCQ, and SSZ4. To study the risk of leukopenia/pancytopaenia associated with the use of MTX compared to LEF, HCQ, and SSZ
• Outcomes:
  Myocardial infarction, stroke, serious infection, opportunistic infection, any infection, lymphoma, leukemia, lung cancer, colo-rectal cancer, any cancer, leukopenia/pancytopenia
• Data analysis plan:
  Propensity scores will be estimated using LASSO and used for stratification (primary) and matching (secondary analysis). Balance will be assessed using standardised mean difference. Cox models will be used to estimate hazard ratios according to exposure. Negative control outcomes will be used to assess residual confounding, and for calibration where applicable. Study diagnostics (power, propensity score distribution, covariate balance) were evaluated by clinicians and epidemiologists to determine which database-target-comparator-outcome-analyses warrant further consideration. Database-target-comparator that identified <10 outcomes in the time-at-risk or contained analyses with baseline covariate with standardized mean difference>0.1 and covariate prevalence difference>0.05 were excluded. All the analyses will be conducted for each database separately, with estimates combined in fixed effects meta-analysis methods where I2 is <=40%.