title: Adherence to disease-modifying antirheumatic drugs and the effects of exposure misclassification on the risk of hospital admission.
abstract: OBJECTIVE
  To describe the effect of different exposure classification strategies for disease-modifying antirheumatic drugs (DMARDs) on drug-outcome associations.
  
  
  METHODS
  We studied the association between DMARD initiation and all-cause hospitalizations in patients with rheumatoid arthritis (RA), 1995-2005. Initiators of DMARDs and oral glucocorticoids were followed for < or =180 days. We compared 2 strategies for exposure classification: a persistent exposure required (PER) approach, in which followup stopped when the regimen changed; and a persistent exposure ignored (PEI) approach, in which followup continued despite regimen changes. For PEI, adherence was assessed using the medication possession ratio. All-cause hospitalization risk was compared among RA regimen initiators using Cox models and methotrexate as the reference.
  
  
  RESULTS
  We identified 28,906 episodes of medication initiation. In PER analyses, tumor necrosis factor alpha antagonists did not increase hospitalization risk compared with methotrexate, whereas leflunomide did (hazard ratio [HR] 1.36, 95% confidence interval [95% CI] 1.1-1.67). Glucocorticoids increased hospitalization risk (HR 1.29, 1.54, and 2.03 for low, medium, and high doses, respectively). PEI results were similar to PER except that infliximab initiation increased the risk of hospitalization compared with methotrexate (HR 1.46, 95% CI 1.19-1.8), and most other effects were closer to the null. In PEI, adherence ranged from 73% for etanercept to 6% for glucocorticoids and adherence to methotrexate was 59%.
  
  
  CONCLUSIONS
  Compared with methotrexate initiation, leflunomide or glucocorticoid initiation consistently increased all-cause hospitalizations in the first 180 days of use. Most PER and PEI estimates were similar; observed differences in risk between these methods were likely due to differences in adherence.
authors.affiliation: Department of Preventive Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-2637, USA. carlos.grijalva@vanderbilt.edu
authors.forename: Carlos G
authors.initials: CG
authors.lastname: Grijalva
authors.forename: Lisa
authors.initials: L
authors.lastname: Kaltenbach
authors.forename: Patrick G
authors.initials: PG
authors.lastname: Arbogast
authors.forename: Edward F
authors.initials: EF
authors.lastname: Mitchel
authors.forename: Marie R
authors.initials: MR
authors.lastname: Griffin
mesh_terms: D016907:Adverse Drug Reaction Reporting Systems / Q000592:standards; D018501:Antirheumatic Agents / Q000008:administration & dosage / Q000009:adverse effects*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy*; D015331:Cohort Studies; D004334:Drug Administration Schedule; D017050:Episode of Care; D005260:Female; D005938:Glucocorticoids / Q000008:administration & dosage / Q000009:adverse effects; D006760:Hospitalization / Q000706:statistics & numerical data*; D006801:Humans; D007555:Isoxazoles / Q000008:administration & dosage / Q000009:adverse effects; D000077339:Leflunomide; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage / Q000009:adverse effects; D008875:Middle Aged; D017063:Outcome Assessment, Health Care / Q000379:methods; D010349:Patient Compliance / Q000706:statistics & numerical data*; D011358:Product Surveillance, Postmarketing / Q000379:methods*; D012189:Retrospective Studies; D013714:Tennessee
chemical_list: D018501:Antirheumatic Agents; D005938:Glucocorticoids; D007555:Isoxazoles; D000077339:Leflunomide; D008727:Methotrexate