title: Incidence and complications of interstitial lung disease in users of tocilizumab, rituximab, abatacept and anti-tumor necrosis factor α agents, a retrospective cohort study.
abstract: BACKGROUND
  Interstitial lung disease (ILD) is a common extra-articular condition in rheumatoid arthritis (RA), but few studies have systematically investigated its incidence and risk factors in patients receiving anti-tumor necrosis factor-alpha (anti-TNFα) agents or alternate mechanisms of action (MOAs) (e.g., T-cell, B-cell, and interleukin-6 inhibitors).
  
  
  METHODS
  RA patients at least 18 years old were selected from the MarketScan databases (2010-2012) if they had at least one prescription/administration of abatacept, rituximab, tocilizumab, or anti-TNF after having discontinued a different biologic agent and meeting enrollment criteria. Cox models estimated the risk of incident ILD and ILD-related hospitalization. Sensitivity analyses used an alternate ILD case definition.
  
  
  RESULTS
  We identified 13,795 episodes of biologic exposure in 11,219 patients. Mean (standard deviation) follow-up was 0.7 (0.5) years. Patients receiving alternate MOA agents were more likely to have had recent exposure to steroids, prior exposure to a greater number of biologics, and history of ILD, anemia, chronic obstructive pulmonary disease, and other pulmonary conditions. When the sensitive definition was used, unadjusted ILD incidence rates (95% confidence interval, or CI) ranged from 4.0 (1.6-8.2, abatacept) to 12.2 (5.6-23.2, infliximab) per 1000 person-years. Being older (hazard ratio (HR) 3.5; 95% CI 2.1-6.0), being male (HR 3.1; 95% CI 1.2-8.4), and having another pulmonary condition (HR 4.8; 95% CI 1.7-13.7) were associated with increased ILD incidence in either sensitive and/or specific models. There were no significant differences by biologic class. Hospitalization rates (95% CI) when the sensitive definition was used ranged from 55.6 (6.7-200.7, tocilizumab) to 262.5 (71.5-672.2, infliximab). In Cox models, recent methotrexate exposure was associated with reduced ILD hospitalization (HR 0.16; 95% CI 0.06-0.46), whereas being male (HR 2.5; 95% CI 1.3-4.8) and having had a hospitalization for asthma (HR 3.4; 95% CI 1.2-9.8) or ILD/pneumonia (HR 2.3; 95% CI 1.1-4.7) in the 12 months prior to index were associated with increased hospitalization risk.
  
  
  CONCLUSIONS
  There were no significant differences in the risk of ILD and its related complications between RA patients receiving anti-TNFα agents and those receiving alternate MOA agents. Further studies are needed that account for differences in baseline characteristics in order to fully evaluate the risk of ILD and its complications.
authors.affiliation: Division of Clinical Immunology and Rheumatology, UAB Arthritis Clinical Intervention Program, University of Alabama at Birmingham, FOT 802D, 510 20th Street South, Birmingham, AL, 35924, USA. jcurtis@uab.edu.
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Curtis
authors.affiliation: Genentech, 1 DNA Way, South San Francisco, CA, 94080, USA. sarsourk@gene.com.
authors.forename: Khaled
authors.initials: K
authors.lastname: Sarsour
authors.affiliation: Genentech, 1 DNA Way, South San Francisco, CA, 94080, USA. napalkov.pavel@gene.com.
authors.forename: Pavel
authors.initials: P
authors.lastname: Napalkov
authors.affiliation: Outcomes Research Solutions, Inc., 303 Wyman Street, Waltham, MA, 02451, USA. laurie.costa@orsolutionsinc.com.
authors.forename: Laurie A
authors.initials: LA
authors.lastname: Costa
authors.affiliation: Outcomes Research Solutions, Inc., 303 Wyman Street, Waltham, MA, 02451, USA. kathy.schulman@orsolutionsinc.com.
authors.forename: Kathy L
authors.initials: KL
authors.lastname: Schulman
mesh_terms: D000069594:Abatacept / Q000627:therapeutic use; D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use; D018501:Antirheumatic Agents / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000150:complications* / Q000188:drug therapy; D015331:Cohort Studies; D005260:Female; D006801:Humans; D015994:Incidence; D017563:Lung Diseases, Interstitial / Q000150:complications* / Q000453:epidemiology*; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D000069283:Rituximab / Q000627:therapeutic use; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents; D014409:Tumor Necrosis Factor-alpha; D000069283:Rituximab; D000069594:Abatacept; C502936:tocilizumab