title: Use of case reports and the Adverse Event Reporting System in systematic reviews: overcoming barriers to assess the link between Crohn's disease medications and hepatosplenic T-cell lymphoma.
abstract: BACKGROUND
  To identify demographic and clinical characteristics associated with cases of hepatosplenic T-cell lymphoma (HSTCL) in patients with Crohn's disease, and to assess strength of evidence for a causal relationship between medications and HSTCL in Crohn's disease.
  
  
  METHODS
  We identified cases of HSTCL in Crohn's disease in studies included in a comparative effectiveness review of Crohn's disease medications, through a separate search of PubMed and Embase for published case reports, and from the Food and Drug Administration (FDA) Adverse Event Reporting System (AERS). We used three causality assessment tools to evaluate the relationship between medication exposure and HSTCL.
  
  
  RESULTS
  We found 37 unique cases of HSTCL in patients with Crohn's disease. Six cases were unique to the published literature and nine were unique to AERS. Cases were typically young (<40 years of age) and male (86%). The most commonly reported medications were anti-metabolites (97%) and anti-tumor necrosis factor alpha (anti-TNFa) medications (76%). Dose and duration of therapy were not consistently reported. Use of aminosalicylates and corticosteroids were rarely reported, despite the high prevalence of these medications in routine treatment. Using the causality assessment tools, it could only be determined that anti-metabolite and anti-TNFa therapies were possible causes of HSTCL in Crohn's disease based on the data contained in the case reports.
  
  
  CONCLUSIONS
  Systematic reviews that incorporate case reports of rare lethal events should search both published literature and AERS, but consideration should be given to the limitations of case reports. In this study, establishing a causative effect other than 'possible' between anti-metabolite or anti-TNFa therapies and HSTCL was not feasible because case reports lacked data required by the causality assessments, and because of the limited applicability of causality assessment tools for rare irreversible events. We recommend minimum reporting requirements for case reports to improve causality assessment and routine reporting of rare life-threatening events, including their absence, in clinical trials to help clinicians determine whether rare adverse events are causally related to a medication.
authors.affiliation: Johns Hopkins University School of Medicine, 733 North Broadway, Baltimore, MD 21205-2196, USA. sselvar1@jhmi.edu
authors.forename: Saranya A
authors.initials: SA
authors.lastname: Selvaraj
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Chairez
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Wilson
authors.forename: Mark
authors.initials: M
authors.lastname: Lazarev
authors.forename: Eric B
authors.initials: EB
authors.lastname: Bass
authors.forename: Susan
authors.initials: S
authors.lastname: Hutfless
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000893:Anti-Inflammatory Agents / Q000009:adverse effects / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized / Q000009:adverse effects / Q000627:therapeutic use; D000963:Antimetabolites / Q000009:adverse effects* / Q000627:therapeutic use; D002648:Child; D003424:Crohn Disease / Q000188:drug therapy*; D003625:Data Collection / Q000379:methods; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D005765:Gastrointestinal Agents / Q000009:adverse effects* / Q000627:therapeutic use; D006801:Humans; D008113:Liver Neoplasms / Q000139:chemically induced*; D016399:Lymphoma, T-Cell / Q000139:chemically induced*; D008297:Male; D008875:Middle Aged; D013160:Splenic Neoplasms / Q000139:chemically induced*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*; D055815:Young Adult
chemical_list: D000893:Anti-Inflammatory Agents; D061067:Antibodies, Monoclonal, Humanized; D000963:Antimetabolites; D005765:Gastrointestinal Agents; D014409:Tumor Necrosis Factor-alpha