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.

Conclusion: 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.

Figure 1

Identification of unique cases by PubMed and Embase searches. AERS, Adverse Event Reporting System; HSTCL, hepatosplenic T-cell lymphoma.

Figure 2

Timeline of medication approval by the Food and Drug Administration (FDA) and occurrence of hepatosplenic T-cell lymphoma (HSTCL). Includes 37 unique cases and nine cases with insufficient reporting, for a total of 46 cases. Each box includes a unique case by year the case was reported. The horizontal axis indicates the year the case was diagnosed. The numbers in each square are ordered oldest to youngest age at HSTCL diagnosis. They match up to the numbers with detailed case information in Additional file 2: Table S2. Vertical arrows indicate years that the particular medications were approved by the FDA. Ustekinumab is not approved by the FDA for Crohn’s disease. The numbers within each box refer to case numbers in Additional file 2: Table S2. Patients were reported through 25 January 2011 (published) and December 2010 (AERS). *Date of case reported as 2007 to 2008. **Date of case reported as 2000 to 2009. AERS, Adverse Event Reporting System; FDA, Food and Drug Administration; HSTCL, hepatosplenic T-cell lymphoma.