All medications were possibly related to HSTCL according to at least one causality assessment tool. Anti-metabolites, biologics, and cyclosporine were possibly related to HSTCL according to all three causality assessment tools. Despite the possible causal relationship found across three different tools for these medications, only the anti-TNFas carry a boxed warning for HSTCL. The label for azathioprine includes a boxed warning for malignancy with mention of HSTCL, and mercaptopurine’s label mentions HSTCL in the non-boxed warnings. The label for cyclosporine mentions the risk of lymphoma in the boxed warnings, but not HSTCL specifically. The labels for natalizumab and ustekinumab do not mention lymphoma. The most common demographic risk factors were male sex and younger age, similar to previous studies [22
]. No comparative study from the main systematic review included a case of HSTCL, and only one study specifically mentioned that no HSTCL cases were observed.
The methods guides for systematic reviews of the Evidence-based Practice Center (EPC) Program and the Cochrane Collaboration recommend using case series in some instances [36
]. Based on the importance of HSTCL to patients, HSTCL’s high mortality and the rarity of HSTCL, we performed a separate search of the published literature for HSTCL case reports and case series, and searched AERS as part of a systematic review for treatments of Crohn’s disease. Our rationale for including cases is consistent with the recommendations of the methods guides. Other systematic reviews have included case reports and case series identified from the literature or cases from AERS based on similar rationale [39
]. In contrast to many previous systematic reviews, we searched both case sources. Searching AERS yielded nine cases not identified in the published literature. However, because the majority of cases were identified in both AERS and the published literature, we had to create a process to identify the overlapping cases.
Insufficient reporting prevented us from determining the uniqueness of all identified cases. A few case reports failed to include patient age or sex. Many cases identified as unique did not include information on medication dose, frequency, or dates of use, even though reporting systems such the FDA AERS request this demographic and medication data on their submission forms [44
]. Incomplete reporting is also prevalent in case reports on other types of adverse medication events, and calls have been made for a standardized list of case report guidelines similar to the checklists created by organizations for other types of observational studies [45
]. Other agencies beside the FDA also request specific demographic, clinical, laboratory, and medication information in adverse event reports [46
]. Nevertheless, no standard checklist exists for case reporting, and journal requirements for case report content are variable [47
The usefulness of case reports to identify potential adverse medication events will be enhanced by a standardized checklist for case reporting. Such a checklist should incorporate information commonly requested for adverse event reports and causality assessment, including: basic demographics, documentation of the use and timing of use of the individual and concomitant medications used to treat the condition (including absence of use), all other medications used by the patient, rechallenge and dechallenge information (including absence), laboratory results (including serum medication levels), and diagnostic tests used to confirm the adverse event. Reporting the complete list of medications used by the cases, rather than focusing on medications previously associated with the adverse events, as was common in the case reports we identified, will also aid in the understanding of drug interactions and the adverse event. Modifying the AERS database to require these elements for submission and standardizing the information in case reports submitted to journals will help to match AERS cases to the published cases, identify trends by items like race that are not consistently reported, and improve causality assessments. The suggested modifications are consistent with the Institute for Safe Medication Practices’s (ISMP) recommendation to update AERS to improve the quality of reporting so that the FDA can make more targeted safety warnings [48
Using the causality assessment tools for an irreversible and almost uniformly fatal condition such as HSTCL was challenging. Based on available data, we could not make any causal assessments other than ‘possible’ for all medications. Some elements, such as rechallenge with medication, are not possible for events that rapidly progress to mortality. Improvement of symptoms for cancer with dechallenge is also rare, although regression of lymphoma with withdrawal of azathioprine has been documented [50
]. Other items in the causality tools required more complete reporting, such as serum medication levels or details of the case confirmation, were not available for all cases. Better case reporting and understanding how to modify causality tools for use with irreversible adverse events will assist in making causality assessments for rare events from case reports. For events such as HSTCL that likely have a complex, multifactorial etiology that may develop over months to years, reporters should be prompted to include more detailed information on patient medical history (few of the reports had details on Crohn’s disease severity and behavior), family history, and the absence of use or past use of certain medications commonly used to treat the underlying disease. This data could be requested as part of the FDA’s existing enhanced safety surveillance of TNFa-blockers and pediatric and young adult malignancy, or even in routine submission of MedWatch forms for adverse events such as malignancy [51
]. Journals can also request that authors provide this history when submitting case reports on malignancies that are possibly associated with medications. Routine reporting of this additional information may accelerate identification of other medications and risk factors associated with the adverse event. Causal assessments can then be modified to incorporate relevant biology and epidemiology and used to prioritize which safety events should be studied further to estimate a rate by medication use.
When possible causality has been established from case reports, trials and observational studies can contribute information to estimate a rate of disease by medication use. Trials and prospective studies may begin collecting information on safety events like HSTCL. If trials and observational studies report the occurrence of these rare events and details of the active or passive collection process, the rate of HSTCL can be estimated. For trials and comparative medication studies, a rate by medication use can be calculated by pooling the studies. Understanding the rate of disease, which is not possible from case reports, can help patients and their caretakers make better treatment decisions. Trials and observational studies should also attempt to collect specific details about the events. For example, the TREAT Registry, a Phase IV study for infliximab, reported a case of fatal peripheral T-cell lymphoma with infliximab and immunomodulator use within 6 months of death [52
]. Readers cannot determine whether the T-cell lymphoma was HSTCL because details were not provided in the main text of the publication or the supplemental table. By providing more detailed information about the cause of death, particularly when a death may be due to a black box warning-related event, Phase IV studies could help to improve understanding of the rate of life-threatening events such as HSTCL in these important safety studies.