BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) is a rare and aggressive 
syndrome of excessive cytokine requiring prompt recognition and aggressive 
therapy.
AIMS: We aimed to systematically characterize HLH in moderate-to-severe 
inflammatory bowel disease (IBD).
METHODS: We performed a systematic review of the literature (PubMED; EMBASE) and 
FDA Adverse Event Reporting System in accordance with the PRISMA statement. Use 
of biologics was used as a surrogate definition for disease severity (consistent 
with usual and contemporary clinical management), to enable identification of 
rare HLH cases with the highest fidelity.
RESULTS: 58 cases of HLH occurring in IBD patients are known (mean age: 
26.0 years, 70% male, 83% with Crohn's disease, mean disease duration 
7.0 years). 34.5% of patients were undergoing induction therapy at HLH 
diagnosis. All cases occurred on patients exposed to anti-TNF agents, but cases 
with anti-integrin or anti-IL-12/23 exposure were reported. 2/3 of cases did not 
report prior AZA/6MP exposure. Underlying opportunistic infection or lymphoma 
was found in > 80% of cases. Survival was 70% if promptly recognized and 
treated. Five patients restarted biologics after HLH resolved, and one patient 
developed recurrent HLH.
CONCLUSIONS: HLH is rare among IBD patients exposed to biologic therapy. Most 
cases had an identifiable infection or malignancy at the time of diagnosis as 
well as history of immunomodulator use. Risk factors may include younger age, 
male gender, presence of Crohn's disease, and induction phase of treatment. Our 
study is not intended to assess risk of HLH with specific IBD therapies.