Significance of low level infliximab in the absence of anti-infliximab antibodies

Bella Ungar*, Adi Anafy, Henit Yanai, Yulia Ron, Miri Yavzori, Orit Picard, Ella Fudim, Ronen Loebstein, Uri Kopylov, Yehuda Chowers, Iris Dotan, Rami Eliakim, Shomron Ben-Horin

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


AIM: To evaluate the prevalence of double negative (DN) sera and the mechanisms responsible for DN status. METHODS: Sera of inflammatory bowel disease patients treated with infliximab (IFX) were tested for drug/antibodies to infliximab (ATI) trough levels and the proportion of DN results was compared between a commercially available double antigen ELISA (with labeled IFX as the detection antibody) and an anti-lambda ELISA (with anti-human lambda chain detection antibody). Repeat testing with lower than customary serum dilution (1:10) was performed. Patients with DN status were matched with IFX+/ATI- controls and were followed-up for subsequent development of non-transient ATI to investigate if DN status precedes ATI. RESULTS: Of 67 sera obtained at time of loss of response, only 6/67 (9%) were DN by anti-lambda ELISA compared to 27/67 (40%) with double antigen ELISA (P < 0.001, Fisher's Exact test). Of the latter 27 sera, 22% were also DN by anti-lambda ELISA, whereas 44% were actually IFX positive (IFX+ATI-), 30% were ATI positive (IFX-ATI+) and 4% were double positive (IFX+ATI+). Re-testing using a 1:10 dilution converted most DN results into IFX+ and /or ATI+ status. Patients with DN status had shorter survival free of non-transient ATI compared with matched controls (log rank test, P < 0.001). In 9/30 (30%) of these patients, non transient ATI occurred before and after the event at which the DN serum was obtained, supporting the view that a DN result may represent a particular time-point along the two curves of ATI titer rise and infliximab drug level decline. CONCLUSION: DN status may result from false negative detection of IFX or ATI by double antigen ELISA, suggesting a transitional state of low-level immunogenicity, rather than non-immunological clearance.

Original languageEnglish
Pages (from-to)1907-1914
Number of pages8
JournalWorld Journal of Gastroenterology
Issue number6
StatePublished - 14 Feb 2015


FundersFunder number
Leona M. and Harry B. Helmsley Charitable Trust


    • Biological therapy
    • Drug response
    • Immunology
    • Inflammatory bowel disease
    • Infliximab


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