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. 2017 Sep 14;8(9):e117.
doi: 10.1038/ctg.2017.44.

Transmembrane TNF-α Density, but not Soluble TNF-α Level, is Associated with Primary Response to Infliximab in Inflammatory Bowel Disease

Azade Amini Kadijani  1   2 , Hamid Asadzadeh Aghdaei  2 , Dario Sorrentino  3   4 , Alireza Mirzaei  5 , Shabnam Shahrokh  5 , Hedieh Balaii  5 , Vu Q Nguyen  3 , Jessica L Mays  3 , Mohammad Reza Zali  6
Affiliations

Transmembrane TNF-α Density, but not Soluble TNF-α Level, is Associated with Primary Response to Infliximab in Inflammatory Bowel Disease

Azade Amini Kadijani et al. Clin Transl Gastroenterol. .

Erratum in

Abstract

Objectives: Anti-tumor necrosis factor (TNF)-α agents like Infliximab (IFX) are effective in the treatment of inflammatory bowel diseases (IBDs) and are widely used. However, a considerable number of patients do not respond or lose response to this therapy. Preliminary evidence suggests that transmembrane TNF-α (tmTNF-α) might be linked to response to IFX by promoting reverse signaling-induced apoptosis in inflammatory cells. The main aim of this study was the evaluation of this hypothesis in primary IFX non-responders.

Methods: A total of 47 IFX naive IBD patients were included in the study. Blood samples were taken before the start of IFX therapy (at week 0) and after induction therapy (at week 14). Endoscopic disease activity and markers of inflammation at baseline and at week 14 were used to evaluate response. Baseline soluble TNF-α (sTNF-α), percentage of circulating TNF-α positive cells, mean fluorescence intensity (MFI) of tmTNF-α, and apoptosis rate at week 14 in the peripheral blood mononuclear cells (PBMCs) were evaluated in IFX responders and non-responders.

Results: Mean sTNF-α was not significantly different in responders compared to non-responders (P=0.13). Mean percentage of tmTNF-α bearing lymphocytes and monocytes was higher in the PBMCs of responders (P=0.05 and P=0.014, respectively). Mean MFI of tmTNF-α in circulating lymphocytes and monocytes was greater in responders (P=0.002 and P<0.001, respectively). Moreover, the mean percentage of apoptosis in PBMCs was significantly greater in responders compared to non-responders (P=0.002).

Conclusions: The percentage of tmTNF-α bearing lymphocytes and monocytes and the intensity of tmTNF-α in the circulating leukocyte population of IBD patients was directly related to primary response to IFX. This was likely due-as assessed by the apoptosis rate-to promotion of inflammatory cell death. Thus, our data suggest that peripheral leukocytes could in principle be used for predicting primary response to IFX in IBD patients.

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Conflict of interest statement

Guarantor of the article: Dario Sorrentino, MD, FRACP.

Specific author contributions: Study concept and design: Hamid Asadzadeh Aghdaei, Azade Amini Kadijani, Dario Sorrentino. Acquisition of data: Azade Amini Kadijani, Hedieh Balaii. Analysis and interpretation of data: Azade Amini Kadijani, Dario Sorrentino. Drafting of the manuscript: Azade Amini Kadijani, Alireza Mirzaei, Vu Nguyen. Critical revision of the manuscript for important intellectual content: Dario Sorrentino, Vu Nguyen. Statistical analysis: Alireza Mirzaei. Administrative, technical, and material support: Mohammad Reza Zali, Shabnam Shahrokh, Jessica L.Mays. Study supervision: Hamid Asadzadeh Aghdaei, Dario Sorrentino.

Financial support: V.N. has received grant support from AbbVie Inc. D.S. has received consulting fees from Abbott/AbbVie, Schering-Plough, MSD, Janssen Research & Development, LLC., Centocor Inc., TechLab, Hoffmann-LaRoche, Giuliani, Schering-Plough, and Ferring; research grants from AbbVie, Janssen Research & Development, LLC, Schering-Plough, TechLab, Centocor and serves in the Speakers Bureau of AbbVie and the National Faculty of Janssen. This study has been supported by Research Institute for Gastroenterology and Liver Disease Shaheed Beheshti University of Medical Sciences.

Potential competing interests: None.

Figures

Figure 1
Figure 1
Flowchart of the study. ATI, antibodies to infliximab; FC, fecal calprotectin; IFX, Infliximab; ITL, Infliximab trough level; PBMC, peripheral blood mononuclear cells; sTNF-α, serum TNF-α tmTNF-α, transmembrane TNF-α.
Figure 2
Figure 2
sTNF-α, tmTNF-α bearing lymphocytes and monocytes, lymphocyte and monocyte tmTNF-α MFI (measured at baseline), and apoptosis in IFX responders and IFX non-responders (measured at 14 weeks). (a) Mean sTNF-α level; (b) percentage of tmTNF-α bearing lymphocytes and monocytes; (c) MFI of tmTNF-α in lymphocytes and monocytes; (d) percentage of apoptosis in PBMCs. IFX, Infliximab; MFI, mean fluorescence intensity; PBMC; sTNF-α, soluble TNF-α tmTNF-α, transmembrane TNF-α. The asterisk indicates a statistically significant difference.
Figure 3
Figure 3
ROC curves for lymphocyte (a) and monocyte (b) MFI. MFI, mean fluorescence intensity; ROC, receiver operating characteristic.
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