Level of Tumor Necrosis Factor Production by Stimulated Blood Mononuclear Cells Can Be Used to Predict Response of Patients With Inflammatory Bowel Diseases to Infliximab

doi:10.1016/j.cgh.2020.03.066

Clinical Gastroenterology and Hepatology

Volume 19, Issue 4, April 2021, Pages 721-731.e1

https://doi.org/10.1016/j.cgh.2020.03.066 Get rights and content

Background & Aims

A substantial proportion patients with inflammatory bowel disease (IBD) have a primary non-response to infliximab; markers are needed to identify patients most likely to respond to treatment. We investigated whether production of tumor necrosis factor (TNF) by peripheral blood mononuclear cells (PBMCs) can be used as a marker to predict response.

Methods

We performed a prospective study of 41 adults with IBD (mean age, 38 years; 21 male; 21 with Crohn’s disease and 20 with ulcerative colitis) not treated with a biologic agent within the past 6 months; patients were given their first infusion of infliximab at a hospital or clinic in Berlin, Germany. We collected data on clinical scores, levels of C-reactive protein, and ultrasound results (Limberg scores) at baseline (before the first infusion) and after 6 weeks (3^rd infliximab infusion). PMBCs were obtained from patients at baseline and 10 healthy individuals (controls) and incubated with lipopolysaccharide. We measured production of cytokines (TNF, interleukin 1 [IL1], IL6, IL8, IL10, IL12p70, and IL22) by ELISA and performed cytometric bead array and flow cytometry analyses. The primary endpoint was clinical response (decrease in Harvey Bradshaw Index scores of 2 or more or decrease in partial Mayo scores of 3 or more at week 6) in patients with PBMCs that produced high vs low levels of TNF.

Results

Responders had a shorter median disease duration (P = .018) and higher median Limberg score (P = .021), than nonresponders. Baseline PBMCs from responders produced significantly more TNF (P = .049) and IL6 (P = .028) than from nonresponders; a level of 500 pg/ml TNF identified responders with 82% sensitivity and 78% specificity. In patients with Crohn’s disease, this cutoff value (500 pg/ml TNF) identified responders with 100% sensitivity and 82% specificity; TNF levels above this level were independently associated with response to infliximab in multivariate analysis (odds ratio, 16.2; 95% CI, 1.8–148.7; P = .014). The percentage of TNF-positive cells was higher among CD14+ monocytes than lymphocytes after stimulation.

Conclusions

Production of a high level of TNF by PBMCs (specifically CD14+ cells) from patients with IBD can identify those most likely to have a clinical response to infliximab therapy. In patients with Crohn’s disease, a cutoff value of 500 pg/ml TNF identified responders with 100% sensitivity and 82% specificity.

Section snippets

Study Design and Patient Samples

All patients with active proven CD or UC resulting in an indication for anti-TNF therapy and without having had biologicals within the past 6 months were invited to participate in this prospective observational study at 2 centers in Berlin (Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, and “MVZ für Gastroenterologie am Bayerischen Platz”, Berlin, Germany) between November 1, 2016 and May 31, 2018. Patients had to be >18 years old and give written informed consent. Infections

Results

Forty-one patients with a mean age of 38 years (standard deviation [SD], 12.8 years) and 10 healthy donors (mean age, 27; SD, 4.9) were available for analysis. The study population consisted of 21 men and 20 women with median disease duration of 3 years. The median HBI at baseline for the 21 CD patients was 10.1, whereas the 20 UC patients started with median pMS of 6.4. Table 1 shows detailed baseline characteristics.

Discussion

TNF staining by endomicroscopy has been shown to predict response to anti-TNF treatment.¹¹ Our data indicate that the less invasive measurement of TNF production of LPS-stimulated PBMCs isolated from peripheral blood of patients before infliximab treatment is a likewise efficient predictor for anti-TNF response. Interestingly, TNF levels in the patients’ serum have been evaluated before with different or no findings.¹⁶^,¹⁷ There is only one study that successfully measured elevated TNF mRNA in

CRediT Authorship Contributions

Bosse R. Jessen (Data curation: Lead; Formal analysis: Lead; Investigation: Lead; Project administration: Supporting; Visualization: Lead; Writing – original draft: Lead)

Yasmina Rodriguez-Sillke (Investigation: Supporting; Writing – review & editing: Equal)

Elena Sonnenberg (Investigation: Supporting; Writing – review & editing: Equal)

Michael Schumann (Investigation: Supporting; Writing – review & editing: Equal)

Andrey Kruglov (Investigation: Supporting; Writing – review & editing: Equal)

Inka

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: Conflicts of interest These authors disclose the following: Donata Lissner has received lecture fees from Falk and AbbVie. Britta Siegmund has served as Consultant for AbbVie, Boehringer, Celgene, Falk, Janssen, Lilly, Pfizer, Prometheus, and Takeda and received speaker’s fees from AbbVie, CED Service GmbH, Falk, Ferring, Janssen, Novartis, and Takeda (BS served as representative of the Charité). Jochen Maul has received consulting fees from AbbVie, Janssen-Cilag, Pharmacosmos, and Takeda and lecture fees and travel accommodations from AbbVie, AstraZeneca, Cellgene, Falk Foundation, Ferring, Janssen-Cilag, MSD, Pfizer, Vifor, and Takeda. Elena Sonnenberg has received consulting fees from AbbVie and Janssen and speaker fees from Dr. Falk Pharma GmbH and Takeda Pharma GmbH. Michael Schumann has served as consultant for Takeda, Dr Schär, and AbbVie. The remaining authors disclose no conflicts.

: Funding Supported with a research grant by Pfizer Inc. The conduct of this study was independent of this funding. Britta Siegmund, Anja Kühl, Michael Schumann, and Andrey Kruglov received additional funding by the SFB-TRR 241 “IEC in IBD” of the German Research Foundation. Bosse Jessen received a scholarship from Berlin Institute of Health to conduct the study. The conduct of this study was independent of this funding.

^b: Authors share co-senior authorship.

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Original ArticleAlimentary TractLevel of Tumor Necrosis Factor Production by Stimulated Blood Mononuclear Cells Can Be Used to Predict Response of Patients With Inflammatory Bowel Diseases to Infliximab

Background & Aims

Methods

Results

Conclusions

Section snippets

Study Design and Patient Samples

Results

Discussion

CRediT Authorship Contributions

Lancet

Lancet

Gastroenterology

Am J Pathol

Am J Gastroenterol

Clin Biochem

Clin Gastroenterol Hepatol

Pharmacol Ther

Infliximab in inflammatory bowel disease

Ther Adv Chronic Dis

Infliximab for induction and maintenance therapy for ulcerative colitis

N Engl J Med

New treatment options for inflammatory bowel diseases

J Gastroenterol

Infection risk associated with anti-TNF-alpha agents: a review

Expert Opinion on Drug Safety

Can we predict the efficacy of anti-TNF-alpha agents?

International Journal of Molecular Sciences

Role for therapeutic drug monitoring during induction therapy with TNF antagonists in IBD: evolution in the definition and management of primary nonresponse

Inflamm Bowel Dis

Systematic review: predicting and optimising response to anti-TNF therapy in Crohn's disease—algorithm for practical management

Aliment Pharmacol Ther

Original Article
Alimentary Tract
Level of Tumor Necrosis Factor Production by Stimulated Blood Mononuclear Cells Can Be Used to Predict Response of Patients With Inflammatory Bowel Diseases to Infliximab