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Loss of Response to Anti-Tumor Necrosis Factor Alpha Therapy in Crohn’s Disease Is Not Associated with Emergence of Novel Inflammatory Pathways

Digestive Diseases and Sciences volume 63, pages 738–745 (2018)Cite this article

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Abstract

Background

While monoclonal antibodies against tumor necrosis factor-α (TNFα) are effective in treating Crohn’s disease (CD), approximately one-third of patients lose response. The mechanisms underlying this loss of response remain elusive.

Aim

We sought to determine if novel biological pathways, including TNFα-independent inflammatory pathways, emerge in those with loss of response to anti-TNFα.

Methods

Using RNA microarray technology in 28 patients with CD, we examined the colonic gene expression differences between those with active inflammation in the setting of loss of response to TNFα-antagonist therapy (“loss of responders”) compared to anti-TNFα naïve patients with active inflammation and those on anti-TNF therapy in disease remission. Pathway enrichment analyses were performed.

Results

We found that colonic expression of chemokines known to drive inflammation (CXCL20, CXCL9, and CXCL10) was elevated in those with loss of response compared to those in remission. Expression of genes critical to modulating oxidative stress burden (DUOX2, DUOXA2, and NOS2) was also elevated. Additionally, MMP3, MMP1, and MMP12 were elevated in those with continued inflammation. Gene enrichment analysis revealed that loss of responders exhibited dysregulation in the cysteine and methionine metabolism pathway, suggesting alteration in oxidative stress burden. There were no differences in genes or pathways between loss of responders and those who were TNFα-naïve. However, loss of response occurred despite the ability of anti-TNFα therapy to normalize APO gene expression.

Conclusion

Our analyses suggest that loss of response to anti-TNFα is not driven by the emergence of pathways that bypass the action or induce resistance to anti-TNFα therapy.

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Funding

5K23DK103119 to MG, Crohn’s and Colitis Foundation senior research award and AGA Elsevier pilot award to ANA, P30 DK043351 to RJX.

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Authors and Affiliations

  1. Gastrointestinal Unit, Massachusetts General Hospital, Harvard Medical School, Blake 4, 55 Fruit Street, Boston, MA, 02114, USA

    Jay Luther, Manish Gala, Suraj J. Patel, Nynke Borren, Ramnik J. Xavier & Ashwin N. Ananthakrishnan

  2. Department of Medicine, Case Western Reserve University, Cleveland, OH, USA

    Maneesh Dave

Authors
  1. Jay Luther
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  2. Manish Gala
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  3. Suraj J. Patel
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  4. Maneesh Dave
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  7. Ashwin N. Ananthakrishnan
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Corresponding author

Correspondence to Ashwin N. Ananthakrishnan.

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Conflict of interest

SJP have equity interest in Heprotech Inc. MG has equity interest in New Amsterdam Genomics. Ananthakrishnan has served on the scientific advisory boards for Gilead, Takeda, and Abbvie. All other authors have no conflicts to declare.

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Luther, J., Gala, M., Patel, S.J. et al. Loss of Response to Anti-Tumor Necrosis Factor Alpha Therapy in Crohn’s Disease Is Not Associated with Emergence of Novel Inflammatory Pathways. Dig Dis Sci 63, 738–745 (2018). https://doi.org/10.1007/s10620-018-4932-8

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  • DOI: https://doi.org/10.1007/s10620-018-4932-8

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