Date Published: October 4, 2018
Publisher: Public Library of Science
Author(s): Katsuyoshi Matsuoka, Shunsuke Hamada, Mikiko Shimizu, Kosaku Nanki, Shinta Mizuno, Hiroki Kiyohara, Mari Arai, Shinya Sugimoto, Yasushi Iwao, Haruhiko Ogata, Tadakazu Hisamatsu, Makoto Naganuma, Takanori Kanai, Mayumi Mochizuki, Masayuki Hashiguchi, Emiko Mizoguchi.
Since anti-tumor necrosis factor (TNF)-α agents (TNF-α inhibitors) induce both clinical response and remission in patients with moderate to severe inflammatory bowel disease (IBD), the use of anti-TNF therapies has fundamentally changed the approach to treatment for patients with IBD. Infliximab (IFX) is a TNF-α inhibitor approved for the induction and remission of Crohn’s disease (CD). However, even among patients who initially demonstrate a clinical response to IFX therapy, secondary loss of response occurs, although the reason remains unknown. We therefore investigated predictive factors associated with the response to IFX in long-term maintenance treatment in Japanese CD patients. Eight types of single-nucleotide polymorphisms (SNPs) were investigated using the real-time PCR method, and patient characteristics were collected from the electronic medical records. The Crohn’s Disease Activity Index criteria were used as the response to IFX therapy. The observation period was 1 year after IFX had been administered for more than 1 year. Associations between the IFX response and patient characteristics were evaluated using the multivariate logistic regression model. We studied 121 unrelated adult Japanese with CD treated for more than 1 year with IFX as outpatients at Keio University Hospital from November 1, 2014 to November 30, 2015. Among them, 71 were classified as in remisson. In multivariate analysis, patients with the TNF-α 857C>T C/C genotype, shorter disease duration, without double dosing, and combination treatment with an immunomodulator had higher remisson rates than those with the C/T or T/T genotype, longer disease duration, with double dosing, and no combination treatment with an immunomodulator. The response to IFX in Japanese CD patients may therefore be predicted by these 4 characteristics in actual clinical practice.
Crohn’s disease (CD) is a chronic inflammatory condition of the gastrointestinal tract with repeated cycles of exacerbation and remission. Although the etiology of CD has not yet been revealed, it is considered to be caused by a breakdown of the intestinal immune system. The excessive production of tumor necrosis factor-α (TNF-α) in the intestinal mucosa driven by an aberrant immune reaction to luminal antigens was demonstrated to cause intestinal inflammation in patients with CD [1–3]. TNF-α further induces the production of proinflammatory cytokines such as interleukin-6, etc., thereby exacerbating inflammation. These observations led to the clinical application of anti-TNF-α antibody in the treatment of CD. Infliximab (IFX), a chimeric anti-TNF-α monoclonal antibody with the constant region of human IgG1 and the mouse-derived specific variable region against TNF-α, has been widely used for the treatment of CD [4,5]. IFX is thought to suppress TNF-α production by three mechanisms of action: 1) neutralization of the biological activity by binding soluble TNF-α; 2) dissociation of TNF-α bound to its receptor; and 3) killing cells that express membrane-bound TNF-α through antibody-dependent cellular cytotoxicity activity.
To establish an individualized IFX treatment strategy in Japanese CD patients, we investigated the association between the therapeutic response during maintenance treatment and patient characteristics including genetic polymorphisms. Multivariate analysis identified longer disease duration, IFX double dosing (10 mg/kg), no concomitant use of an IM, and the TNF-α -857 C>T (rs1799724) polymorphism as factors related to nonremission during IFX maintenance therapy.
We showed that remission during IFX maintenance therapy in Japanese CD patients was associated with the TNF-α 857C>T C/C genotype, shorter disease duration, no double dosing, and combination treatment with an IM. These results could potentially be utilized to establish an individualized IFX treatment strategy for Japanese or other CD patients.