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P570. Clinical and basic studies to understand factors associated with the loss of response to infliximab in patients with Crohn's disease

A. Yamada1, K. Sono1, K. Takeuchi1, Y. Suzuki1, 1Sakura Medical Center, Toho university, Internal Medicine, Sakura city, Japan

Background

The efficacy of infliximab (IFX) has validated the role of tumor necrosis factor (TNF)-α in the immunopathogenesis of Crohn's disease (CD). However, antibodies to IFX emerge, which impair its efficacy as well as being a significant factor in the adverse side effects associated with anti-TNF therapy. Accordingly, understanding factor(s) associated with the loss of response (LOR) to IFX and treatment of IFX non-responders are major clinical challenges. With these issues in mind, this study was undertaken with a major interest in understanding and evaluating factors associated with the LOR to IFX in patients with CD.

Methods

Seventy-four patients with CD under maintenance IFX therapy, 36 IFX responders (Group I) and 38 with the LOR to IFX (Group II) were included in this study. IFX trough level, CD activity index (CDAI) and immunological markers during IFX maintenance therapy were measured. Adsorptive granulocyte/monocyte apheresis (GMA) with the Adacolumn was applied to patients with LOR.

Results

The durations of CD, 9.3±5.5 yr (P = 0.02) and IFX therapy, 3.4±2.0 yr (P = 0.01) in Group II were significantly longer than in Group I. Similarly, C-reactive protein (P < 0.0001) and CDAI (P < 0.0001) in Group II were higher as compared with Group I. The median trough IFX was 4.7 µg/mL in Group I and 8.4 µg/mL in Group II, while the dose frequency was 56 days in Group I and 28 days in Group II. Soluble interleukin-2 receptor (sIL-2R) was higher in Group II vs Group I (P < 0.001). Seropositive rates of anti-nuclear antibodies (ANA) and circulating immune complexes (CIC) in Group II were 50.0% (P > 0.05) and 68.4% (P < 0.01), significantly higher vs Group I. Patients with the LOR duration >1.5 yr showed higher CDAI and sIL-2R (P < 0.05) vs patients with LOR duration <1.5 yr. Fifteen Group II patients received GMA plus IFX combination therapy and 46.7% responded. IL-10 increased in GMA-responders (P < 0.05), while CIC (P = 0.0237) and ANA (P = 0.0463) decreased.

Conclusion

Our impression is that LOR to IFX is triggered by an inadequate regulatory T-cell expansion. Regardless of its clinical efficacy, GMA has been associated with a significant rise in circulating lymphocyte counts including the regulatory CD4+CD25+ regulatory T cell phenotype. Accordingly, GMA should benefit patients with the LOR to IFX by correcting relevant parameters of immune pathology in these patients.