Factors associated with the loss of response to infliximab in patients with Crohn's disease.
OBJECTIVE
The efficacy of infliximab (IFX) has validated the role of TNF-α in the immunopathogenesis of Crohn's disease (CD). However, antibodies to IFX emerge, which impair its efficacy. This study investigated factor(s) associated with the loss of response (LOR) to IFX and how IFX non-responders may be treated.


METHODS
Seventy-four patients, 36 IFX responders (GI) and 38 with LOR (GII) were included. Trough IFX level, CD activity index (CDAI) and immunological markers during IFX maintenance therapy were measured. Adsorptive granulocyte/monocyte apheresis (GMA) was applied to patients with LOR.


RESULTS
The durations of CD, 9.3 ± 5.5 yr and IFX therapy, 3.4 ± 2.0 yr in GII were longer vs GI (P=0.02, P=0.01). Similarly, C-reactive protein (P<0.0001) and CDAI (P<0.0001) in GII were higher. The median trough IFX was 4.7 μg/mL in GI and 8.4 μg/mL in GII, while the dose frequency was 8 weeks in GI and 4 weeks in GII. Soluble interleukin-2 receptor (sIL-2R) was higher in GII vs GI (P<0.001). Seropositive rates of anti-nuclear antibodies (ANA) and circulating immune complexes (CIC) in GII were 50.0% and 68.4%, significantly higher vs GI (P<0.05, P<0.01). Patients with LOR duration <1.5 yr showed higher CDAI and sIL-2R (P<0.05) vs patients with LOR duration <1.5 yr. Fifteen GII patients received GMA plus IFX combination and 46.7% responded. IL-10 increased in GMA-responders (P<0.05), while CIC and ANA decreased (P=0.0237, P=0.0463).


CONCLUSIONS
Patients with LOR to IFX had dysregulated immune response despite uncompromised trough IFX level. Further, inadequate T-cell differentiation by IFX was suggested. GMA appeared to benefit LOR patients by immunoregulation.
Internal Medicine, Toho University, Sakura Medical Centre, Chiba, Japan.
Koji
K
Sono
Akihiro
A
Yamada
Yasushi
Y
Yoshimatsu
Nobuo
N
Takada
Yasuo
Y
Suzuki
D000293:Adolescent; D000328:Adult; D000368:Aged; D000974:Antibodies, Antinuclear / Q000097:blood; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000936:Antigen-Antibody Complex / Q000097:blood; D001781:Blood Component Removal; D002097:C-Reactive Protein / Q000378:metabolism; D003424:Crohn Disease / Q000097:blood* / Q000188:drug therapy*; D003710:Demography; D005260:Female; D006801:Humans; D000069285:Infliximab; D008297:Male; D008875:Middle Aged; D018448:Models, Immunological; D016896:Treatment Outcome
D000974:Antibodies, Antinuclear; D000911:Antibodies, Monoclonal; D000936:Antigen-Antibody Complex; D002097:C-Reactive Protein; D000069285:Infliximab