ANCA pattern and LTA haplotype relationship to clinical responses to anti-TNF antibody treatment in Crohn's disease.
OBJECTIVE
In the clinical trial, a lower response to infliximab was observed in some patients after multiple infusions, suggesting that clinical subgroups of Crohn's disease (CD) exist based on response to anti-tumor necrosis factor (anti-TNF). The aim of this study was to characterize these subgroups further by antineutrophil cytoplasmic antibody (ANCA) pattern and TNF genotype.


METHODS
Crohn's Disease Activity Index (CDAI) data from the North American patients in the clinical trial (n = 59) were evaluated as the response parameter. Speckled ANCA (sANCA) subjects were ANCA positive by ELISA with a speckling over the entire neutrophil on indirect immunofluorescence. Genotypes were determined for polymorphisms in the TNF/lymphotoxin alpha (LTA) region.


RESULTS
Response to infliximab as median change in CDAI was placebo (least response) < perinuclear ANCA (pANCA) < not pANCA or sANCA < sANCA (greatest response) (P(overall) = 0.003; 4 weeks). The response of subjects with sANCA was significantly different from that of placebo at all time points; that of pANCA subjects was not. Homozygotes for the LTA NcoI-TNFc-aa13L-aa26 haplotype 1-1-1-1 did not respond (P(overall) = 0.007).


CONCLUSIONS
These observations suggest that sANCA may identify a CD subgroup with a better response to infliximab and that pANCA and homozygosity for the LTA 1-1-1-1 haplotype may identify subgroups with a poorer response.
Taylor
K D
KD
Division of Medical Genetics, Cedars-Sinai Medical Center, Los Angeles, California, USA. kent.taylor@cshs.org
Plevy
S E
SE
Yang
H
H
Landers
C J
CJ
Barry
M J
MJ
Rotter
J I
JI
Targan
S R
SR
D019268:Antibodies, Antineutrophil Cytoplasmic / Q000097:blood*; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D003424:Crohn Disease / Q000097:blood / Q000235:genetics / Q000628:therapy*; D006239:Haplotypes; D006801:Humans; D000069285:Infliximab; D008233:Lymphotoxin-alpha / Q000235:genetics*; D018895:Microsatellite Repeats; D011110:Polymorphism, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*
D019268:Antibodies, Antineutrophil Cytoplasmic; D000911:Antibodies, Monoclonal; D008233:Lymphotoxin-alpha; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab