METHODS OF DETERMINING RESPONSIVENESS TO ANTI-TNF ALPHA THERAPY IN INFLAMMATORY BOWEL DISEASE
The present invention relates to methods of prognosing responsiveness to anti-TNFα therapy by determining the presence or absence of risk factors in the individual. In one embodiment, the risk factors are genetic markers, serological markers and/or clinical phenotypes associated with non-responsiveness to treatment with anti-TNFα therapy in an individual diagnosed with IBD.
1 . A method of determining a high risk relative to a normal subject of non-responsiveness to treatment with an anti tumor necrosis factor alpha (TNFα) therapy in an individual, comprising:
obtaining a sample from the individual;
assaying the sample for the presence or absence of one or more genetic and/or serological risk factors; and
determining the high risk relative to a normal subject of non-responsiveness to the anti TNFα therapy based on the presence of one or more risk factors carried by the individual.
2 . The method of claim 1 , wherein the presence of each genetic and/or serological risk factor has an additive effect on increasing the risk of non-responsiveness in the individual.
3 . The method of claim 1 , wherein the individual is diagnosed with inflammatory bowel disease (IBD).
4 . The method of claim 1 , wherein the individual is diagnosed with ulcerative colitis (UC).
5 . The method of claim 1 , wherein the individual is a child.
6 . The method of claim 1 , wherein the one or more genetic risk factors comprise genetic variants at the loci of tachykinin receptor 1 (TACR1), family with sequence similarity 19 member A4 (FAM19A4), phosphatase and actin regulator 3 (PHACTR3) and/or bromodomain and WD repeat domain containing 1 (BRWD1).
7 . The method of claim 1 , wherein the one or more genetic risk factors comprise SEQ. ID. NO.: 1, SEQ. ID. NO.: 2, SEQ. ID. NO.: 3, SEQ. ID NO.: 4, SEQ. ID. NO.: 5 and/or SEQ. ID. NO.: 6.
8 . The method of claim 1 , wherein the one or more genetic risk factors comprise SEQ. ID. NO.: 7, SEQ. ID. NO.: 8, SEQ. ID. NO.: 9, SEQ. ID. NO.: 10, SEQ. ID. NO.: 11, SEQ. ID. NO.: 12, SEQ. ID. NO.: 13, SEQ. ID. NO.: 14, SEQ. ID. NO.: 15, and/or SEQ. ID. NO.: 16.
9 . The method of claim 1 , wherein the one or more genetic risk factors comprise SEQ. ID. NO.: 17, SEQ. ID. NO.: 8, SEQ. ID. NO.: 19, and/or SEQ. ID. NO.: 6.
10 . The method of claim 1 , wherein the one or more genetic risk factors comprise genetic variants at the loci of ATG16, Orf13, inducible T-cell co-stimulator ligand (ICOSLG) and/or major histocompatibility complex class II DQ alpha 1 (HLADQA1).
11 . The method of claim 1 , wherein one of the one or more serological risk factors comprise perinuclear anti-neutrophil cytoplasmic antibody (pANCA).
12 . The method of claim 1 , wherein the anti TNFα therapy comprises infliximab.
13 . The method of claim 1 , wherein the anti TNFα therapy comprises cyclosporin.
14 . A method of determining a significant likelihood of responsiveness to treatment with anti tumor necrosis factor alpha (TNF-α) therapy in an individual, comprising:
obtaining a sample from the individual;
assaying the sample for the presence of one or more serological markers associated with responsiveness to anti TNFα therapy; and
determining a significant likelihood of responsiveness based on the presence of one or more serological markers associated with responsiveness to anti TNFα therapy.
15 . The method of claim 14 , wherein the individual is diagnosed with inflammatory bowel disease (IBD).
16 . The method of claim 14 , wherein the individual is diagnosed with ulcerative colitis (UC).
17 . The method of claim 14 , wherein the individual is a child.
18 . The method of claim 14 , wherein one of the one or more serological markers comprises anti- saccharomyces cerevisiae antibodies (ASCA).
19 . A method of predicting a high risk relative to a normal subject of non-responsiveness to anti tumor necrosis factor alpha (TNF-α) therapy in an individual with inflammatory bowel disease (IBD), comprising;
determining the presence or absence of one or more nonresponsive genetic risk variants;
determining the presence or absence of positive expression of perinuclear anti-neutrophil cytoplasmic antibody (pANCA);
determining the presence or absence of an ulcerative colitis phenotype; and
predicting a high risk relative to a normal subject of non responsiveness to anti TNF-α therapy based on the presence of one or more responsive risk variants, the presence of positive expression of pANCA, and/or the presence of the ulcerative colitis phenotype.
20 . The method of claim 19 , wherein one of the one or more nonresponsive genetic risk variants comprise variants at the genetic loci of tachykinin receptor 1 (TACR1), family with sequence similarity 19 member A4 (FAM19A4), phosphatase and actin regulator 3 (PHACTR3) and/or bromodomain and WD repeat domain containing 1 (BRWD1).
21 . The method of claim 19 , wherein the high risk relative to a normal subject of non-responsiveness comprises a range of 7 to 10 fold increase in risk of non-responsiveness to treatment with anti TNFα therapy.
22 . A method of diagnosing an inflammatory bowel disease (IBD) subtype in an individual, comprising:
obtaining a sample from the individual;
assaying the sample for the presence or absence of one or more genetic and/or serological risk factors of nonresponsiveness to anti TNFα therapy; and
diagnosing the IBD subtype based upon the presence of one or more genetic and/or serological risk factors of nonresponsiveness to anti TNFα therapy.
23 . The method of claim 22 , wherein the individual is a child.
24 . The method of claim 22 , wherein the one or more genetic risk factors comprise genetic variants at the loci of tachykinin receptor 1 (TACR1), family with sequence similarity 19 member A4 (FAM19A4), phosphatase and actin regulator 3 (PHACTR3) and/or bromodomain and WD repeat domain containing 1 (BRWD1).
25 . The method of claim 22 , wherein the one or more genetic risk factors comprise SEQ. ID. NO.: 1, SEQ. ID. NO.: 2, SEQ. ID. NO.: 3, SEQ. ID NO.: 4, SEQ. ID. NO.: 5 and/or SEQ. ID. NO.: 6.
26 . The method of claim 22 , wherein the one or more genetic risk factors comprise SEQ. ID. NO.: 7, SEQ. ID. NO.: 8, SEQ. ID. NO.: 9, SEQ. ID. NO.: 10, SEQ. ID. NO.: 11, SEQ. ID. NO.: 12, SEQ. ID. NO.: 13, SEQ. ID. NO.: 14, SEQ. ID. NO.: 15, and/or SEQ. ID. NO.: 16.
27 . The method of claim 22 , wherein the one or more genetic risk factors comprise SEQ. ID. NO.: 17, SEQ. ID. NO.: 8, SEQ. ID. NO.: 19, and/or SEQ. ID. NO.: 6.
28 . The method of claim 22 , wherein one of the one or more serological risk factors comprise perinuclear anti-neutrophil cytoplasmic antibody (pANCA).
29 . A method of treating an individual, comprising:
diagnosing the individual as susceptible to non-responsiveness to anti tumor necrosis factor alpha (TNF-α) therapy; and
treating the individual.
30 . The method of claim 29 , wherein treating the individual comprises administering a therapeutically effective dosage of natalizumab.
31 . The method of claim 29 , wherein the individual has inflammatory bowel disease (IBD).