Methods of determining responsiveness to anti-tnf alpha therapy in inflammatory bowel disease

Abstract

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).