Methods and compositions for prediction of response to treatment of inflammatory bowel disease

Abstract

To provide biomarkers indicative of the response to treatment of inflammatory bowel disease, including ulcerative colitis (UC) and Crohn's disease (CD), probes capable of detecting biomarkers for predicting the response to treatment of inflammatory bowel disease, and related methods and kits.SOLUTION: A method for predicting a response of a subject diagnosed with inflammatory bowel disease (IBD) to an anti-interleukin (IL) treatment of the IBD, the method comprising determining a pattern of a panel of biomarkers comprising CMTM2, C5AR1, FGF2, GK, HGF, IL1RN, LILRA2, NAMPT, PAPPA, SNCA, SOD2, or STEAP4, wherein the pattern of the biomarker panel predicts the response to the anti-IL treatment in the subject.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention generally aims to predict the response to the treatment of inflammatory bowel disease in a subject and provides methods, reagents, and kits useful for this purpose. A panel of biomarkers indicative of the response to the treatment of inflammatory bowel disease, including ulcerative colitis and Crohn's disease, a probe capable of detecting the panel of biomarkers, and related methods and kits for predicting the response to the treatment of inflammatory bowel disease are provided herein. Also provided herein is a panel of biomarkers indicative of the response to a combination therapy for treating inflammatory bowel disease. disease. disease are also provided herein.

Background Art

[0002] Inflammatory bowel disease (IBD) is a chronic disease accompanied by uncontrolled inflammation of the digestive system, and Crohn's disease (CD) and ulcerative colitis (UC) represent two major subtypes of the disease. The treatment options for patients with IBD have been significantly improved by the introduction of biological agents, which has reduced the frequency of hospital visits and surgeries (Rutgeerts, et al., Gastroenterology, 20 09, 136: 1182-1197). However, even biological agents such as golimumab (anti-TNF treatment) show a high clinical non-response rate of up to 50% (Sandborn, e t al., Gastroenterology, 2014, 146: 85-95; qu iz e14-15). As new drugs with clearly different mechanisms of action become available, it is possible to identify subsets of patients who have clearly different responses to different anti-inflammatory treatments and... tal., Gastroenterology, 2014, 146: 85-95; qu iz e14-15). As new drugs with clearly different mechanisms of action become available, it is possible to identify subsets of patients who have clearly different responses to different anti-inflammatory treatments and...​​ If possible, it can be beneficial in many ways, including reducing the number of patients receiving ineffective treatments, achieving higher response rates, and avoiding treading through ineffective treatments by treating predicted non-responder patients with alternative and combination therapies. For this purpose, many previous studies have identified candidate biomarkers for predicting response to anti-TNF therapy in IBD. (Arijs, et al ., Gut., 2009, 58:1612-1619; Kolho, et al., Am

[0003] . J. Gastroenterol., 2015, 110:921-930; Shaw, et al., Genome Med., 2016, 8:75; Ferrante, et al., Inflamm. Bowel Dis., 2007, 13:123-128; Zhou, et al., mSystems, 2018, 3; West et al., Nat. Med., 2017, 23:579-589). However, all of these studies either had a small number of samples used or were not prospectively validated in an independent cohort, so their clinical utility is limited. Therefore, it is desirable to develop biomarkers that preferably predict response to IBD treatment and identify responder and / or non-responder patients before the subject receives treatment for the disease. Similarly, it is generally necessary to develop biomarkers that predict response to combination therapies for IBD. Biomarkers can also be used for other purposes, such as having the function of stratifying patients in clinical trials.

[0004]

[0005] The foregoing discussion is presented merely to provide a better understanding of the nature of the problems faced by the art and should not be construed in any way as an admission of prior art. Nor should any reference cited herein be construed as an admission that such reference constitutes "prior art" of this application. Rather, any reference cited herein is not to be construed as an admission that such reference constitutes "prior art" of this application. Nor should any reference cited herein be construed as an admission that such reference constitutes "prior art" of this application. SUMMARY OF THE INVENTION MEANS FOR SOLVING THE PROBLEM

[0006] The present invention relates to predicting the response to the treatment of inflammatory bowel disease in a subject, and provides methods, reagents, and kits useful for this purpose. In one aspect, a method for predicting the response of a subject diagnosed with inflammatory bowel disease (IBD) to anti-interleukin (IL) therapy for IBD, comprising:

[0007] detecting a panel of biomarkers comprising 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 biomarkers selected from the group consisting of CKLF-like MARVEL transmembrane domain-containing 2 (CMTM2), complement C5a receptor 1 (C5AR1), fibroblast growth factor 2 (FGF2), glycerol kinase (GK), hepatocyte growth factor (HGF), interleukin 1 receptor antagonist (IL1RN), leukocyte immunoglobulin-like receptor A2 (LILRA2), nicotinamide phosphoribosyltransferase (NAMPT), pappalysin 1 (PAPPA), synuclein alpha (SNCA), superoxide dismutase 2, mitochondrial (SOD2), STEAP4 metalloreductase (STEAP4), and zinc finger BED-type containing 3 (ZBED3). (ZBED3). contacting a set of probes capable of being formed with a sample from a subject; b. determining the pattern of the panel of biomarkers; comprising wherein the pattern of the biomarker panel predicts the response to anti-IL therapy in the subject is provided herein.

[0008] In other embodiments, the panel of biomarkers provided herein includes CMTM2, C 5AR1, FGF2, GK, HGF, IL1RN, LILRA2, NAMPT, PAPP A, SNCA, SOD2, STEAP4, and ZBED3.

[0009] In some embodiments, the sample is obtained before the subject is treated with anti-IL therapy .

[0010] In certain embodiments, the probes provided herein are selected from the group consisting of aptamers, antibodies, affibodies, peptides, and nucleic acids. In one embodiment, the probe is a nucleic acid. In other embodiments, the probe is selected from the group consisting of SEQ ID NOs: 1-14, SEQ ID NO: 17, SEQ ID NO: 20, SEQ ID NO: 23, SEQ ID NO: 26, SEQ ID NO: 29, SEQ ID NO: 32, SEQ ID NO: 35, SEQ ID NO: 38, SEQ ID NO: 41, SEQ ID NO: 44, SEQ ID NO: 47, and SEQ ID NO: 50. selected from the group consisting of

[0011] In some embodiments, the pattern of the panel of biomarkers provided herein is determined by (a) determining the baseline gene expression levels of the panel of biomarkers in the subject and (b) determining a signature score for each sample.

[0012] ​​​​In certain embodiments, gene expression levels are determined by quantitative polymerase chain reaction (qPCR). In other embodiments, the qPCR primers are selected from the group consisting of SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 33 , SEQ ID NO: 34, SEQ ID NO: 36, SEQ ID NO: 37, SEQ ID NO: 39, SEQ ID NO: 40, SEQ ID NO: 42, SEQ ID NO: 43, SEQ ID NO: 45, SEQ ID NO: 46, SEQ ID NO: 48, SEQ ID NO: 49, SEQ ID NO: 51, and SEQ ID NO: 52.

[0013] In some embodiments, if the signature score of a panel of biomarkers exceeds a predetermined threshold indicating a response, the subject is predicted to be a responder to anti-interleukin (IL) therapy for IBD. In some embodiments, the level of the predetermined threshold is selected from the group consisting of -3.9 000 to 1.1000. In some embodiments, the level of the predetermined threshold is -3.8234. In some embodiments, the level of the predetermined threshold is 1.0000.

[0014] In another aspect, a method of predicting the response of a subject diagnosed with inflammatory bowel disease (IBD) to treatment with a Janus kinase inhibitor (JAKi) for IBD, comprising (a) CKLF-like MARVEL transmembrane domain-containing 2 (CMTM2), complement C5a receptor 1 (C5AR1), fibroblast growth factor 2 (FGF2), glycerol kinase (GK) , hepatocyte growth factor (HGF), interleukin 1 receptor antagonist (IL1RN) , leukocyte immunoglobulin-like receptor A2 (LILRA2), nicotinamide phosphoribosyl (b) determining the expression levels of one or more biomarkers selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, 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, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34, SEQ ID NO: 35, SEQ ID NO: 36, SEQ ID NO: 37, SEQ ID NO: 38, SEQ ID NO: 39, SEQ ID NO: 40, SEQ ID NO: 41, SEQ ID NO: 42, SEQ ID NO: 43, SEQ ID NO: 44, SEQ ID NO: 45, SEQ ID NO: 46, SEQ ID NO: 47, SEQ ID NO: 48, SEQ ID NO: 49, SEQ ID NO: 50, SEQ ID NO: 51, SEQ ID NO: 52, SEQ ID NO: 53, SEQ ID NO: 54, SEQ ID NO: 55, SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 59, SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, SEQ ID NO: 69, SEQ ID NO: 70, SEQ ID NO: 71, SEQ ID NO: 72, SEQ ID NO: 73, SEQ ID NO: 74, SEQ ID NO: 75, SEQ ID NO: 76, SEQ ID NO: 77, SEQ ID NO: 78, SEQ ID NO: 79, SEQ ID NO: 80, SEQ ID NO: 81, SEQ ID NO: ​Transferase (NAMPT), Pappalysin 1 (PAPPA), Synuclein alpha (SNCA), Superoxide Dismutase 2, Mitochondrial (SOD2), S TEAP4 Metalloreductase (STEAP4), and Zinc Finger BED-Type Containing 3 (ZBED3) selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 biomarkers, contacting a set of probes capable of detecting the panel of biomarkers with a sample derived from a subject, and b. determining a pattern of the panel of biomarkers, comprising wherein the pattern of the panel of biomarkers predicts a response to JALi treatment in the subject, a method is provided herein.

[0015] In some embodiments, the sample is obtained before the subject is treated with JAKi therapy.

[0016] In some embodiments, if the signature score of the panel of biomarkers exceeds a predetermined threshold indicating a response, the subject is predicted to be a responder to JAKi therapy for IBD. In some embodiments, the level of the predetermined threshold is selected from the group consisting of -3.9000 to 1.1000. In some embodiments, the level of the predetermined threshold is -3. 8234. In some embodiments, the level of the predetermined threshold is 1.0000.

[0017] In yet another aspect, a method for predicting a negative response to anti-inflammatory treatment of inflammatory bowel disease (IBD) in a subject diagnosed with IBD, comprising contacting a set of probes capable of detecting a panel of biomarkers selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 biomarkers including Transferase (NAMPT), Pappalysin 1 (PAPPA), Synuclein alpha (SNCA), Superoxide Dismutase 2, Mitochondrial (SOD2), S TEAP4 Metalloreductase (STEAP4), and Zinc Finger BED-Type Containing 3 (ZBED3) with a sample derived from the subject, ​​​a. CKLF-like MARVEL transmembrane domain-containing 2 (CMTM2), complement C5a receptor 1 (C5AR1), fibroblast growth factor 2 (FGF2), glycerol kinase (GK) , hepatocyte growth factor (HGF), interleukin 1 receptor antagonist (IL1RN) , leukocyte immunoglobulin-like receptor A2 (LILRA2), nicotinamide phosphoribosyl transferase (NAMPT), pappalysin 1 (PAPPA), synuclein alpha (SNCA), superoxide dismutase 2, mitochondrial (SOD2), S TEAP4 metalloreductase (STEAP4), and zinc finger BED-type containing 3 (ZBED3) selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 biomarkers, contacting a set of probes capable of detecting a panel of biomarkers with a sample from a subject, and b. determining a baseline gene expression level of the panel of biomarkers in the sample and c. determining a signature score for each sample, comprising wherein when the signature score of the panel of biomarkers is below a predetermined threshold indicating non-response, the subject is predicted to be a non-responder to anti-inflammatory treatment for IBD, a method is provided herein. In one aspect, a method for predicting a negative response to anti-inflammatory treatment for inflammatory bowel disease (IBD) in a subject diagnosed with IBD, comprising

[0018] a. CKLF-like MARVEL transmembrane domain-containing 2 (CMTM2), complement C5a receptor 1 (C5AR1), fibroblast growth factor 2 (FGF2), glycerol kinase (GK) b. hepatocyte growth factor (HGF), interleukin 1 receptor antagonist (IL1RN) c. leukocyte immunoglobulin-like receptor A2 (LILRA2), nicotinamide phosphoribosyl , hepatocyte growth factor (HGF), interleukin 1 receptor antagonist (IL1RN) , leukocyte immunoglobulin-like receptor A2 (LILRA2), nicotinamide phosphoribosyl transferase (NAMPT), pappalysin 1 (PAPPA), synuclein alpha (SNCA), superoxide dismutase 2, mitochondrial (SOD2), S TEAP4 metalloreductase (STEAP4), and zinc finger BED-type containing 3 (ZBED3), a set of probes capable of detecting a panel of biomarkers consisting of is contacted with a sample from a subject, b. determining the baseline gene expression levels of the panel of biomarkers in the sample by quantitative polymerase chain reaction (qPCR), and c. determining a signature score for each sample, comprising where the signature score of the panel of biomarkers is below a predetermined threshold indicating non-response, the subject is predicted to be a non-responder to anti-inflammatory treatment for IBD, a method is provided herein.

[0019] In some embodiments, the sample is obtained before the subject is treated with anti-inflammatory treatment. .

[0020] In certain embodiments, the method provided herein further comprises administering to the subject one or more of the anti-inflammatory treatments for IBD.

[0021] In some embodiments, non-responder subjects have one or more of the characteristics selected from the group consisting of high disease burden, microbial dysbiosis, and high levels of inflammatory activity.

[0022] In other embodiments, non-responder subjects are identified as candidates for combination therapy.

[0023] In one aspect, the combination therapy provided herein is selected from the group consisting of anti-inflammatory therapy, antibiotics, immunomodulators, antidiarrheal agents, analgesics, iron supplementation, and calcium and vitamin D supplementation and includes two or more therapies.

[0024] In another aspect, the combination therapy provided herein targets one or more standard pathways selected from the group consisting of granulocyte adhesion and extravasation, agranulocyte adhesion and extravasation, the osteoarthritis pathway, the role of macrophages, fibroblasts, and endothelial cells in rheumatoid arthritis, liver fibrosis and activation of hepatic stellate cells, inhibition of matrix metalloproteinases, atherosclerotic signaling, bladder cancer signaling, the role of pattern recognition receptors in the recognition of bacteria and viruses, and HMGB1 signaling, and administering to the subject one or more agents that target said one or more standard pathways.

[0025] In some embodiments, the anti-inflammatory therapy provided herein is anti-tumor necrosis factor (TNF) therapy, JAK inhibitor (JAKi) therapy, or anti-interleukin (IL) therapy. In some embodiments, the anti-inflammatory therapy is anti-IL-23 or anti-IL-12 / 23 therapy. In other embodiments, the anti-IL therapy is ustekinumab. In some embodiments, the anti-inflammatory therapy is JAK inhibitor therapy. In other embodiments, the anti-inflammatory therapy is anti-TNF therapy. In some embodiments, the anti-TNF therapy is golimumab.

[0026] In one aspect, a method of treating a subject diagnosed with inflammatory bowel disease (IBD), ​​​​​​​​​a. Predicting the response of the subject to anti-inflammatory treatment for IBD, (i) CKLF-like MARVEL transmembrane domain-containing 2 (CMTM2), complement C5a receptor 1 (C5AR1), fibroblast growth factor 2 (FGF2), glycerol kinase (GK ), hepatocyte growth factor (HGF), interleukin 1 receptor antagonist (IL1RN ), leukocyte immunoglobulin-like receptor A2 (LILRA2), nicotinamide phosphoribosyl transferase (NAMPT), pappalysin 1 (PAPPA), synuclein alpha (SNCA), superoxide dismutase 2, mitochondrial (SOD2), STEAP4 metalloreductase (STEAP4), and zinc finger BED-type containing 3 (ZBED3), detecting a panel of biomarkers comprising 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 , 11, 12, or 13 biomarkers selected from the group consisting of, with a set of probes capable of doing so, contacting the sample from the subject, and (ii) determining the pattern of the panel of biomarkers, including, predicting that the pattern of the panel of biomarkers predicts the response of the subject to anti-inflammatory treatment in the subject, and b. administering to the subject a therapeutically effective amount of one or more anti-inflammatory therapeutic agents, is provided herein. In a further embodiment, if the signature score of the panel of biomarkers exceeds a predetermined threshold indicating a response, the subject is predicted to be a responder to anti-inflammatory treatment for IBD.

[0027] In some embodiments, the level of the predetermined threshold is from -3.9000 to 1.1000 . ​​selected from the group consisting of. In some embodiments, the level of the predetermined threshold is -3.823 4. In some embodiments, the level of the predetermined threshold is 1.0000.

[0028] In another aspect, a method of treating a subject diagnosed with inflammatory bowel disease (IBD), comprising: a. predicting that the subject is a non-responder to anti-inflammatory treatment for IBD, wherein: (i) detecting a panel of biomarkers comprising 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 biomarkers selected from the group consisting of CKLF-like MARVEL transmembrane domain-containing 2 (CMTM2), complement C5a receptor 1 (C5AR1), fibroblast growth factor 2 (FGF2), glycerol kinase (GK), hepatocyte growth factor (HGF), interleukin 1 receptor antagonist (IL1RN), leukocyte immunoglobulin-like receptor A2 (LILRA2), nicotinamide phosphoribosyltransferase (NAMPT), pappalysin 1 (PAPPA), synuclein alpha (SNCA), superoxide dismutase 2, mitochondrial (SOD2), STEAP4 metalloreductase (STEAP4), and zinc finger BED-type containing 3 (ZBED3) with a set of probes capable of doing so, by contacting the set of probes with a sample from the subject; and (ii) determining a baseline gene expression level of the panel of biomarkers in the sample; (iii) determining a signature score for each sample, wherein: the signature score of the panel of biomarkers is below a predetermined threshold indicating non-response, ​​​​​​​​​​If the subject is predicted to be a non-responder to anti-inflammatory treatment for IBD, And, b. administering to the subject a therapeutically effective amount of one or more anti-inflammatory therapeutic agents. Methods are provided herein, including:

[0029] In further embodiments, the biomarkers for the methods of treating a subject provided herein are The car panel includes CMTM2, C5AR1, FGF2, GK, HGF, IL1RN, and LI LRA2, NAMPT, PAPPA, SNCA, SOD2, STEAP4, and ZBED In some embodiments, the sample is collected before the subject is treated with the anti-inflammatory treatment. In certain embodiments, the probes provided herein are aptamers, antibodies, In one embodiment, the protease is selected from the group consisting of an affibody, a peptide, and a nucleic acid. In other embodiments, the probe is a nucleic acid. SEQ ID NO: 20, SEQ ID NO: 23, SEQ ID NO: 26, SEQ ID NO: 29, SEQ ID NO: 32, SEQ ID NO: 3 5, SEQ ID NO: 38, SEQ ID NO: 41, SEQ ID NO: 44, SEQ ID NO: 47, and SEQ ID NO: 50 In some embodiments, the biomarkers provided herein are selected from the group consisting of: The pattern of the panel of biomarkers is determined by (a) the baseline of the panel of biomarkers in the subject; (b) determining a signature score for each sample; In certain embodiments, gene expression levels are determined by quantitative polymerase chain reaction (PCR). In another embodiment, the qPCR primers are , SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 33, SEQ ID NO: 34, SEQ ID NO: 36, SEQ ID NO: 37, SEQ ID NO: 39, SEQ ID NO: 40, SEQ ID NO: 42, SEQ ID NO: 43, SEQ ID NO: 45, SEQ ID NO: 46, SEQ ID NO: 4 8, SEQ ID NO: 49, SEQ ID NO: 51, and SEQ ID NO: 52, and is selected from the group consisting thereof.

[0030] In a further embodiment, the predicted non-responder subject is identified as a candidate for combination therapy. A method of treating a subject diagnosed with inflammatory bowel disease (IBD), comprising predicting that the subject is a non-responder to anti-inflammatory treatment for IBD, and administering to the subject a combination therapy comprising two or more treatments selected from the group consisting of anti-inflammatory treatment, antibiotics, immunomodulators, antidiarrheals, analgesics, iron supplementation, and calcium and vitamin D supplementation. A method is provided in the present specification. In a further embodiment, the combination therapy targets one or more standard pathways selected from the group consisting of granulocyte adhesion and extravasation, agranulocyte adhesion and extravasation, the osteoarthritis pathway, the role of macrophages, fibroblasts and endothelial cells in rheumatoid arthritis, liver fibrosis and activation of hepatic stellate cells, inhibition of matrix metalloproteases, atherosclerotic signaling, bladder cancer signaling, the role of pattern recognition receptors in the recognition of bacteria and viruses, and HMGB1 signaling, and comprises administering to the subject one or more agents that target one or more of the selected standard pathways. In some embodiments, the anti-inflammatory treatment provided in the present specification for a method of treating a subject diagnosed with IBD is anti-tumor necrosis factor (TNF) treatment, Janus kinase inhibitor (JAKi) treatment, or anti-interleukin (IL) treatment. In some embodiments, the anti-inflammatory treatment

[0031] In some embodiments, the anti-inflammatory treatment provided in the present specification for a method of treating a subject diagnosed with IBD is anti-tumor necrosis factor (TNF) treatment, Janus kinase inhibitor (JAKi) treatment, or anti-interleukin (IL) treatment. In some embodiments, the anti-inflammatory treatment ​​​​​​​​The treatment is anti-IL-23 or anti-IL-12 / 23 treatment. In other embodiments, the anti-IL treatment is ustekinumab. In some embodiments, the anti-inflammatory treatment is JAK inhibitor treatment is. In other embodiments, the anti-inflammatory treatment is anti-TNF treatment. In some embodiments is, the anti-TNF treatment is golimumab.

[0032] In certain embodiments, the methods provided herein further include predicting a response based on one or more other characteristics of the subject . In other embodiments, the other characteristics are selected from the group consisting of the subject's protein levels, gut microbiota, histological findings, and clinical characteristics .

[0033] In some embodiments, the methods provided herein include determining a response 6, 30, or 5 0 weeks or 6, 30, or 50 weeks after treatment, or at any point in between .

[0034] In one aspect, the sample is a tissue sample or a blood sample.

[0035] In one aspect, the IBD is at least one of ulcerative colitis (UC) or Crohn's disease (CD).

[0036] In some embodiments, the subject has previously failed or been intolerant to at least one treatment selected from the group consisting of vedolizumab, corticosteroids, azathioprine (AZA), and 6-mercaptopurine (6MP), or the subject has shown corticosteroid dependence.

[0037] In one aspect, a kit for predicting the response to treatment in a subject diagnosed with inflammatory bowel disease (IBD) comprises a set of isolated probes capable of detecting a panel of biomarkers selected from the group consisting of CKLF-like MARVEL transmembrane domain-containing 2 (CMTM2), complement C5a receptor 1 (C5AR1), fibroblast growth factor 2 (FGF2), glycerol kinase (GK), hepatocyte growth factor (HGF), interleukin 1 receptor antagonist (IL1RN), leukocyte immunoglobulin-like receptor A2 (LILRA2), nicotinamide phosphoribosyltransferase (NAMPT), pappalysin 1 (PAPPA), synuclein alpha (SNCA), superoxide dismutase 2, mitochondrial (SOD2), STEAP4 metalloreductase (STEAP4), and zinc finger BED-type containing 3 (ZBED3), wherein the panel comprises at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 biomarkers selected from the group. A kit containing such a panel of biomarkers is provided herein.

[0038] In another aspect, the kit provided herein comprises CKLF-like MARVEL transmembrane domain-containing 2 (CMTM2), complement C5a receptor 1 (C5AR1), fibroblast growth factor 2 ( FGF2), glycerol kinase (GK), hepatocyte growth factor (HGF), interleukin 1 receptor antagonist (IL1RN), leukocyte immunoglobulin-like receptor A2 (LI LRA2), nicotinamide phosphoribosyltransferase (NAMPT), pappalysin 1 (PAPPA), synuclein alpha (SNCA), superoxide dismutase 2, mitochondrial (SOD2), STEAP4 metalloreductase (STEAP 4), and zinc finger BED-type containing 3 (ZBED3). 4) and a set of isolated probes capable of detecting all of the biomarkers selected from the group consisting of zinc finger BED type containing 3 (ZBED3). The set includes a set of isolated probes capable of detecting these biomarkers.

[0039] In some embodiments, the kit further includes a therapeutic agent.

[0040] Further aspects, features, and advantages of the present invention will be better understood by reading the "Detailed Description of the Invention" and the "Claims". It will be better understood by reading the "Detailed Description of the Invention" and the "Claims".

Brief Description of the Drawings

[0041] The above summary and the following detailed description of the preferred embodiments of the present application will be better understood when read in conjunction with the accompanying drawings. However, it should be understood that the present application is not limited to the embodiments shown in the drawings themselves. The above summary and the following detailed description of the preferred embodiments of the present application will be better understood when read in conjunction with the accompanying drawings. However, it should be understood that the present application is not limited to the embodiments shown in the drawings themselves. It should be understood that the present application is not limited to the embodiments shown in the drawings themselves.

[0042] This patent or application documents include at least one color printed drawing(s). A reproduction of this patent or patent application publication having color drawings will be provided by the Patent Office upon payment of the necessary fees if requested. A reproduction of this patent or patent application publication having color drawings will be provided by the Patent Office upon payment of the necessary fees if requested. It will be provided by the Patent Office upon payment of the necessary fees if requested.

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DETAILED DESCRIPTION OF THE INVENTION

[0043] In the background art, various publications, papers and patents are also cited or will be described. Each of these references is hereby incorporated by reference in its entirety into this specification. This discussion of documents, operations, materials, devices, articles, etc. contained in this specification is for the purpose of providing context for the present invention. Such discussion is not an admission that any or all of these things constitute a part of the prior art with respect to any invention disclosed or claimed in this patent.

[0044] Unless otherwise defined, all technical and scientific terms used in this specification have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. If not, the specific terms used in this specification have the meanings as set forth herein.

[0045] As used in this specification and the appended claims, the singular forms "a", "an", and " the" are to be noted as including plural referents unless the context clearly dictates otherwise.

[0046] Unless otherwise specified, all numerical values such as concentrations or concentration ranges described in this specification are to be understood as being modified in all instances by the term "about". Thus, the numerical values typically include ±10% of the recited value. For example, a concentration of 1 mg / mL includes 0.9 mg / mL to 1.1 mg / mL. Similarly, a concentration range of 1% to 10 %(w / v) includes 0.9%(w / v) to 11%(w / v). When used in this specification, the use of a numerical range includes all possible subranges, including integers and fractional values within the range, and all individual numerical values within that range, unless the context clearly indicates otherwise.

[0047] ​​Unless otherwise specified, the term "at least" preceding a series of elements is to be understood as referring to all of the elements of the series. One of ordinary skill in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the present invention. As used herein, the terms "comprises," "comprising," "includes," "including," "has," "having," "contains," or "containing," or any other variation thereof, are intended to cover a non-exclusive inclusion, such that a composition, mixture, process, method, article, or apparatus that comprises, includes, has, contains a stated integer or group of integers does not exclude other integers or groups of integers not expressly listed or inherent to such composition, mixture, process, method, article, or apparatus. Further, unless expressly stated to the contrary, "or" refers to an inclusive "or" and not to an exclusive "or."

[0048] For example, a condition A or B is satisfied by any one of the following: A is true (or present) and B is false (or not present), A is false (or not present) and B is true (or present), and both A and B are true (or present). For example, a composition, mixture, process, method, article, or apparatus that includes a series of elements is not necessarily limited to only those elements; it may contain other elements not expressly listed or inherent to such composition, mixture, process, method, article, or apparatus.

[0049] The term "about" as used herein when referring to the dimensions or characteristics of the components of the preferred invention terms such as "approximately", "generally", "substantially", etc. are understood by those skilled in the art to mean that the stated dimensions / characteristics are not strict boundaries or parameters, and also do not exclude minor differences from those that are functionally the same or similar. It should also be understood that at a minimum, such references including numerical parameters will include variants in which the least significant digit does not change when using the mathematical and industrial principles (e.g., rounding, measurement, or other systematic errors, manufacturing tolerances, etc.) accepted in the art.

[0050] The term "expressing" or "expression" as used herein, when referring to a gene, refers to the transcription from a gene that gives an RNA nucleic acid molecule that is at least partially complementary to a region of one of the two nucleic acid strands. The term "expresses" or "expression" also, as used herein, refers to the translation from an RNA molecule that gives a protein, polypeptide, or a portion thereof.

[0051] As used herein, a "biomarker" is a gene or protein whose level of expression or concentration in a sample varies or indicates a condition compared to the level in a normal or healthy sample. The biomarkers disclosed herein are genes and / or proteins whose level of expression or concentration, or the timing of expression or concentration, correlates with the prognosis of inflammatory bowel disease (e.g., ulcerative colitis and / or Crohn's disease).

[0052] The terms "polypeptide" and "protein" used interchangeably herein refer to peptides Refers to a polymer of three or more amino acids in a serial array, linked via a bond. The term "poly peptide" includes proteins, protein fragments, protein analogs, oligopeptides, etc. When used herein, the term "polypeptide" may refer to a peptide. The amino acids that make up a polypeptide may be of natural origin or synthetic. A po lypeptide can be purified from a biological sample. Polypeptides, proteins, or peptides also include modified polypeptides, proteins, and peptides, for example, glycopo lypeptides, glycoproteins, or glycopeptides; or lipopolypeptides, lipotanu proteins, or lipopeptides.

[0053] The terms "antibody", "immunoglobulin", or "Ig" used interchangeably herein refer to fully assembled antibodies and antibody fragments that retain the ability to specifically bind to an antigen. Antibodies provided herein include synthetic antibodies, monoclonal antibodies, polycl onal antibodies, recombinantly produced antibodies, multispecific antibodies (including bispecific antibodies), human antibodies, humanized antibodies, chimeric antibodies, intrabodies, single-chain Fv (scFv) (e.g., including single-specificity, bispecificity, etc.), camelized antibodies, Fab fragments, F(ab’) fragments disulfide-bonded Fv (sdFv), anti-idiotype (anti-Id) antibodies, and any epitope-binding fragment of the foregoing, but are not limited thereto.

[0054] As used herein, "probe" refers to any molecule or agent that can selectively bind to an intended target biomolecule. The target molecule is a biomarker, for example, a nucle otide transcripts, or biomarkers encoded by or linked to biomarkers The probes may be synthesized by one skilled in the art or may be prepared by the method of the present invention. The probes may be derived from suitable biological preparations in view of the disclosure. Examples of molecules that can be used as probes include: RNA, DNA, proteins, peptides, antibodies, aptamers, affibodies, and organic molecules These include, but are not limited to, children.

[0055] As used herein, the "baseline gene expression" of a gene in a subject refers to the time at which the subject It refers to the gene expression level of a gene in a subject before the subject is treated with an IBD therapy.

[0056] An "upregulated" mRNA is generally one that is increased in a given treatment or condition. "Down-regulated" mRNAs generally do not respond to a given treatment or condition. In some situations, the mRNA level may be decreased by a given amount. The mRNA from the patient sample may remain unchanged following treatment or condition. "Upregulated" when treated with a drug compared to untreated controls This upregulation can be, for example, about 5%, about 1%, or even more than the control mRNA level. 0%, approx. 20%, approx. 30%, approx. 40%, approx. 50%, approx. 60%, approx. 70%, approx. 80%, approx. 9 0%, approx. 100%, approx. 200%, approx. 300%, approx. 500%, approx. 1,000%, approx. 5,00 Alternatively, the mRNA may be increased by a specific compound or other agent. are "downregulated" or expressed at lower levels in response to administration of It may also be the case. The downregulated mRNA may be, for example, a comparative control mRNA at levels of about 99%, about 95%, about 90%, about 80%, about 70%, about 60%, about 50%, about 40%, about 30%, about 20%, about 10%, about 1%, or less.

[0057] Similarly, the level of a polypeptide or protein biomarker from a patient sample may increase when treated with a drug compared to an untreated control. This increase may be about 5%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 100%, about 200%, about 3 00%, about 500%, about 1,000%, about 5,000%, or more of the comparative control protein level. Alternatively the level of the protein biomarker may decrease in response to the administration of a particular compound or other agent This decrease may be, for example, about 99%, about 95 %, about 90%, about 80%, about 70%, about 60%, about 50%, about 40%, about 30%, about 20 %, about 10%, about 1%, or less of the comparative control protein level.

[0058] The terms "subject" and "patient" can be used interchangeably herein. As used herein "subject" means any animal, preferably a mammal, most preferably a human. As used herein, the term "mammal" includes any mammal Examples of mammals include, but are not limited to, cows, horses, h zujis, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, etc., more preferably humans. In one embodiment, the subject is a mammal diagnosed with a disease or disorder A mammal, such as a human. In another embodiment, the subject is a mammal at risk of developing a disease or disorder, such as a human. A mammal, such as a human, having a risk of developing a disease or disorder.

[0059] As used herein, "sample" is intended to include any sampling of cells, tissues, or body fluids from which the expression of a biomarker can be detected. Examples of such samples include, but are not limited to, biopsies, smears, blood, lymph, urine, saliva, or any other body secretion or derivative thereof. Blood can include, for example, whole blood, plasma, serum, or any derivative of blood. Samples can be obtained from a subject by a variety of techniques known to those of skill in the art. As used herein, "treatment" refers to both therapeutic treatment and prophylactic or preventative measures, the purpose of which is to prevent or slow down (attenuate) the targeted pathological condition or disorder. Those in need of treatment include those diagnosed with a disorder, as well as those at risk of having a disorder (e.g., genetic predisposition ) or those attempting to prevent a disorder. The terms "prevent," "preventing," and "prevention" refer to reducing the likelihood of the onset (or recurrence) of a disease, disorder, condition, or related symptoms.

[0060] As used herein, a "response" to treatment in a subject diagnosed with inflammatory bowel disease (IBD) can be a positive or negative response to treatment. As used herein, a "positive response" to IBD treatment is mucosal healing, clinical response, obtained from IBD treatment or remission, or a combination thereof, as compared to before treatment. A "negative response" to IBD treatment is a lack of improvement or worsening of the disease state as compared to before treatment. or remission, or a combination thereof, as compared to before treatment. A "negative response" to IBD treatment is a lack of improvement or worsening of the disease state as compared to before treatment. Those diagnosed with a disorder, as well as those at risk of having a disorder (e.g., genetic predisposition ) or those attempting to prevent a disorder. The terms "prevent," "preventing," and "prevention" refer to reducing the likelihood of the onset (or recurrence) of a disease, disorder, condition, or related symptoms. As used herein, "prevent," "preventing," and "prevention" refer to reducing the likelihood of the onset (or recurrence) of a disease, disorder, condition, or related symptoms. As used herein, "prevent," "preventing," and "prevention" refer to reducing the likelihood of the onset (or recurrence) of a disease, disorder, condition, or related symptoms.

[0061] As used herein, a "response" to treatment in a subject diagnosed with inflammatory bowel disease (IBD) can be a positive or negative response to treatment. As used herein, a "response" to treatment in a subject diagnosed with inflammatory bowel disease (IBD) can be a positive or negative response to treatment. As used herein, a "positive response" to IBD treatment is mucosal healing, clinical response, obtained from IBD treatment Refers to a response that includes at least one of a response and clinical remission. Mucosal healing is defined as 0 or 1 as defined by the Mayo endoscopic subscore. Clinical response is a reduction of at least 3 points and ≥ 30% in the total Mayo score from baseline, accompanied by a reduction of at least 1 point in the rectal bleeding subscore from baseline, or an absolute rectal bleeding subscore of 0 or 1. Clinical remission is defined as a total Mayo score of 2 or less and the absence of individual subscores exceeding 1 point. For example, a positive response to IBD treatment can be complete mucosal healing and histological normalization, including a Mayo endoscopic subscore of 0 or 1 and a grade of 0 or 1 on the Geboes histological scale for ulcerative colitis (UC). As used herein, a "negative response" or "no response" to IBD treatment refers to no response in terms of mucosal healing, clinical response, and clinical remission obtained from IBD treatment.

[0062] As used herein, a "responder" means a subject having a positive response to IBD treatment.

[0063] As used herein, a "non-responder" means a subject having no response or a negative response to IBD treatment. For example, a non-responder may not have a clinical response to IBD treatment, and a non-responder may have an endoscopic subscore of 2 or 3 and a grade of 4 or 5 on the histological scale.

[0064] A clinical response to IBD treatment can be indicated by an improvement in an indicator of disease activity, recovery of clinical symptoms, or any other measure of disease activity. Such indicators of the disease are ulcerative It is the Mayo score for ulcerative colitis (UC). The Mayo score is calculated as the sum of four subscores: frequency of bowel movements, rectal bleeding, endoscopic findings, and physician's global assessment (PGA). It is an established and validated disease activity index for mild, moderate, and severe ulcerative colitis (UC), and ranges from 0 to 12. A score of 3 - 5 points indicates mild active disease, a score of 6 - 10 points indicates moderate active disease, and a score of 11 - 12 points indicates severe disease. The partial Mayo score, which is the Mayo score without the endoscopic subscore, is calculated as the sum of the frequency of bowel movements, rectal bleeding, and physician's global assessment subscores, and ranges from 0 to 9. The modified Mayo score, which is the Mayo score without the PGA subscore, is calculated as the sum of the frequency of bowel movements, rectal bleeding, and endoscopic subscores, and ranges from 0 to 9. Other disease activity indices for UC include, for example, the Ulcerative Colitis Endoscopic Index of Severity (UCEIS) score and the Bristol stool form scale (BSFS) score. The UCEIS score provides a comprehensive assessment of the endoscopic severity of UC based on mucosal vascular pattern, bleeding, and ulceration (Travis et al., Gut. 61:535 - 542(2012)). The score ranges from 3 to 11, and a higher score indicates more severe disease by endoscopy. The BSFS score is used to classify the consistency (or form) of human feces into seven categories (Lewis and Heaton, Scand J Gastroenterol. 32(9):920 - 924(1997)). ​​​​​​

[0065] As used herein, the term "administer" with respect to the methods of the present invention refers to preventing, treating, or curing a syndrome, disorder, or disease (e.g., inflammatory bowel disease (IBD)) therapeutically or prophylactically. Such methods include administering an effective amount of the therapeutic agent at different times during the course of treatment or simultaneously in a combined form. The methods of the present invention are understood to encompass all known therapeutic treatment regimens.

[0066] The term "effective amount" or "therapeutically effective amount" refers to an amount of an active compound, agent, combination of therapeutic compounds, or pharmaceutical composition thereof provided herein that elicits a biological or medical response that a researcher, veterinarian, physician, or other clinician is seeking to achieve, including preventing, treating, or curing a syndrome, disorder, or disease being treated, or the symptoms of a syndrome, disorder, or disease (e.g., IBD) being treated, in a tissue system, animal, or human.

[0067] As used herein, the term "target" means to inhibit, modulate, up-regulate, down-regulate, enhance, or bind. As used herein, an "agent that targets a pathway" refers to an agent that inhibits, modulates, up-regulates, down-regulates, enhances, or binds to one or more known members of the pathway.

[0068] As used herein, "STEAP4" refers to STEAP4 metalloreductase. STEAP4 is tumor necrosis factor, alpha-induced protein, mouse 6 transmembrane prostate epithelial antigen, TNFAIP9, STAMP2, or tumor necrosis alpha-induced adipose-related protein ​ is also known in the art as a protein.

[0069] As used herein, "CMTM2" refers to CKLF-like MARVEL transmembrane domain containing 2. CMTM2 is also known in the art as chemokine-like factor superfamily member 2, CKL FSF2, or CKLF-like MARVEL transmembrane domain containing 2. is also known in the art.

[0070] As used herein, "C5AR1" refers to complement C5a receptor 1. C5AR1 is also known in the art as C5a anaphylatoxin chemotactic receptor 1, complement component 5a receptor 1, C5a-R, C 5R1, C5AR, complement component 5 receptor 1, CD88 antigen, or C5A. is also known in the art.

[0071] As used herein, "FGF2" refers to fibroblast growth factor 2. FGF2 is also known in the art as heparin-binding growth factor 2, HBGF-2, FGF-2, BFGF, FGFB, basic fibro blast growth factor, or prostato tropin.

[0072] As used herein, "GK" refers to glycerol kinase. GK is also known in the art as ATP : glycerol 3-phosphotransferase, glycerol kinase, GK1, or GKD is also known in the art.

[0073] As used herein, "HGF" refers to hepatocyte growth factor. HGF is fibroblast derived tumor cell cytotoxic factor, lung fibroblast-derived mitogen, hepatopoietin-A, scatter factor, HPTA, SF, deafness, autosomal recessive 39, DFNB39, F-TCF, or Also known in the art as HGFB.

[0074] As used herein, "IL1RN" refers to an interleukin 1 receptor antagonist. IL1RN refers to IL1 inhibitors, ICIL-1RA, IL1F3, IL1RA, IRAP, intracellular interleukin-1 receptor antagonist, or type II interleukin Also known in the art as leukin-1 receptor antagonists.

[0075] As used herein, "LILRA2" refers to leukocyte immunoglobulin-like receptor A2. LILRA2 is a member of the leukocyte immunoglobulin-like receptor, subfamily A (TM domain). (having phenotype), member 2, leukocyte immunoglobulin-like receptor 7, CD85 antigen-like family - Member H, immunoglobulin-like transcript 1, leukocyte Ig-like receptor A2, ILT1, LIR 7, or also known in the art as the CD85h antigen.

[0076] As used herein, "NAMPT" refers to nicotinamide phosphoribosyltransferase. NAMPT refers to visfatin, PBEF1, or pre-B-cell cytokines. Also known in the art as Ronnie Enhancement Factor 1.

[0077] As used herein, "PAPPA" refers to papalysin 1. PAPPA is a Insulin-like growth factor-dependent IGF-binding protein-4 protease, differentially expressed in placenta 1 protein, non-specific BCL2 ARE-binding protein 2, IGF-dependent IGFBP-4 protein Also known as protease, pregnancy-associated plasma protein A, ASBABP2, or DIPLA1 It is known in the art.

[0078] As used herein, "SNCA" refers to synuclein alpha. SNCA is also known in the art as , PARK1, NACP, Parkinson's disease (autosomal dominant, Lewy body) 4, amyloid precursor non-A4 component, AD amyloid non-A-beta component, truncated alpha-synuclein , or PARK4.

[0079] As used herein, "SOD2" refers to superoxide dismutase 2, mitochondrial . SOD2 is also known in the art as superoxide dismutase 2, testicular supernatant sperm-binding protein, manganese-containing superoxide dismutase, indophenol oxidase B, or Mn-SOD.

[0080] As used herein, "ZBED3" refers to zinc finger BED-type containing 3 . ZBED3 is also known in the art as an Axin-interacting protein .

[0081] Diagnosis of IBD Inflammatory bowel diseases (IBD), such as ulcerative colitis (UC) and Crohn's disease (CD), are chronic intermittent diseases that cause structural damage to the intestinal wall. In UC, the inflammation is limited to the mucosa and spreads proximally from the rectum. CD can be located in any part of the gastrointestinal tract and is characterized by transmural inflammation and complications. The first clues in diagnosing IBD are symptoms including persistent diarrhea, blood and / or mucus in the stool (more common in UC than in CD), fever, and abdominal pain. The diagnosis of IBD is usually confirmed by blood tests, endoscopic procedures, and imaging procedures.

[0082]

[0083] Blood test Examples of blood tests are CBC counts such as white blood cell (WBC) and red blood cell (RBC) counts, electrolyte panels, liver function tests, and fecal occult blood tests (also called guaiac tests or occult blood tests). A high WBC count can be a sign that there is inflammation somewhere in the body. A low RBC count can be a sign that there is bleeding somewhere in the body (if not obvious from visible blood in the stool), or, further, can indicate the amount of blood lost compared to previous RBC count levels. .

[0084] An electrolyte panel measures the levels of sodium, potassium, chloride, and carbon dioxide in the body . Chronic diarrhea can bring these electrolytes to abnormally low levels.

[0085] Liver function tests (LFTs) measure alanine transaminase (ALT), aspartate trans aminase (AST), alkaline phosphatase (ALP), albumin, total tan protein, and total and direct bilirubin levels. Abnormal levels can be caused by malnutrition due to the digestive tract not absorbing nutrients that it is supposed to absorb. .

[0086] Fecal occult blood tests (also called guaiac tests or occult blood tests) are used to examine stool for traces of blood that cannot be seen with the naked eye. Stool can also be tested for the presence of bacterial infections that can cause symptoms. .

[0087] Endoscopic procedures Endoscopy is a procedure where a doctor uses special instruments to view and manipulate the organs and blood vessels inside a patient's body. This allows a surgeon to see problems inside the body without making a large incision. It becomes possible. Endoscopes are classified into different categories based on the body regions to be examined. classified.

[0088] Colonoscopy is an endoscopic procedure used to examine the inside of the colon, which can advance beyond the area reachable by sigmoidoscopy. Colonoscopy is useful for detecting colon cancer, ulcers, inflammation, and other problems in the colon. Also, biopsies can be taken during colonoscopy and examined for clues in making a diagnosis. beyond the area reachable by sigmoidoscopy. Colonoscopy is useful for detecting colon cancer, ulcers, inflammation, and other problems in the colon. Also, biopsies can be taken during colonoscopy and examined for clues in making a diagnosis. .

[0089] Sigmoidoscopy is an endoscopic procedure used to examine the last third of the large intestine, including the rectum and sigmoid colon. This examination can be used to look for cancer, abnormal growths (polyps), inflammation, and ulcers. ulcers.

[0090] Upper gastrointestinal endoscopy is used to view the esophagus, stomach, and duodenum (the first part of the small intestine). This can be used to find the cause of swallowing difficulties, nausea, vomiting, reflux, bleeding, indigestion, abdominal pain, or chest pain. This can be used to find the cause of swallowing difficulties, nausea, vomiting, reflux, bleeding, indigestion, abdominal pain, or chest pain.

[0091] Capsule endoscopy is sometimes used to aid in the diagnosis of Crohn's disease that affects the small intestine. The patient swallows a capsule that contains a camera. The images are transmitted to a recorder, and then the capsule passes painlessly out of the body with the feces. Endoscopy with biopsy may also be needed to further confirm the diagnosis of Crohn's disease. The patient swallows a capsule that contains a camera. The images are transmitted to a recorder, and then the capsule passes painlessly out of the body with the feces. Endoscopy with biopsy may also be needed to further confirm the diagnosis of Crohn's disease.

[0092] Imaging techniques Common imaging techniques used in the diagnosis of IBD include X-ray, computed tomography (CT), and magnetic resonance imaging (MRI). include X-ray, computed tomography (CT), and magnetic resonance imaging (MRI).​​​

[0093] X-rays are quick, inexpensive, and non-invasive, and abdominal x-rays can reveal whether the intestines are narrowed, blocked, or dilated. A barium enema (also called a barium enema) can show whether the rectum and a special type of X-ray that uses barium sulfate and air to outline the lining of the colon The results may indicate polyps, tumors, or diverticulosis. ) X-rays are used to examine the esophagus, stomach, and duodenum (the first part of the small intestine). This is a type of line. Sometimes it is used to examine the small intestine.

[0094] A CT scan is a specialized x-ray technique that provides more detail than a standard x-ray. CT enterography provides a better view of the small intestine in addition to the entire intestine. This test is performed in many medical facilities using barium It became the successor to X-rays.

[0095] MRI scanners use magnetic fields and radio waves to create detailed images of organs and tissues. MRI may be used to evaluate fistulas around the anal area (pelvic MRI) or small bowel (MR enterography). Unlike CT, there is no radiation exposure with MRI.

[0096] Treatment of IBD In the treatment of inflammatory bowel disease (IBD), therapeutic agents reduce the inflammation that causes the signs and symptoms. This can reduce the risk of complications and lead to not only symptom relief but also long-term remission. IBD treatment usually involves either medication or surgery. Medications for IBD Treatment These include anti-inflammatory, antibiotic, immunomodulatory, antidiarrheal, pain reliever, iron supplement, and calcium supplement. Examples include, but are not limited to, mu and vitamin D supplementation.

[0097] Anti-inflammatory drugs Anti-inflammatory treatment is often the first step in the treatment of IBD. Anti-inflammatory drugs and include, but are not limited to, aminosalicylates, corticosteroids, anti-tumor necrosis factor (TNF) agents, JAK inhibitors, anti-interleukin agents, and anti-integrin agents.

[0098] Examples of anti-TNF drugs include infliximab (Remicade), adalimumab (H umira), and golimumab (Simponi). JAK inhibitors can be inhibitors against one or more of the four JAK members: JAK1, JAK2, JAK3, and TYK2. Examples of JAK inhibitors include filgotinib, peficitinib, tofacitinib (Xeljanz / Jakvinus), and upadacitinib. (Xeljanz / Jakvinus), and upadacitinib. Anti-interleukin (IL) agents can be anti-IL-1, anti-IL-6, anti-IL-10, anti-IL- 13, anti-IL-17, anti-IL-12 / 23, or anti-IL-23 agents. Anti-IL-12 / 23 agents including ustekinumab (Stelara) are also called IL-12 / 23 blockers. Examples of anti-IL-23 include BI655066, briakinumab, guselkumab , tildrakizumab, and ustekinumab (Stelara). Examples of anti-integrin drugs include vedolizumab and natalizumab.

[0099] Oral or rectal aminosalicylates help control IBD inflammation by delivering compounds containing 5-aminosalicylic acid (5-ASA) to the intestine. ​​It is possible. Examples of aminosalicylic acids are sulfasalazine, mesalamine, olsalazine, and balsalazide. These medications are used for both ulcerative colitis and Crohn's disease but are far more effective for ulcerative colitis and are not used as much for Crohn's disease.

[0100] Corticosteroids are rapid-acting anti-inflammatory drugs and are used to treat acute (sudden onset and / or short-term) exacerbations. Because of the known side effects, physicians prefer to either avoid it completely or prescribe it for only a short period. Corticosteroids can be given orally, rectally, or intravenously. Examples of corticosteroids are prednisone, prednisolone, or methylprednisolone. Budesonide is a slightly different type of steroid that is absorbed by the body very little and thus has far fewer side effects.

[0101] Antibiotics Antibiotics given orally or intravenously are selectively used in patients with Crohn's disease and in IBD patients who develop an infection caused by Clostridium difficile. Examples of antibiotics are metronidazole and ciprofloxacin.

[0102] Immunomodulators IBD is thought to be caused by an overactive immune system. Immunomodulators function by calming the immune system and help reduce inflammation. These can be given orally or by injection. Examples of immunomodulators are azathioprine (AZA), cyclosporine, 6-mercaptopurine (6MP), and methotrexate (in the case of Crohn's disease ). ).

[0103] Combination therapy One or more of the treatments included above, as well as other IBD treatments well known in the art can be used in combination to treat patients with IBD. One or more of the treatments can be administered before, simultaneously with, or after other treatments described in this specification One or more treatments and additional treatments can be administered to a patient simultaneously or sequentially by the same or different routes of administration. The suitability of a particular route of administration for a particular treatment depends on the treatment itself. Routes of administration for the treatment of IBD are known to those of ordinary skill in the art. See, for example, Physicians Desk Reference Reference See, for example, Physicians Desk Reference

[0104] In certain embodiments, the combination therapies described herein can be administered periodically to patients with IBD Cycling therapy involves administering an active agent over a period of time, followed by a period of rest, and repeating this sequential administration Cycling therapy can reduce the development of resistance to one or more of the treatments, avoid or reduce one or more side effects of one of the treatments, and / or improve the effectiveness of the treatment and / or reduce the occurrence of side effects of one of the treatments, and / or improve the effectiveness of the treatment and / or improve the effectiveness of the treatment

[0105] As used herein, the term "in combination" does not limit the order in which treatments (e.g., prophylactic and / or therapeutic agents) are administered to a patient with IBD. In one embodiment, the first treatment is administered before the second treatment provided herein (e.g., 5 minutes, 15 minutes, 3 0 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks is administered (weeks ago). In one embodiment, the first treatment is the second treatment provided herein is administered simultaneously with the administration of. In one embodiment, the first treatment is the second treatment is administered after (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks , 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks later).

[0106] Various treatments including any of the above-exemplified treatments can be used in combination. Combination therapies can include two or more treatments selected from the group consisting of anti-inflammatory treatments, antibiotics, immunomodulators, antidiarrheals, analgesics, iron supplementation, and

[0107] calcium and vitamin D supplementation. Examples of combination therapies include, for example, administering two or more anti-inflammatory drugs to the same subject, administering one or more anti-inflammatory drugs in combination with one or more antibiotics to the same subject, administering one or more anti-inflammatory drugs in combination with one or more immunomodulators to the same subject, administering one or more immunomodulators in combination with one or more antibiotics to the same subject, and administering one or more immunomodulators in combination with one or more antibiotics and one or more anti-inflammatory drugs to the same subject, but are not limited thereto. In view of the teachings and guidance provided herein, one of ordinary skill in the art will understand that the disclosure herein is intended to cover all combinations and permutations of two or more IBD treatments. Accordingly, the various combinations and permutations described herein are illustrative and not intended to be limiting.

[0108] Combination therapy may also include administering to a subject one or more agents that target one or more cells or signaling pathways in combination with one or more immunomodulators, one or more antibiotics, and one or more anti-inflammatory drugs. Exemplary pathways include granulocyte adhesion and extravasation. Exemplary agents that target granulocyte adhesion and extravasation include, but are not limited to, C5AR, ERM, IC AM1, ICAM2, VCAM, Mac1, LFA1, Itgα9, and Itgβ1. Agents that target granulocyte adhesion and extravasation are well known in the art . . . .

[0109] Exemplary pathways include agranulocyte adhesion and extravasation. Exemplary agents that target agranulocyte adhesion and extravasation include, but are not limited to, C5AR, ERM, ICAM1, ICAM2, VC AM, Mac1, LFA1, Itgα9, and Itgβ1. Agents that target agranulocyte adhesion and extravasation are well known in the art . . .

[0110] Exemplary pathways include the osteoarthritis pathway. Exemplary agents that target the osteoarthritis pathway include, but are not limited to, Wnt, β-catenin, MMP3, and Runx2 . . Agents that target the osteoarthritis pathway are well known in the art .

[0111] Exemplary pathways include the roles of macrophages, fibroblasts, and endothelial cells in rheumatoid arthritis. Exemplary agents that target the roles of macrophages, fibroblasts, and endothelial cells in rheumatoid arthritis include MyD88, IRAK, PI3K, TRA cells in rheumatoid arthritis. Exemplary agents that target the roles of macrophages, fibroblasts, and endothelial cells in rheumatoid arthritis include MyD88, IRAK, PI3K, TRA cells, and endothelial cells in rheumatoid arthritis include MyD88, IRAK, PI3K, TRA DD, TRAF2, IKK, IKB, JAK2, IKK, PKC, and NFKB are included, but not limited thereto. Agents targeting the roles of macrophages, fibroblasts, and endothelial cells in rheumatoid arthritis are well known in the art.

[0112] Exemplary pathways include liver fibrosis and activation of hepatic stellate cells. Exemplary agents targeting liver fibrosis and activation of hepatic stellate cells include ERK, p38, PDGF-BB, PDGFR, JNK, SREBP2, and miR-33a, but are not limited thereto. Agents targeting liver fibrosis and activation of hepatic stellate cells are well known in the art.

[0113] Exemplary pathways include inhibition of matrix metalloproteinases. Exemplary agents targeting inhibition of matrix metalloproteinases include TIMP1, TIMP2, TIMP3, TIMP4, TSP2, TSPI2, and a2-macroglobulin, but are not limited thereto. Agents targeting inhibition of matrix metalloproteinases are well known in the art.

[0114] Exemplary pathways include atherosclerotic signaling. Exemplary agents targeting atherosclerotic signaling include HO-1 and MAPK, but are not limited thereto. Agents targeting atherosclerotic signaling are well known in the art.

[0115] Exemplary pathways include bladder cancer signaling. Targeting Exemplary agents include, but are not limited to, HRAS, FGFR3, CDKN2A, and p53 RB. Agents targeting bladder cancer signaling pathways are well known in the art.

[0116] Exemplary pathways include the role of pattern recognition receptors in the recognition of bacteria and viruses. Exemplary agents targeting the role of pattern recognition receptors in the recognition of bacteria and viruses include, but are not limited to, NOD1, NOD2, NFKB, ERK1 / 2, IRF7, and PKC. Agents targeting the role of pattern recognition receptors in the recognition of bacteria and viruses are well known in the art.

[0117] Exemplary pathways include HMGB1 signaling. Exemplary agents targeting HMGB1 signaling include, but are not limited to, TLR-4, TLR-2, RAGE, NFkB, and MEK. Agents targeting HMGB1 signaling are well known in the art.

[0118] Based on the teachings and disclosures provided herein, one of ordinary skill in the art will be able to make and use various combination therapies of the various agents disclosed herein and other agents known in the art that target one or more of the disclosed pathways.

[0119] A biomarker panel and probe for predicting response to IBD treatment, and method of use International Publication No. 2010 / 044952 (A2), the entire contents of which are incorporated herein by reference, discloses 109 probe sets mapped to 81 unique genes. ​​​​​​A prediction panel is disclosed. A set of 109 probe sets had significantly different expression at baseline between responders and non-responders (fold change > 2, P <.05). The panel of 109 probe sets was able to classify patients as responders or non-responders prior to infliximab treatment. (fold change > 2, P <.05). The panel of 109 probe sets was able to classify patients as responders or non-responders prior to infliximab treatment. (fold change > 2, P <.05). The panel of 109 probe sets was able to classify patients as responders or non-responders prior to infliximab treatment.

[0120] The panel of 109 probe sets was able to predict week 8 response with >90% sensitivity and specificity. A gene signature (molecular prediction signature or MPS) containing 13 unique genes predicted responders to TNF antagonist treatment with mixed results, highlighting the challenges in developing clinical biomarkers for response to treatment due to heterogeneous patient populations and variability in endoscopic scoring. (molecular prediction signature or MPS) containing 13 unique genes predicted responders to TNF antagonist treatment with mixed results, highlighting the challenges in developing clinical biomarkers for response to treatment due to heterogeneous patient populations and variability in endoscopic scoring. (molecular prediction signature or MPS) containing 13 unique genes predicted responders to TNF antagonist treatment with mixed results, highlighting the challenges in developing clinical biomarkers for response to treatment due to heterogeneous patient populations and variability in endoscopic scoring. (molecular prediction signature or MPS) containing 13 unique genes predicted responders to TNF antagonist treatment with mixed results, highlighting the challenges in developing clinical biomarkers for response to treatment due to heterogeneous patient populations and variability in endoscopic scoring. (molecular prediction signature or MPS) containing 13 unique genes predicted responders to TNF antagonist treatment with mixed results, highlighting the challenges in developing clinical biomarkers for response to treatment due to heterogeneous patient populations and variability in endoscopic scoring.

[0121] However, despite the low specificity of MPS in predicting responders to TNF antagonist treatment in some cohorts, the present invention finds that MPS exhibits a high negative predictive value (NPV) that is reflected in a high rate (78% - 89%) of true negative predictions in three independent TNF antagonist clinical trials. The usefulness of MPS for identifying non-responders to TNF antagonist treatment is further demonstrated in the present invention in an independent clinical trial using TNF antagonists in a different ethnic population (Japanese), and in clinical trials evaluating anti-inflammatory interventions other than TNF antagonists such as JAK inhibitors and anti-interleukin (IL) therapies. In particular, predicted non-responder patients cannot be distinguished by clinical measures or inflammatory markers, but this non-responder group (NPV) that is reflected in a high rate (78% - 89%) of true negative predictions in three independent TNF antagonist clinical trials. The usefulness of MPS for identifying non-responders to TNF antagonist treatment is further demonstrated in the present invention in an independent clinical trial using TNF antagonists in a different ethnic population (Japanese), and in clinical trials evaluating anti-inflammatory interventions other than TNF antagonists such as JAK inhibitors and anti-interleukin (IL) therapies. In particular, predicted non-responder patients cannot be distinguished by clinical measures or inflammatory markers, but this non-responder group (NPV) that is reflected in a high rate (78% - 89%) of true negative predictions in three independent TNF antagonist clinical trials. The usefulness of MPS for identifying non-responders to TNF antagonist treatment is further demonstrated in the present invention in an independent clinical trial using TNF antagonists in a different ethnic population (Japanese), and in clinical trials evaluating anti-inflammatory interventions other than TNF antagonists such as JAK inhibitors and anti-interleukin (IL) therapies. In particular, predicted non-responder patients cannot be distinguished by clinical measures or inflammatory markers, but this non-responder group (NPV) that is reflected in a high rate (78% - 89%) of true negative predictions in three independent TNF antagonist clinical trials. The usefulness of MPS for identifying non-responders to TNF antagonist treatment is further demonstrated in the present invention in an independent clinical trial using TNF antagonists in a different ethnic population (Japanese), and in clinical trials evaluating anti-inflammatory interventions other than TNF antagonists such as JAK inhibitors and anti-interleukin (IL) therapies. In particular, predicted non-responder patients cannot be distinguished by clinical measures or inflammatory markers, but this non-responder group (NPV) that is reflected in a high rate (78% - 89%) of true negative predictions in three independent TNF antagonist clinical trials. The usefulness of MPS for identifying non-responders to TNF antagonist treatment is further demonstrated in the present invention in an independent clinical trial using TNF antagonists in a different ethnic population (Japanese), and in clinical trials evaluating anti-inflammatory interventions other than TNF antagonists such as JAK inhibitors and anti-interleukin (IL) therapies. In particular, predicted non-responder patients cannot be distinguished by clinical measures or inflammatory markers, but this non-responder group (NPV) that is reflected in a high rate (78% - 89%) of true negative predictions in three independent TNF antagonist clinical trials. The usefulness of MPS for identifying non-responders to TNF antagonist treatment is further demonstrated in the present invention in an independent clinical trial using TNF antagonists in a different ethnic population (Japanese), and in clinical trials evaluating anti-inflammatory interventions other than TNF antagonists such as JAK inhibitors and anti-interleukin (IL) therapies. In particular, predicted non-responder patients cannot be distinguished by clinical measures or inflammatory markers, but this non-responder group (NPV) that is reflected in a high rate (78% - 89%) of true negative predictions in three independent TNF antagonist clinical trials. The usefulness of MPS for identifying non-responders to TNF antagonist treatment is further demonstrated in the present invention in an independent clinical trial using TNF antagonists in a different ethnic population (Japanese), and in clinical trials evaluating anti-inflammatory interventions other than TNF antagonists such as JAK inhibitors and anti-interleukin (IL) therapies. In particular, predicted non-responder patients cannot be distinguished by clinical measures or inflammatory markers, but this non-responder group (NPV) that is reflected in a high rate (78% - 89%) of true negative predictions in three independent TNF antagonist clinical trials. The usefulness of MPS for identifying non-responders to TNF antagonist treatment is further demonstrated in the present invention in an independent clinical trial using TNF antagonists in a different ethnic population (Japanese), and in clinical trials evaluating anti-inflammatory interventions other than TNF antagonists such as JAK inhibitors and anti-interleukin (IL) therapies. In particular, predicted non-responder patients cannot be distinguished by clinical measures or inflammatory markers, but this non-responder group (NPV) that is reflected in a high rate (78% - 89%) of true negative predictions in three independent TNF antagonist clinical trials. The usefulness of MPS for identifying non-responders to TNF antagonist treatment is further demonstrated in the present invention in an independent clinical trial using TNF antagonists in a different ethnic population (Japanese), and in clinical trials evaluating anti-inflammatory interventions other than TNF antagonists such as JAK inhibitors and anti-interleukin (IL) therapies. In particular, predicted non-responder patients cannot be distinguished by clinical measures or inflammatory markers, but this non-responder group Having specific gene expression and microbiome signatures that assist in targeting the group is.

[0122] In general, the present invention relates to predicting the response or non - response to treatment in a subject diagnosed with IBD, and provides methods, reagents, and kits useful for this purpose. Biomarkers indicating and / or predicting the response or non - response to IBD treatment are provided herein. A panel of biomarkers (e.g., genes or proteins expressed in a subject at a specific time point) indicating and / or predicting the response or non - response to combination IBD treatment is provided herein. In certain embodiments, a subject having a negative response or non - responder is a strong candidate for combination therapy. Regarding predicting the response or non - response to IBD treatment, methods, reagents, and kits useful for this purpose are provided. Biomarkers indicating and / or predicting the response or non - response to IBD treatment are provided herein. Regarding predicting the response or non - response to IBD treatment, methods, reagents, and kits useful for this purpose are provided. Biomarkers indicating and / or predicting the response or non - response to IBD treatment are provided herein. Regarding predicting the response or non - response to IBD treatment, methods, reagents, and kits useful for this purpose are provided. Biomarkers indicating and / or predicting the response or non - response to IBD treatment are provided herein. In certain embodiments, the present invention provides a panel of biomarkers (e.g., genes or proteins expressed in a subject at a specific time point) indicating that a subject has either a positive or negative response to IBD treatment. Regarding predicting the response or non - response to IBD treatment, methods, reagents, and kits useful for this purpose are provided. Biomarkers indicating and / or predicting the response or non - response to IBD treatment are provided herein. Regarding predicting the response or non - response to IBD treatment, methods, reagents, and kits useful for this purpose are provided. Biomarkers indicating and / or predicting the response or non - response to IBD treatment are provided herein. Regarding predicting the response or non - response to IBD treatment, methods, reagents, and kits useful for this purpose are provided. Biomarkers indicating and / or predicting the response or non - response to IBD treatment are provided herein.

[0123] A method for predicting the response of a subject diagnosed with inflammatory bowel disease (IBD) to anti - inflammatory treatment of IBD is provided herein. In one embodiment, IBD is ulcerative colitis. Regarding predicting the response or non - response to IBD treatment, methods, reagents, and kits useful for this purpose are provided. Biomarkers indicating and / or predicting the response or non - response to IBD treatment are provided herein. In another embodiment, IBD is Crohn's disease.

[0124] In one embodiment, the subject is any animal. In another embodiment, the subject is a mammal. In one embodiment, the subject is a human. In one embodiment, the subject is a human diagnosed with IBD. In another embodiment, the subject is a human diagnosed with ulcerative colitis. In one embodiment, the subject is a human diagnosed with Crohn's disease. Regarding predicting the response or non - response to IBD treatment, methods, reagents, and kits useful for this purpose are provided. Biomarkers indicating and / or predicting the response or non - response to IBD treatment are provided herein. Regarding predicting the response or non - response to IBD treatment, methods, reagents, and kits useful for this purpose are provided. Biomarkers indicating and / or predicting the response or non - response to IBD treatment are provided herein. Regarding predicting the response or non - response to IBD treatment, methods, reagents, and kits useful for this purpose are provided. Biomarkers indicating and / or predicting the response or non - response to IBD treatment are provided herein.

[0125] In certain embodiments, the response to IBD treatment is predicted before the subject is treated. It occurs. In certain embodiments, the response to IBD treatment is predicted after the subject has been treated. Measured.

[0126] In certain embodiments, the response to treatment in a subject is a positive response. In one embodiment, The positive response is characterized by at least one of mucosal healing, clinical response, or clinical remission. In certain embodiments, the response is a negative response or non-response. In one embodiment, The negative response or non-response to IBD treatment is characterized by not having at least one of mucosal healing, clinical response, and clinical remission. Among them. Characteristic.

[0127] In some embodiments, the method includes contacting a set of probes with a sample from a subject. In some embodiments, the sample includes any sampling of cells, tissues, or Body fluids from the subject. In one embodiment, the sample is a tissue sample. In one embodiment, the sample is a biopsy. In one embodiment, the sample is a colon biopsy. In one embodiment, the sample is a smear. In one embodiment, the sample is blood. In one embodiment, the sample is lymph fluid. In one embodiment, the sample is Urine. In one embodiment, the sample is saliva. In one embodiment, the sample is feces. In one embodiment, the sample is obtained before the subject is treated with anti-inflammatory therapy. .

[0128] The probe can be any molecule or agent that specifically detects a biomarker. In certain Embodiments, the probe is selected from the group consisting of aptamers, antibodies, affibodies, peptides, and nucleic acids. In one embodiment, the probe is an aptamer. The aptamer is Is. , an oligonucleotide or peptide that specifically binds to a target molecule. An aptamer is usually prepared by selection from a large random sequence pool. Examples of aptamers useful in the present invention include oligonucleotides such as DNA, RNA or nucleic acid analogs that bind to the biomarkers of the present invention, or peptides. In one embodiment, the apt amer is a single-stranded DNA-based protein affinity binding reagent. In another embodiment, the probe is an antibody. In one embodiment, the probe is an affibody. In another embodiment the probe is a peptide. In one embodiment, the probe is a nucleic acid. In one embodiment the nucleic acid probe is an oligonucleotide that hybridizes to the gene or mRNA of a biomarker . In another embodiment, the nucleic acid probe is cDNA synthesized from the mRNA of a biomarker . In one embodiment, the probe is selected from the group consisting of SEQ ID NOs: 1-14, SEQ ID NO: 17, SEQ ID NO: 20, SEQ ID NO: 23, SEQ ID NO: 26, SEQ ID NO: 29, SEQ ID NO: 32 , SEQ ID NO: 35, SEQ ID NO: 38, SEQ ID NO: 41, SEQ ID NO: 44, SEQ ID NO: 47, and SEQ ID NO: 50.

[0129] In other embodiments, CKLF-like MARVEL transmembrane domain-containing 2 (CMTM2), complement C5a receptor 1 (C5AR1), fibroblast growth factor 2 (FGF2), glycerol kinase (GK), hepatocyte growth factor (HGF), interleukin 1 receptor antagonist (IL1RN), leukocyte immunoglobulin-like receptor A2 (LILRA2), nicotinamide phosphoribosyltransferase (NAMPT), pappalysin 1 (PAPPA), alpha-synuclein (SNCA), superoxide dismutase 2, mitochondrial ( SOD2), STEAP4 metalloreductase (STEAP4), and zinc finger 1, 2, 3, 4, 5, 6, 7, selected from the group consisting of zinc finger BED-type containing 3 (ZBED3) A panel of biomarkers comprising 8, 9, 10, 11, 12, or 13 biomarkers A set of probes capable of detecting is contacted with the sample.

[0130] In some embodiments, CKLF-like MARVEL transmembrane domain-containing 2 (CMTM2 ), complement C5a receptor 1 (C5AR1), fibroblast growth factor 2 (FGF2), glycerol kinase (GK), hepatocyte growth factor (HGF), interleukin 1 receptor antagonist nist (IL1RN), leukocyte immunoglobulin-like receptor A2 (LILRA2), nicotine amide phosphoribosyltransferase (NAMPT), pappalysin 1 (PAPPA) , synuclein alpha (SNCA), superoxide dismutase 2, mitochondrial ria (SOD2), STEAP4 metalloreductase (STEAP4), and zinc finger 1, 2, 3, 4, 5, 6 selected from the group consisting of finger BED-type containing 3 (ZBED3) , 7, 8, 9, 10, 11, 12, or 13 biomarkers consisting of a biomarker A set of probes capable of detecting is contacted with the sample.

[0131] In some embodiments, CKLF-like MARVEL transmembrane domain-containing 2 (CMTM2 ), complement C5a receptor 1 (C5AR1), fibroblast growth factor 2 (FGF2), glycerol kinase (GK), hepatocyte growth factor (HGF), interleukin 1 receptor antagonist nist (IL1RN), leukocyte immunoglobulin-like receptor A2 (LILRA2), nicotine A panel of biomarkers selected from the group consisting of nicotinamide phosphoribosyltransferase (NAMPT), pappalysin 1 (PAPPA), synuclein alpha (SNCA), superoxide dismutase 2, mitochondrial (SOD2), STEAP4 metalloreductase (STEAP4), and zinc finger BED type containing 3 (ZBED3). A set of probes capable of detecting the panel of biomarkers is contacted with a sample.

[0132] In other embodiments, CKLF-like MARVEL transmembrane domain containing 2 (CMTM2), complement component C5a receptor 1 (C5AR1), fibroblast growth factor 2 (FGF2), glycerol kinase ( GK), hepatocyte growth factor (HGF), interleukin 1 receptor antagonist (IL1RN), leukocyte immunoglobulin-like receptor A2 (LILRA2), nicotinamide phosphoribosyltransferase (NAMPT), pappalysin 1 (PAPPA), syn uclein alpha (SNCA), superoxide dismutase 2, mitochondrial ([[]]END]] SOD2), STEAP4 metalloreductase (STEAP4), and zinc finger BED type containing 3 (ZBED3). A set of probes capable of detecting a panel of biomarkers comprising one biomarker selected from the group consisting of is contacted with a sample. In one embodiment, the biomarker is CMTM2. In one embodiment, the biomarker is C5AR1. In one embodiment, the biomarker is FGF2. In one embodiment, the biomarker is GK. In one embodiment, the biomarker is H GF. In one embodiment, the biomarker is IL1RN. In one embodiment, The biomarker is LILRA2. In one embodiment, the biomarker is NAMP T. In one embodiment, the biomarker is PAPPA. In one embodiment, the biomarker is SNCA. In one embodiment, the biomarker is SOD2 . In one embodiment, the biomarker is STEAP4. In one embodiment, the biomarker is ZBED3.

[0133] In other embodiments, CKLF-like MARVEL transmembrane domain-containing 2 (CMTM2), complement component C5a receptor 1 (C5AR1), fibroblast growth factor 2 (FGF2), glycerol kinase (GK), hepatocyte growth factor (HGF), interleukin 1 receptor antagonist (IL1RN), leukocyte immunoglobulin-like receptor A2 (LILRA2), nicotinamide phosphoribosyltransferase (NAMPT), pappalysin 1 (PAPPA), synuclein alpha (SNCA), superoxide dismutase 2, mitochondrial (SOD2), STEAP4 metalloreductase (STEAP4), and zinc finger BED type-containing 3 (ZBED3) are included in a set of probes that can detect a panel of biomarkers including two biomarkers selected from the group consisting of and contacted with a sample. In other embodiments, CKLF-like MARVEL transmembrane domain-containing 2 (CMTM2), complement component C5a receptor 1 (C5AR1), fibroblast growth factor 2 (FGF2), glycerol kinase .

[0134] In other embodiments, CKLF-like MARVEL transmembrane domain-containing 2 (CMTM2), complement component C5a receptor 1 (C5AR1), fibroblast growth factor 2 (FGF2), glycerol kinase (GK), hepatocyte growth factor (HGF), interleukin 1 receptor antagonist (IL1RN), leukocyte immunoglobulin-like receptor A2 (LILRA2), nicotinamide Phosphoribosyltransferase (NAMPT), pappalysin 1 (PAPPA), syn uclein alpha (SNCA), superoxide dismutase 2, mitochondrial ( SOD2), STEAP4 metalloreductase (STEAP4), and zinc finger BED type containing 3 (ZBED3) selected from the group consisting of three biomarkers, a set of probes capable of detecting a panel of biomarkers is contacted with a sample .

[0135] In other embodiments, CKLF-like MARVEL transmembrane domain containing 2 (CMTM2), complement component C5a receptor 1 (C5AR1), fibroblast growth factor 2 (FGF2), glycerol kinase (GK), hepatocyte growth factor (HGF), interleukin 1 receptor antagonist (IL1RN), leukocyte immunoglobulin-like receptor A2 (LILRA2), nicotinamide phosphoribosyltransferase (NAMPT), pappalysin 1 (PAPPA), syn uclein alpha (SNCA), superoxide dismutase 2, mitochondrial ( SOD2), STEAP4 metalloreductase (STEAP4), and zinc finger BED type containing 3 (ZBED3) selected from the group consisting of four biomarkers, a set of probes capable of detecting a panel of biomarkers is contacted with a sample .

[0136] In other embodiments, CKLF-like MARVEL transmembrane domain containing 2 (CMTM2), complement component C5a receptor 1 (C5AR1), fibroblast growth factor 2 (FGF2), glycerol kinase (GK), hepatocyte growth factor (HGF), interleukin 1 receptor antagonist (IL1RN), leukocyte immunoglobulin-like receptor A2 (LILRA2), nicotinamide phosphoribosyltransferase (NAMPT), pappalysin 1 (PAPPA), syn nuclein alpha (SNCA), superoxide dismutase 2, mitochondrial ( SOD2), STEAP4 metalloreductase (STEAP4), and zinc finger BED type containing 3 (ZBED3), a panel of biomarkers comprising 5 biomarkers selected from the group consisting of A set of probes capable of detecting the biomarker panel is contacted with a sample .

[0137] In other embodiments, CKLF-like MARVEL transmembrane domain-containing 2 (CMTM2), complement C5a receptor 1 (C5AR1), fibroblast growth factor 2 (FGF2), glycerol kinase (GK), hepatocyte growth factor (HGF), interleukin 1 receptor antagonist (IL1RN), leukocyte immunoglobulin-like receptor A2 (LILRA2), nicotinamide phosphoribosyltransferase (NAMPT), pappalysin 1 (PAPPA), syn nuclein alpha (SNCA), superoxide dismutase 2, mitochondrial ( SOD2), STEAP4 metalloreductase (STEAP4), and zinc finger BED type containing 3 (ZBED3), a panel of biomarkers comprising 6 biomarkers selected from the group consisting of A set of probes capable of detecting the biomarker panel is contacted with a sample .

[0138] In other embodiments, CKLF-like MARVEL transmembrane domain-containing 2 (CMTM2), complement C5a receptor 1 (C5AR1), fibroblast growth factor 2 (FGF2), glycerol kinase Nase (GK), hepatocyte growth factor (HGF), interleukin 1 receptor antagonist (IL1RN), leukocyte immunoglobulin-like receptor A2 (LILRA2), nicotinamide phosphoribosyltransferase (NAMPT), pappalysin 1 (PAPPA), syn nuclein alpha (SNCA), superoxide dismutase 2, mitochondrial ( SOD2), STEAP4 metalloreductase (STEAP4), and zinc finger BED type containing 3 (ZBED3) consisting of a panel of 7 biomarkers selected from the group A set of probes capable of detecting the biomarker panel is contacted with the sample .

[0139] In other embodiments, CKLF-like MARVEL transmembrane domain-containing 2 (CMTM2), complement C5a receptor 1 (C5AR1), fibroblast growth factor 2 (FGF2), glycerol kinase Nase (GK), hepatocyte growth factor (HGF), interleukin 1 receptor antagonist (IL1RN), leukocyte immunoglobulin-like receptor A2 (LILRA2), nicotinamide phosphoribosyltransferase (NAMPT), pappalysin 1 (PAPPA), syn nuclein alpha (SNCA), superoxide dismutase 2, mitochondrial ( SOD2), STEAP4 metalloreductase (STEAP4), and zinc finger BED type containing 3 (ZBED3) consisting of a panel of 8 biomarkers selected from the group A set of probes capable of detecting the biomarker panel is contacted with the sample .

[0140] In other embodiments, CKLF-like MARVEL transmembrane domain-containing 2 (CMTM2), complement Complement C5a receptor 1 (C5AR1), fibroblast growth factor 2 (FGF2), glycerol kinase (GK), hepatocyte growth factor (HGF), interleukin 1 receptor antagonist (IL1RN), leukocyte immunoglobulin-like receptor A2 (LILRA2), nicotinamide phosphoribosyltransferase (NAMPT), pappalysin 1 (PAPPA), synuclein alpha (SNCA), superoxide dismutase 2, mitochondrial ( SOD2), STEAP4 metalloreductase (STEAP4), and zinc finger BED-type containing 3 (ZBED3), a set of probes capable of detecting a panel of 9 biomarkers selected from the group consisting of is contacted with a sample.

[0141] In other embodiments, CKLF-like MARVEL transmembrane domain-containing 2 (CMTM2), complement C5a receptor 1 (C5AR1), fibroblast growth factor 2 (FGF2), glycerol kinase (GK), hepatocyte growth factor (HGF), interleukin 1 receptor antagonist (IL1RN), leukocyte immunoglobulin-like receptor A2 (LILRA2), nicotinamide phosphoribosyltransferase (NAMPT), pappalysin 1 (PAPPA), synuclein alpha (SNCA), superoxide dismutase 2, mitochondrial ( SOD2), STEAP4 metalloreductase (STEAP4), and zinc finger BED-type containing 3 (ZBED3), a set of probes capable of detecting a panel of 10 biomarkers selected from the group consisting of is contacted with a sample.

[0142] ​​In other embodiments, 11 biomarkers selected from the group consisting of CKLF-like MARVEL transmembrane domain-containing 2 (CMTM2), complement component C5a receptor 1 (C5AR1), fibroblast growth factor 2 (FGF2), glycerol kinase (GK), hepatocyte growth factor (HGF), interleukin 1 receptor antagonist (IL1RN), leukocyte immunoglobulin-like receptor A2 (LILRA2), nicotinamide phosphoribosyltransferase (NAMPT), pappalysin 1 (PAPPA), synuclein alpha (SNCA), superoxide dismutase 2, mitochondrial ( SOD2), STEAP4 metalloreductase (STEAP4), and zinc finger BED-type containing 3 (ZBED3) can be detected by contacting a sample with a set of probes that can detect a panel of biomarkers.

[0143] In other embodiments, 12 biomarkers selected from the group consisting of CKLF-like MARVEL transmembrane domain-containing 2 (CMTM2), complement component C5a receptor 1 (C5AR1), fibroblast growth factor 2 (FGF2), glycerol kinase (GK), hepatocyte growth factor (HGF), interleukin 1 receptor antagonist (IL1RN), leukocyte immunoglobulin-like receptor A2 (LILRA2), nicotinamide phosphoribosyltransferase (NAMPT), pappalysin 1 (PAPPA), synuclein alpha (SNCA), superoxide dismutase 2, mitochondrial ( SOD2), STEAP4 metalloreductase (STEAP4), and zinc finger BED-type containing 3 (ZBED3) can be detected by contacting a sample with a set of probes that can detect a panel of biomarkers. ​​​​

[0144] One embodiment includes a probe capable of detecting a biomarker comprising STEAP4 metalloreductase (STEAP4). In a further embodiment, the set of probes comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 biomarkers selected from the group consisting of STEAP4 metalloreductase (STEAP4), CKLF-like MARVEL transmembrane domain-containing 2 (CMTM2), complement C5a receptor 1 (C5AR1), fibroblast growth factor 2 (FGF2), glycerol kinase (GK), hepatocyte growth factor (HGF), interleukin 1 receptor antagonist (IL1RN), leukocyte immunoglobulin-like receptor A2 (LILRA2), nicotinamide phosphoribosyltransferase (NAMPT), pappalysin 1 (PAPPA), synuclein alpha (SNCA), superoxide dismutase 2, mitochondrial (SOD2), and zinc finger BED-type containing 3 (ZBED3), and can detect a panel of biomarkers. In one embodiment, STEAP4 metalloreductase (STEAP4), CKLF-like MARVEL transmembrane domain-containing 2 (CMTM2), complement C5a receptor 1 (C5AR1), fibroblast growth factor 2 (FGF2), glycerol kinase (GK), hepatocyte growth factor (HGF), interleukin 1 receptor antagonist (IL1RN), leukocyte immunoglobulin-like receptor A2 (LILRA2), nicotinamide phosphoribosyltransferase (NAMPT), pappalysin 1 (PAPPA), synuclein alpha (SNCA), superoxide dismutase 2, mitochondrial (SOD2),

[0145] ​​​​​​​​​​​​​​​​A panel of biomarkers comprising one biomarker selected from the group consisting of STEAP4 metalloreductase (STEAP4), CKLF-like MARVEL transmembrane domain-containing 2 (CMTM2), complement C5a receptor 1 (C5AR1), fibroblast growth factor 2 (FGF2), glycerol kinase (GK), hepatocyte growth factor (HGF), interleukin 1 receptor antagonist (IL1RN), leukocyte immunoglobulin-like receptor A2 (LILRA2), nicotinamide phosphoribosyltransferase (NAMPT), pappalysin 1 (PAPPA), synuclein alpha (SNCA), superoxide dismutase 2, mitochondrial (SOD2), and zinc finger BED-type containing 3 (ZBED3) is detected by contacting a sample with a set of probes capable of detecting the panel of biomarkers. In some embodiments, a set of probes capable of detecting a panel of biomarkers comprising one biomarker selected from the group consisting of STEAP4 metalloreductase (STEAP4), CKLF-like MARVEL transmembrane domain-containing 2 (CMTM2), complement C5a receptor 1 (C5AR1), fibroblast growth factor 2 (FGF2), glycerol kinase (GK), hepatocyte growth factor (HGF), interleukin 1 receptor antagonist (IL1RN), leukocyte immunoglobulin-like receptor A2 (LILRA2), nicotinamide phosphoribosyltransferase (NAMPT), pappalysin 1 (PAPPA), synuclein alpha (SNCA), superoxide dismutase 2, mitochondrial (SOD2), and zinc finger BED-type containing 3 (ZBED3) is contacted with a sample. In some embodiments, a set of probes capable of detecting a panel of biomarkers comprising two biomarkers selected from the group consisting of STEAP4 metalloreductase (STEAP4), CKLF-like MARVEL transmembrane domain-containing 2 (CMTM2), complement C5a receptor 1 (C5AR1), fibroblast growth factor 2 (FGF2), glycerol kinase (GK), hepatocyte growth factor (HGF), interleukin 1 receptor antagonist (IL1RN), leukocyte immunoglobulin-like receptor A2 (LILRA2), nicotinamide phosphoribosyltransferase (NAMPT), pappalysin 1 (PAPPA), synuclein alpha (SNCA), superoxide dismutase 2, mitochondrial (SOD2), and zinc finger BED-type containing 3 (ZBED3) is contacted with a sample.

[0146] In some embodiments, a set of probes capable of detecting a panel of biomarkers comprising two biomarkers selected from the group consisting of STEAP4 metalloreductase (STEAP4), CKLF-like MARVEL transmembrane domain-containing 2 (CMTM2), complement C5a receptor 1 (C5AR1), fibroblast growth factor 2 (FGF2), glycerol kinase (GK), hepatocyte growth factor (HGF), interleukin 1 receptor antagonist (IL1RN), leukocyte immunoglobulin-like receptor A2 (LILRA2), nicotinamide phosphoribosyltransferase (NAMPT), pappalysin 1 (PAPPA), synuclein alpha (SNCA), superoxide dismutase 2, mitochondrial (SOD2), and zinc finger BED-type containing 3 (ZBED3) is contacted with a sample. In some embodiments, a set of probes capable of detecting a panel of biomarkers comprising two biomarkers selected from the group consisting of STEAP4 metalloreductase (STEAP4), CKLF-like MARVEL transmembrane domain-containing 2 (CMTM2), complement C5a receptor 1 (C5AR1), fibroblast growth factor 2 (FGF2), glycerol kinase (GK), hepatocyte growth factor (HGF), interleukin 1 receptor antagonist (IL1RN), leukocyte immunoglobulin-like receptor A2 (LILRA2), nicotinamide phosphoribosyltransferase (NAMPT), pappalysin 1 (PAPPA), synuclein alpha (SNCA), superoxide dismutase 2, mitochondrial (SOD2), and zinc finger BED-type containing 3 (ZBED3) is contacted with a sample. In some embodiments, a set of probes capable of detecting a panel of biomarkers comprising two biomarkers selected from the group consisting of STEAP4 metalloreductase (STEAP4), CKLF-like MARVEL transmembrane domain-containing 2 (CMTM2), complement C5a receptor 1 (C5AR1), fibroblast growth factor 2 (FGF2), glycerol kinase (GK), hepatocyte growth factor (HGF), interleukin 1 receptor antagonist (IL1RN), leukocyte immunoglobulin-like receptor A2 (LILRA2), nicotinamide phosphoribosyltransferase (NAMPT), pappalysin 1 (PAPPA), synuclein alpha (SNCA), superoxide dismutase 2, mitochondrial (SOD2), and zinc finger BED-type containing 3 (ZBED3) is contacted with a sample. In some embodiments, a set of probes capable of detecting a panel of biomarkers comprising two biomarkers selected from the group consisting of STEAP4 metalloreductase (STEAP4), CKLF-like MARVEL transmembrane domain-containing 2 (CMTM2), complement C5a receptor 1 (C5AR1), fibroblast growth factor 2 (FGF2), glycerol kinase (GK), hepatocyte growth factor (HGF), interleukin 1 receptor antagonist (IL1RN), leukocyte immunoglobulin-like receptor A2 (LILRA2), nicotinamide phosphoribosyltransferase (NAMPT), pappalysin 1 (PAPPA), synuclein alpha (SNCA), superoxide dismutase 2, mitochondrial (SOD2), and zinc finger BED-type containing 3 (ZBED3) is contacted with a sample. In some embodiments, a set of probes capable of detecting a panel of biomarkers comprising two biomarkers selected from the group consisting of STEAP4 metalloreductase (STEAP4), CKLF-like MARVEL transmembrane domain-containing 2 (CMTM2), complement C5a receptor 1 (C5AR1), fibroblast growth factor 2 (FGF2), glycerol kinase (GK), hepatocyte growth factor (HGF), interleukin 1 receptor antagonist (IL1RN), leukocyte immunoglobulin-like receptor A2 (LILRA2), nicotinamide phosphoribosyltransferase (NAMPT), pappalysin 1 (PAPPA), synuclein alpha (SNCA), superoxide dismutase 2, mitochondrial (SOD2), and zinc finger BED-type containing 3 (ZBED3) is contacted with a sample. In some embodiments, a set of probes capable of detecting a panel of biomarkers comprising two biomarkers selected from the group consisting of STEAP4 metalloreductase (STEAP4), CKLF-like MARVEL transmembrane domain-containing 2 (CMTM2), complement C5a receptor 1 (C5AR1), fibroblast growth factor 2 (FGF2), glycerol kinase (GK), hepatocyte growth factor (HGF), interleukin 1 receptor antagonist (IL1RN), leukocyte immunoglobulin-like receptor A2 (LILRA2), nicotinamide phosphoribosyltransferase (NAMPT), pappalysin 1 (PAPPA), synuclein alpha (SNCA), superoxide dismutase 2, mitochondrial (SOD2), and zinc finger BED-type containing 3 (ZBED3) is contacted with a sample. In some embodiments, a set of probes capable of detecting a panel of biomarkers comprising two biomarkers selected from the group consisting of STEAP4 metalloreductase (STEAP4), CKLF-like MARVEL transmembrane domain-containing 2 (CMTM2), complement C5a receptor 1 (C5AR1), fibroblast growth factor 2 (FGF2), glycerol kinase (GK), hepatocyte growth factor (HGF), interleukin 1 receptor antagonist (IL1RN), leukocyte immunoglobulin-like receptor A2 (LILRA2), nicotinamide phosphoribosyltransferase (NAMPT), pappalysin 1 (PAPPA), synuclein alpha (SNCA), superoxide dismutase 2, mitochondrial (SOD2), and zinc finger BED-type containing 3 (ZBED3) is contacted with a sample. In some embodiments, a set of probes capable of detecting a panel of biomarkers comprising two biomarkers selected from the group consisting of STEAP4 metalloreductase (STEAP4), CKLF-like MARVEL transmembrane domain-containing 2 (CMTM2), complement C5a receptor 1 (C5AR1), fibroblast growth factor 2 (FGF2), glycerol kinase (GK), hepatocyte growth factor (HGF), interleukin 1 receptor antagonist (IL1RN), leukocyte immunoglobulin-like receptor A2 (LILRA2), nicotinamide phosphoribosyltransferase (NAMPT), pappalysin 1 (PAPPA), synuclein alpha (SNCA), superoxide dismutase 2, mitochondrial (SOD2), and zinc finger BED-type containing 3 (ZBED3) is contacted with a sample. In some embodiments, a set of probes capable of detecting a panel of biomarkers comprising two biomarkers selected from the group consisting of STEAP4 metalloreductase (STEAP4), CKLF-like MARVEL transmembrane domain-containing 2 (CMTM2), complement C5a receptor 1 (C5AR1), fibroblast growth factor 2 (FGF2), glycerol kinase (GK), hepatocyte growth factor (HGF), interleukin 1 receptor antagonist (IL1RN), leukocyte immunoglobulin-like receptor A2 (LILRA2), nicotinamide phosphoribosyltransferase (NAMPT), pappalysin 1 (PAPPA), synuclein alpha (SNCA), superoxide dismutase 2, mitochondrial (SOD2), and zinc finger BED-type containing 3 (ZBED3) is contacted with a sample. In some embodiments, a set of probes capable of detecting a panel of biomarkers comprising two biomarkers selected from the group consisting of STEAP4 metalloreductase (STEAP4), CKLF-like MARVEL transmembrane domain-containing 2 (CMTM2), complement C5a receptor 1 (C5AR1), fibroblast growth factor 2 (FGF2), glycerol kinase (GK), hepatocyte growth factor (HGF), interleukin 1 receptor antagonist (IL1RN), leukocyte immunoglobulin-like receptor A2 (LILRA2), nicotinamide phosphoribosyltransferase (NAMPT), pappalysin 1 (PAPPA), synuclein alpha (SNCA), superoxide dismutase 2, mitochondrial (SOD2), and zinc finger BED-type containing 3 (ZBED3) is contacted with a sample.

[0147] In some embodiments, a set of probes capable of detecting a panel of biomarkers comprising two biomarkers selected from the group consisting of STEAP4 metalloreductase (STEAP4), CKLF-like MARVEL transmembrane domain-containing 2 (CMTM2), complement C5a receptor 1 (C5AR1), fibroblast growth factor 2 (FGF2), glycerol kinase (GK), hepatocyte growth factor (HGF), interleukin 1 receptor antagonist (IL1RN), leukocyte immunoglobulin-like receptor A2 (LILRA2), nicotinamide phosphoribosyltransferase (NAMPT), pappalysin 1 (PAPPA), synuclein alpha (SNCA), superoxide dismutase 2, mitochondrial (SOD2), and zinc finger BED-type containing 3 (ZBED3) is contacted with a sample. In some embodiments, a set of probes capable of detecting a panel of biomarkers comprising two biomarkers selected from the group consisting of STEAP4 metalloreductase (STEAP4), CKLF-like MARVEL transmembrane domain-containing 2 (CMTM2), complement C5a receptor 1 (C5AR1), fibroblast growth factor 2 (FGF2), glycerol kinase (GK), hepatocyte growth factor (HGF), interleukin 1 receptor antagonist (IL1RN), leukocyte immunoglobulin-like receptor A2 (LILRA2), nicotinamide phosphoribosyltransferase (NAMPT), pappalysin 1 (PAPPA), synuclein alpha (SNCA), superoxide dismutase 2, mitochondrial (SOD2), and zinc finger BED-type containing 3 (ZBED3) is contacted with a sample. In some embodiments, a set of probes capable of detecting a panel of biomarkers comprising two biomarkers selected from the group consisting of STEAP4 metalloreductase (STEAP4), CKLF-like MARVEL transmembrane domain-containing 2 (CMTM2), complement C5a receptor 1 (C5AR1), fibroblast growth factor 2 (FGF2), glycerol kinase (GK), hepatocyte growth factor (HGF), interleukin 1 receptor antagonist (IL1RN), leukocyte immunoglobulin-like receptor A2 (LILRA2), nicotinamide phosphoribosyltransferase (NAMPT), pappalysin 1 (PAPPA), synuclein alpha (SNCA), superoxide dismutase 2, mitochondrial (SOD2), and zinc finger BED-type containing 3 (ZBED3) is contacted with a sample. In some embodiments, a set of probes capable of detecting a panel of biomarkers comprising two biomarkers selected from the group consisting of STEAP4 metalloreductase (STEAP4), CKLF-like MARVEL transmembrane domain-containing 2 (CMTM2), complement C5a receptor 1 (C5AR1), fibroblast growth factor 2 (FGF2), glycerol kinase (GK), hepatocyte growth factor (HGF), interleukin 1 receptor antagonist (IL1RN), leukocyte immunoglobulin-like receptor A2 (LILRA2), nicotinamide phosphoribosyltransferase (NAMPT), pappalysin 1 (PAPPA), synuclein alpha (SNCA), superoxide dismutase 2, mitochondrial (SOD2), and zinc finger BED-type containing 3 (ZBED3) is contacted with a sample. In some embodiments, a set of probes capable of detecting a panel of biomarkers comprising two biomarkers selected from the group consisting of STEAP4 metalloreductase (STEAP4), CKLF-like MARVEL transmembrane domain-containing 2 (CMTM2), complement C5a receptor 1 (C5AR1), fibroblast growth factor 2 (FGF2), glycerol kinase (GK), hepatocyte growth factor (HGF), interleukin 1 receptor antagonist (IL1RN), leukocyte immunoglobulin-like receptor A2 (LILRA2), nicotinamide phosphoribosyltransferase (NAMPT), pappalysin 1 (PAPPA), synuclein alpha (SNCA), superoxide dismutase 2, mitochondrial (SOD2), and zinc finger BED-type containing 3 (ZBED3) is contacted with a sample. In some embodiments, a set of probes capable of detecting a panel of biomarkers comprising two biomarkers selected from the group consisting of STEAP4 metalloreductase (STEAP4), CKLF-like MARVEL transmembrane domain-containing 2 (CMTM2), complement C5a receptor 1 (C5AR1), fibroblast growth factor 2 (FGF2), glycerol kinase (GK), hepatocyte growth factor (HGF), interleukin 1 receptor antagonist (IL1RN), leukocyte immunoglobulin-like receptor A2 (LILRA2), nicotinamide phosphoribosyltransferase (NAMPT), pappalysin 1 (PAPPA), synuclein alpha (SNCA), superoxide dismutase 2, mitochondrial (SOD2), and zinc finger BED-type containing 3 (ZBED3) is contacted with a sample. CA), superoxide dismutase 2, mitochondrial (SOD2), and zinc finger BED type containing 3 (ZBED3) A panel of biomarkers comprising three biomarkers selected from the group consisting of A set of probes capable of detecting a panel of biomarkers comprising three biomarkers selected from the group consisting of CA), superoxide dismutase 2, mitochondrial (SOD2), and zinc finger BED type containing 3 (ZBED3) is contacted with a sample Contact with the sample

[0148] In some embodiments, STEAP4 metalloreductase (STEAP4) and CK CKLF-like MARVEL transmembrane domain containing 2 (CMTM2), complement C5a receptor 1 (C5AR1), fibroblast growth factor 2 (FGF2), glycerol kinase (GK), hepatocyte growth factor (HGF), interleukin 1 receptor antagonist (IL1RN), leukocyte immunoglobulin-like receptor A2 (LILRA2), nicotinamide phosphoribosyltransferase (NAMPT), pappalysin 1 (PAPPA), synuclein alpha (SNCA), superoxide dismutase 2, mitochondrial (SOD2), and zinc finger BED type containing 3 (ZBED3) R1), fibroblast growth factor 2 (FGF2), glycerol kinase (GK), hepatocyte growth factor (HGF), interleukin 1 receptor antagonist (IL1RN), leukocyte immunoglobulin-like receptor A2 (LILRA2), nicotinamide phosphoribosyltransferase (NAMPT), pappalysin 1 (PAPPA), synuclein alpha (SNCA), superoxide dismutase 2, mitochondrial (SOD2), and zinc finger BED type containing 3 (ZBED3) A panel of biomarkers comprising four biomarkers selected from the group consisting of A set of probes capable of detecting a panel of biomarkers comprising four biomarkers selected from the group consisting of CA), superoxide dismutase 2, mitochondrial (SOD2), and zinc finger BED type containing 3 (ZBED3) is contacted with a sample R1), fibroblast growth factor 2 (FGF2), glycerol kinase (GK), hepatocyte growth factor (HGF), interleukin 1 receptor antagonist (IL1RN), leukocyte immunoglobulin-like receptor A2 (LILRA2), nicotinamide phosphoribosyltransferase (NAMPT), pappalysin 1 (PAPPA), synuclein alpha (SNCA), superoxide dismutase 2, mitochondrial (SOD2), and zinc finger BED type containing 3 (ZBED3) CA), superoxide dismutase 2, mitochondrial (SOD2), and zinc finger BED type containing 3 (ZBED3) A panel of biomarkers comprising four biomarkers selected from the group consisting of CA), superoxide dismutase 2, mitochondrial (SOD2), and zinc finger BED type containing zBED3 A set of probes capable of detecting a panel of biomarkers comprising four biomarkers selected from the group consisting of CA), superoxide dismutase 2, mitochondrial (SOD2), and zinc finger BED type containing 3 (ZBED3) is contacted with a sample Contact with the sample

[0149] In some embodiments, STEAP4 metalloreductase (STEAP4) and CK CKLF-like MARVEL transmembrane domain containing 2 (CMTM2), complement C5a receptor 1 (C5AR1), fibroblast growth factor 2 (FGF2), glycerol kinase (GK), hepatocyte growth factor (HGF), interleukin 1 receptor antagonist (IL1RN), leukocyte immunoglobulin-like receptor A2 (LILRA2), nicotinamide phosphoribosyltransferase (NAMPT), pappalysin 1 (PAPPA), synuclein alpha (SNCA), superoxide dismutase 2, mitochondrial (SOD2), and zinc finger BED type containing 3 (ZBED3) R1), fibroblast growth factor 2 (FGF2), glycerol kinase (GK), hepatocyte growth factor (HGF), interleukin 1 receptor antagonist (IL1RN), leukocyte immunoglobulin-like receptor A2 (LILRA2), nicotinamide phosphoribosyltransferase (NAMPT), pappalysin 1 (PAPPA), synuclein alpha (SNCA), superoxide dismutase 2, mitochondrial (SOD2), and zinc finger BED type containing 3 (ZBED3) A panel of biomarkers comprising four biomarkers selected from the group consisting of A set of probes capable of detecting a panel of biomarkers comprising four biomarkers selected from the group consisting of CA), superoxide dismutase 2, mitochondrial (SOD2), and zinc finger BED type containing 3 (ZBED3) is contacted with a sample Enolase (NAMPT), Pappalysin 1 (PAPPA), Synuclein alpha (SN CA), Superoxide dismutase 2, mitochondrial (SOD2), and Zinc finger BED type containing 3 (ZBED3) A panel of biomarkers comprising five biomarkers selected from the group consisting of A set of probes capable of detecting a panel of biomarkers is contacted with a sample .

[0150] In some embodiments, STEAP4 metalloreductase (STEAP4) and CK LF-like MARVEL transmembrane domain containing 2 (CMTM2), Complement C5a receptor 1 (C5AR1) , Fibroblast growth factor 2 (FGF2), Glycerol kinase (GK), Hepatocyte growth factor (HGF), Interleukin 1 receptor antagonist (IL1RN), Leukocyte immune globulin-like receptor A2 (LILRA2), Nicotinamide phosphoribosyltransferase (NAMPT), Pappalysin 1 (PAPPA), Synuclein alpha (SN CA), Superoxide dismutase 2, mitochondrial (SOD2), and Zinc finger BED type containing 3 (ZBED3) A panel of biomarkers comprising six biomarkers selected from the group consisting of CA), Superoxide dismutase 2, mitochondrial (SOD2), and Zinc finger BED type containing 3 (ZBED3) A set of probes capable of detecting a panel of biomarkers is contacted with a sample .

[0151] In some embodiments, STEAP4 metalloreductase (STEAP4) and CK LF-like MARVEL transmembrane domain containing 2 (CMTM2), Complement C5a receptor 1 (C5AR1) , Fibroblast growth factor 2 (FGF2), Glycerol kinase (GK), Hepatocyte growth factor (HGF), Interleukin 1 receptor antagonist (IL1RN), Leukocyte immune globulin-like receptor A2 (LILRA2) ​Immune globulin-like receptor A2 (LILRA2), nicotinamide phosphoribosyltransferase (NAMPT), pappalysin 1 (PAPPA), synuclein alpha (SN CA), superoxide dismutase 2, mitochondrial (SOD2), and zinc finger BED type containing 3 (ZBED3) selected from the group consisting of 7 biomarkers A set of probes capable of detecting a panel of biomarkers comprising the same is contacted with a sample

[0152] In some embodiments, STEAP4 metalloreductase (STEAP4) and CK LF-like MARVEL transmembrane domain-containing 2 (CMTM2), complement C5a receptor 1 (C5A R1), fibroblast growth factor 2 (FGF2), glycerol kinase (GK), hepatocyte growth factor (HGF), interleukin 1 receptor antagonist (IL1RN), leukocyte immune globulin-like receptor A2 (LILRA2), nicotinamide phosphoribosyltransferase (NAMPT), pappalysin 1 (PAPPA), synuclein alpha (SN CA), superoxide dismutase 2, mitochondrial (SOD2), and zinc finger BED type containing 3 (ZBED3) selected from the group consisting of 8 biomarkers A set of probes capable of detecting a panel of biomarkers comprising the same is contacted with a sample

[0153] In some embodiments, STEAP4 metalloreductase (STEAP4) and CK LF-like MARVEL transmembrane domain-containing 2 (CMTM2), complement C5a receptor 1 (C5A R1), fibroblast growth factor 2 (FGF2), glycerol kinase (GK), hepatocyte growth Hepatocyte growth factor (HGF), interleukin 1 receptor antagonist (IL1RN), leukocyte immunoglobulin-like receptor A2 (LILRA2), nicotinamide phosphoribosyltransferase (NAMPT), pappalysin 1 (PAPPA), synuclein alpha (SNCA), superoxide dismutase 2, mitochondrial (SOD2), and zinc finger BED-type containing 3 (ZBED3) A set of probes capable of detecting a panel of biomarkers comprising nine biomarkers selected from the group consisting of Hepatocyte growth factor (HGF), interleukin 1 receptor antagonist (IL1RN), leukocyte immunoglobulin-like receptor A2 (LILRA2), nicotinamide phosphoribosyltransferase (NAMPT), pappalysin 1 (PAPPA), synuclein alpha (SNCA), superoxide dismutase 2, mitochondrial (SOD2), and zinc finger BED-type containing 3 (ZBED3) is contacted with a sample In some embodiments, a set of probes capable of detecting a panel of biomarkers comprising ten biomarkers selected from the group consisting of STEAP4 metalloreductase (STEAP4), CKLF-like MARVEL transmembrane domain-containing 2 (CMTM2), complement C5a receptor 1 (C5AR1), fibroblast growth factor 2 (FGF2), glycerol kinase (GK), hepatocyte growth factor (HGF), interleukin 1 receptor antagonist (IL1RN), leukocyte immunoglobulin-like receptor A2 (LILRA2), nicotinamide phosphoribosyltransferase (NAMPT), pappalysin 1 (PAPPA), synuclein alpha (SNCA), superoxide dismutase 2, mitochondrial (SOD2), and zinc finger BED-type containing 3 (ZBED3) is contacted with a sample In some embodiments, a set of probes capable of detecting a panel of biomarkers comprising ten biomarkers selected from the group consisting of STEAP4 metalloreductase (STEAP4), CKLF-like MARVEL transmembrane domain-containing 2 (CMTM2), complement C5a receptor 1 (C5AR1), fibroblast growth factor 2 (FGF2), glycerol kinase (GK), hepatocyte growth factor (HGF), interleukin 1 receptor antagonist (IL1RN), leukocyte immunoglobulin-like receptor A2 (LILRA2), nicotinamide phosphoribosyltransferase (NAMPT), pappalysin 1 (PAPPA), synuclein alpha (SNCA), superoxide dismutase 2, mitochondrial (SOD2), and zinc finger BED-type containing 3 (ZBED3) is contacted with a sample A set of probes capable of detecting a panel of biomarkers comprising nine biomarkers selected from the group consisting of Hepatocyte growth factor (HGF), interleukin 1 receptor antagonist (IL1RN), leukocyte immunoglobulin-like receptor A2 (LILRA2), nicotinamide phosphoribosyltransferase (NAMPT), pappalysin 1 (PAPPA), synuclein alpha (SNCA), superoxide dismutase 2, mitochondrial (SOD2), and zinc finger BED-type containing 3 (ZBED3) is contacted with a sample

[0154] In some embodiments, STEAP4 metalloreductase (STEAP4), CKLF-like MARVEL transmembrane domain-containing 2 (CMTM2), complement C5a receptor 1 (C5AR1), fibroblast growth factor 2 (FGF2), glycerol kinase (GK), hepatocyte growth factor (HGF), interleukin 1 receptor antagonist (IL1RN), leukocyte immunoglobulin-like receptor A2 (LILRA2), nicotinamide phosphoribosyltransferase (NAMPT), pappalysin 1 (PAPPA), synuclein alpha (SNCA), superoxide dismutase 2, mitochondrial (SOD2), and zinc finger BED-type containing 3 (ZBED3) A set of probes capable of detecting a panel of biomarkers comprising ten biomarkers selected from the group consisting of STEAP4 metalloreductase (STEAP4), CKLF-like MARVEL transmembrane domain-containing 2 (CMTM2), complement C5a receptor 1 (C5AR1), fibroblast growth factor 2 (FGF2), glycerol kinase (GK), hepatocyte growth factor (HGF), interleukin 1 receptor antagonist (IL1RN), leukocyte immunoglobulin-like receptor A2 (LILRA2), nicotinamide phosphoribosyltransferase (NAMPT), pappalysin 1 (PAPPA), synuclein alpha (SNCA), superoxide dismutase 2, mitochondrial (SOD2), and zinc finger BED-type containing 3 (ZBED3) is contacted with a sample In some embodiments, STEAP4 metalloreductase (STEAP4), CKLF-like MARVEL transmembrane domain-containing 2 (CMTM2), complement C5a receptor 1 (C5AR1), fibroblast growth factor 2 (FGF2), glycerol kinase (GK), hepatocyte growth factor (HGF), interleukin 1 receptor antagonist (IL1RN), leukocyte immunoglobulin-like receptor A2 (LILRA2), nicotinamide phosphoribosyltransferase (NAMPT), pappalysin 1 (PAPPA), synuclein alpha (SNCA), superoxide dismutase 2, mitochondrial (SOD2), and zinc finger BED-type containing 3 (ZBED3) Hepatocyte growth factor (HGF), interleukin 1 receptor antagonist (IL1RN), leukocyte immunoglobulin-like receptor A2 (LILRA2), nicotinamide phosphoribosyltransferase (NAMPT), pappalysin 1 (PAPPA), synuclein alpha (SNCA), superoxide dismutase 2, mitochondrial (SOD2), and zinc finger BED-type containing 3 (ZBED3) In some embodiments, STEAP4 metalloreductase (STEAP4), CKLF-like MARVEL transmembrane domain-containing 2 (CMTM2), complement C5a receptor 1 (C5AR1), fibroblast growth factor 2 (FGF2), glycerol kinase (GK), hepatocyte growth factor (HGF), interleukin 1 receptor antagonist (IL1RN), leukocyte immunoglobulin-like receptor A2 (LILRA2), nicotinamide phosphoribosyltransferase (NAMPT), pappalysin 1 (PAPPA), synuclein alpha (SNCA), superoxide dismutase 2, mitochondrial (SOD2), and zinc finger BED-type containing 3 (ZBED3) Hepatocyte growth factor (HGF), interleukin 1 receptor antagonist (IL1RN), leukocyte immunoglobulin-like receptor A2 (LILRA2), nicotinamide phosphoribosyltransferase (NAMPT), pappalysin 1 (PAPPA), synuclein alpha (SNCA), superoxide dismutase 2, mitochondrial (SOD2), and zinc finger BED-type containing 3 (ZBED3) In some embodiments, STEAP4 metalloreductase (STEAP4), CKLF-like MARVEL transmembrane domain-containing 2 (CMTM2), complement C5a receptor 1 (C5AR1), fibroblast growth factor 2 (FGF2), glycerol kinase (GK), hepatocyte growth factor (HGF), interleukin 1 receptor antagonist (IL1RN), leukocyte immunoglobulin-like receptor A2 (LILRA2), nicotinamide phosphoribosyltransferase (NAMPT), pappalysin 1 (PAPPA), synuclein alpha (SNCA), superoxide dismutase 2, mitochondrial (SOD2), and zinc finger BED-type containing 3 (ZBED3) A set of probes capable of detecting a panel of biomarkers comprising ten biomarkers selected from the group consisting of STEAP4 metalloreductase (STEAP4), CKLF-like MARVEL transmembrane domain-containing 2 (CMTM2), complement C5a receptor 1 (C5AR1), fibroblast growth factor 2 (FGF2), glycerol kinase (GK), hepatocyte growth factor (HGF), interleukin 1 receptor antagonist (IL1RN), leukocyte immunoglobulin-like receptor A2 (LILRA2), nicotinamide phosphoribosyltransferase (NAMPT), pappalysin 1 (PAPPA), synuclein alpha (SNCA), superoxide dismutase 2, mitochondrial (SOD2), and zinc finger BED-type containing 3 (ZBED3) is contacted with a sample A set of probes capable of detecting a panel of biomarkers comprising ten biomarkers selected from the group consisting of STEAP4 metalloreductase (STEAP4), CKLF-like MARVEL transmembrane domain-containing 2 (CMTM2), complement C5a receptor 1 (C5AR1), fibroblast growth factor 2 (FGF2), glycerol kinase (GK), hepatocyte growth factor (HGF), interleukin 1 receptor antagonist (IL1RN), leukocyte immunoglobulin-like receptor A2 (LILRA2), nicotinamide phosphoribosyltransferase (NAMPT), pappalysin 1 (PAPPA), synuclein alpha (SNCA), superoxide dismutase 2, mitochondrial (SOD2), and zinc finger BED-type containing 3 (ZBED3) is contacted with a sample A set of probes capable of detecting a panel of biomarkers comprising ten biomarkers selected from the group consisting of STEAP4 metalloreductase (STEAP4), CKLF-like MARVEL transmembrane domain-containing 2 (CMTM2), complement C5a receptor 1 (C5AR1), fibroblast growth factor 2 (FGF2), glycerol kinase (GK), hepatocyte growth factor (HGF), interleukin 1 receptor antagonist (IL1RN), leukocyte immunoglobulin-like receptor A2 (LILRA2), nicotinamide phosphoribosyltransferase (NAMPT), pappalysin 1 (PAPPA), synuclein alpha (SNCA), superoxide dismutase 2, mitochondrial (SOD2), and zinc finger BED-type containing 3 (ZBED3) is contacted with a sample

[0155] In some embodiments, STEAP4 metalloreductase (STEAP4), CKLF-like MARVEL transmembrane domain-containing 2 (CMTM2), complement C5a receptor 1 (C5AR1), fibroblast growth factor 2 (FGF2), glycerol kinase (GK), hepatocyte growth factor (HGF), interleukin 1 receptor antagonist (IL1RN), leukocyte immunoglobulin-like receptor A2 (LILRA2), nicotinamide phosphoribosyltransferase (NAMPT), pappalysin 1 (PAPPA), synuclein alpha (SNCA), superoxide dismutase 2, mitochondrial (SOD2), and zinc finger BED-type containing 3 (ZBED3) A set of probes capable of detecting a panel of biomarkers comprising ten biomarkers selected from the group consisting of STEAP4 metalloreductase (STEAP4), CKLF-like MARVEL transmembrane domain-containing 2 (CMTM2), complement C5a receptor 1 (C5AR1), fibroblast growth factor 2 (FGF2), glycerol kinase (GK), hepatocyte growth factor (HGF), interleukin 1 receptor antagonist (IL1RN), leukocyte immunoglobulin-like receptor A2 (LILRA2), nicotinamide phosphoribosyltransferase (NAMPT), pappalysin 1 (PAPPA), synuclein alpha (SNCA), superoxide dismutase 2, mitochondrial (SOD2), and zinc finger BED-type containing 3 (ZBED3) is contacted with a sample R1), fibroblast growth factor 2 (FGF2), glycerol kinase (GK), hepatocyte growth factor (HGF), interleukin 1 receptor antagonist (IL1RN), leukocyte immune globulin-like receptor A2 (LILRA2), nicotinamide phosphoribosyltransferase (NAMPT), pappalysin 1 (PAPPA), synuclein alpha (SN CA), superoxide dismutase 2, mitochondrial (SOD2), and zinc finger BED-type containing 3 (ZBED3), a panel of biomarkers comprising 11 biomarkers selected from the group consisting of: a set of probes capable of detecting the panel of biomarkers is contacted with a sample.

[0156] In view of the teachings and guidance provided herein, one of ordinary skill in the art will understand that the disclosure herein is a method for predicting the response of a subject diagnosed with inflammatory bowel disease (IBD) to anti-inflammatory treatment of IBD, the method comprising: a. contacting the probe or set of probes disclosed above with a sample derived from the subject; b. determining the pattern of the panel of biomarkers; wherein the pattern of the panel of biomarkers is intended to include a method for predicting the response of the subject to anti-inflammatory treatment. Anti-inflammatory treatment can be, for example, anti-interleukin (anti-IL) or

[0157] JAK inhibitor treatment. In another embodiment, a method for predicting the response of a subject diagnosed with inflammatory bowel disease (IBD) to anti-inflammatory 1 (C5AR1), fibroblast growth factor 2 (FGF2), glycerol kinase (GK) , hepatocyte growth factor (HGF), interleukin 1 receptor antagonist (IL1RN) , leukocyte immunoglobulin-like receptor A2 (LILRA2), nicotinamide phosphoribosyl transferase (NAMPT), pappalysin 1 (PAPPA), synuclein alpha (SNCA), superoxide dismutase 2, mitochondrial (SOD2), S TEAP4 metalloreductase (STEAP4), and zinc finger BED-type containing 3 (ZBED3) selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 biomarkers, contacting a set of probes capable of detecting the biomarker panel with a sample from a subject, and b. determining the pattern of the biomarker panel, comprising wherein the pattern of the biomarker panel predicts the response of the subject to anti-inflammatory treatment. Anti-inflammatory treatment can be, for example, anti-interleukin (anti-IL) or JAK inhibitor treatment.

[0158] In other embodiments, a method for predicting the response of a subject diagnosed with inflammatory bowel disease (IBD) to anti-interleukin treatment for IBD, comprising a. CKLF-like MARVEL transmembrane domain-containing 2 (CMTM2), complement C5a receptor 1 (C5AR1), fibroblast growth factor 2 (FGF2), glycerol kinase (GK) , hepatocyte growth factor (HGF), interleukin 1 receptor antagonist (IL1RN) , leukocyte immunoglobulin-like receptor A2 (LILRA2), nicotinamide phosphoribosyl , and nicotinamide phosphoribosyltransferase (NAMPT) selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, ​Transferase (NAMPT), Pappalysin 1 (PAPPA), Synuclein alpha (SNCA), Superoxide dismutase 2, mitochondrial (SOD2), S TEAP4 metalloreductase (STEAP4), and Zinc finger BED-type containing 3 (ZBED3) selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 biomarkers to detect a panel of biomarkers, contacting a set of probes with a sample from a subject, and b. determining the pattern of the panel of biomarkers, comprising wherein the pattern of the biomarker panel predicts the response to anti-IL therapy in the subject, a method is provided herein.

[0159] A method for predicting the response of a subject diagnosed with inflammatory bowel disease (IBD) to JAK inhibitor therapy for IBD, comprising a. CKLF-like MARVEL transmembrane domain-containing 2 (CMTM2), Complement C5a receptor 1 (C5AR1), Fibroblast growth factor 2 (FGF2), Glycerol kinase (GK) , Hepatocyte growth factor (HGF), Interleukin 1 receptor antagonist (IL1RN) , Leukocyte immunoglobulin-like receptor A2 (LILRA2), Nicotinamide phosphoribosyl transferase (NAMPT), Pappalysin 1 (PAPPA), Synuclein alpha (SNCA), Superoxide dismutase 2, mitochondrial (SOD2), S TEAP4 metalloreductase (STEAP4), and Zinc finger BED-type containing 3 (ZBED3) selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, Detecting a panel of biomarkers comprising 11, 12, or 13 biomarkers contacting a set of probes capable of doing so with a sample from a subject, and b. determining a pattern of the panel of biomarkers, comprising wherein the pattern of the panel of biomarkers predicts a response to JAK inhibitor treatment in the subject is provided herein.

[0160] A method for predicting a response to anti-inflammatory treatment of inflammatory bowel disease (IBD) in a subject diagnosed with IBD, comprising a. contacting a probe capable of detecting a biomarker comprising STEAP4 metalloreductase (STEAP4) with a sample from a subject, and b. determining a pattern of a panel of biomarkers, comprising wherein the pattern of the panel of biomarkers predicts a response to anti-inflammatory treatment in the subject is provided herein. The anti-inflammatory treatment can be, for example, anti-interleukin (anti-IL) or JAK inhibitor treatment.

[0161] A method for predicting a response to anti-inflammatory treatment of inflammatory bowel disease (IBD) in a subject diagnosed with IBD, comprising a. STEAP4 metalloreductase (STEAP4) and CKLF-like MARVEL transmembrane domain-containing 2 (CMTM2), complement C5a receptor 1 (C5AR1), fibroblast growth factor 2 (FGF2), glycerol kinase (GK), hepatocyte growth factor (HGF), interleukin 1 receptor antagonist (IL1RN), leukocyte immunoglobulin-like receptor A2 (LILRA2), nicotinamide phosphoribosyltransferase (NAMPT) ​​​​​ ) Papain 1 (PAPPA), synuclein alpha (SNCA), superoxide dismutase 2, mitochondrial (SOD2), and zinc finger BED-type containing 3 (ZBED3), a panel of biomarkers comprising 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 , 11, or 12 biomarkers, and contacting a set of probes capable of detecting the panel with a sample from a subject, b. determining the pattern of the panel of biomarkers, comprising wherein the pattern of the panel of biomarkers predicts the response of the subject to anti-inflammatory treatment. An anti-inflammatory treatment can be, for example, anti-interleukin (anti-IL) or JAK inhibitor treatment. A method for predicting the response of a subject diagnosed with inflammatory bowel disease (IBD) to anti-interleukin treatment for IBD,

[0162] comprising a. STEAP4 metalloreductase (STEAP4) and CKLF-like MARVEL transmembrane domain-containing 2 (CMTM2), complement C5a receptor 1 (C5AR1), fibroblast growth factor 2 (FGF2), glycerol kinase (GK), hepatocyte growth factor (HGF), interleukin 1 receptor antagonist (IL1RN), leukocyte immunoglobulin-like receptor A2 (LILRA2), nicotinamide phosphoribosyltransferase (NAMPT ), Papain 1 (PAPPA), synuclein alpha (SNCA), superoxide dismutase 2, mitochondrial (SOD2), and zinc finger BED-type containing ) 3 (ZBED3), a panel of biomarkers comprising 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 selected from the group consisting of, 11, or 12 biomarkers, and , 11, or 12 biomarkers, contacting a set of probes capable of detecting a panel of biomarkers with a sample from a subject, and b. determining the pattern of the panel of biomarkers, comprising wherein the pattern of the biomarker panel predicts the response to anti-IL therapy in the subject, is provided herein.

[0163] A method for predicting the response of a subject diagnosed with inflammatory bowel disease (IBD) to JAK inhibitor therapy for IBD, comprising a. detecting a panel of biomarkers comprising 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 biomarkers selected from the group consisting of STEAP4 metalloreductase (STEAP4), CKLF-like MARVEL transmembrane domain-containing 2 (CMTM2), complement C5a receptor 1 (C5AR1), fibroblast growth factor 2 (FGF2), glycerol kinase (GK), hepatocyte growth factor (HGF), interleukin 1 receptor antagonist (IL1RN), leukocyte immunoglobulin-like receptor A2 (LILRA2), nicotinamide phosphoribosyltransferase (NAMPT), pappalysin 1 (PAPPA), synuclein alpha (SNCA), superoxide dismutase 2, mitochondrial (SOD2), and zinc finger BED-type containing 3 (ZBED3) by contacting a set of probes capable of detecting the panel of biomarkers with a sample from the subject, and b. determining the pattern of the panel of biomarkers, wherein the pattern of the panel of biomarkers predicts the response to JAK inhibitor therapy in the subject. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 biomarkers selected from the group consisting of STEAP4 metalloreductase (STEAP4), CKLF-like MARVEL transmembrane domain-containing 2 (CMTM2), complement C5a receptor 1 (C5AR1), fibroblast growth factor 2 (FGF2), glycerol kinase (GK), hepatocyte growth factor (HGF), interleukin 1 receptor antagonist (IL1RN), leukocyte immunoglobulin-like receptor A2 (LILRA2), nicotinamide phosphoribosyltransferase (NAMPT), and b. determining the pattern of the panel of biomarkers, wherein the pattern of the panel of biomarkers predicts the response A method for predicting a response is provided herein.

[0164] The pattern of the panel of biomarkers provided herein is determined by (a) determining the baseline gene expression levels of the panel of biomarkers in a subject, and (b) determining a signature score for each sample. The pattern of the panel of biomarkers provided herein is determined by (a) determining the baseline gene expression levels of the panel of biomarkers in a subject, and (b) determining a signature score for each sample. The pattern of the panel of biomarkers provided herein is determined by (a) determining the baseline gene expression levels of the panel of biomarkers in a subject, and (b) determining a signature score for each sample.

[0165] Any method available in the art for detecting the expression of a biomarker is included herein. The expression, presence, or amount of the biomarker of the present invention can be detected at the nucleic acid level (e.g., as an RNA transcript) or at the protein level. "Detecting or determining the expression of a biomarker" is intended to include determining the amount or presence of a protein or its RNA transcript for the biomarkers disclosed herein. Thus, "detecting the expression" includes cases where it is determined that the biomarker is not expressed, not detectably expressed, expressed at a low level, expressed at a normal level, or overexpressed. Any method available in the art for detecting the expression of a biomarker is included herein. The expression, presence, or amount of the biomarker of the present invention can be detected at the nucleic acid level (e.g., as an RNA transcript) or at the protein level. "Detecting or determining the expression of a biomarker" is intended to include determining the amount or presence of a protein or its RNA transcript for the biomarkers disclosed herein. Thus, "detecting the expression" includes cases where it is determined that the biomarker is not expressed, not detectably expressed, expressed at a low level, expressed at a normal level, or overexpressed. Any method available in the art for detecting the expression of a biomarker is included herein. The expression, presence, or amount of the biomarker of the present invention can be detected at the nucleic acid level (e.g., as an RNA transcript) or at the protein level. "Detecting or determining the expression of a biomarker" is intended to include determining the amount or presence of a protein or its RNA transcript for the biomarkers disclosed herein. Thus, "detecting the expression" includes cases where it is determined that the biomarker is not expressed, not detectably expressed, expressed at a low level, expressed at a normal level, or overexpressed. Any method available in the art for detecting the expression of a biomarker is included herein. The expression, presence, or amount of the biomarker of the present invention can be detected at the nucleic acid level (e.g., as an RNA transcript) or at the protein level. "Detecting or determining the expression of a biomarker" is intended to include determining the amount or presence of a protein or its RNA transcript for the biomarkers disclosed herein. Thus, "detecting the expression" includes cases where it is determined that the biomarker is not expressed, not detectably expressed, expressed at a low level, expressed at a normal level, or overexpressed. Any method available in the art for detecting the expression of a biomarker is included herein. The expression, presence, or amount of the biomarker of the present invention can be detected at the nucleic acid level (e.g., as an RNA transcript) or at the protein level. "Detecting or determining the expression of a biomarker" is intended to include determining the amount or presence of a protein or its RNA transcript for the biomarkers disclosed herein. Thus, "detecting the expression" includes cases where it is determined that the biomarker is not expressed, not detectably expressed, expressed at a low level, expressed at a normal level, or overexpressed. Any method available in the art for detecting the expression of a biomarker is included herein. The expression, presence, or amount of the biomarker of the present invention can be detected at the nucleic acid level (e.g., as an RNA transcript) or at the protein level. "Detecting or determining the expression of a biomarker" is intended to include determining the amount or presence of a protein or its RNA transcript for the biomarkers disclosed herein. Thus, "detecting the expression" includes cases where it is determined that the biomarker is not expressed, not detectably expressed, expressed at a low level, expressed at a normal level, or overexpressed. Any method available in the art for detecting the expression of a biomarker is included herein. The expression, presence, or amount of the biomarker of the present invention can be detected at the nucleic acid level (e.g., as an RNA transcript) or at the protein level. "Detecting or determining the expression of a biomarker" is intended to include determining the amount or presence of a protein or its RNA transcript for the biomarkers disclosed herein. Thus, "detecting the expression" includes cases where it is determined that the biomarker is not expressed, not detectably expressed, expressed at a low level, expressed at a normal level, or overexpressed. Any method available in the art for detecting the expression of a biomarker is included herein. The expression, presence, or amount of the biomarker of the present invention can be detected at the nucleic acid level (e.g., as an RNA transcript) or at the protein level. "Detecting or determining the expression of a biomarker" is intended to include determining the amount or presence of a protein or its RNA transcript for the biomarkers disclosed herein. Thus, "detecting the expression" includes cases where it is determined that the biomarker is not expressed, not detectably expressed, expressed at a low level, expressed at a normal level, or overexpressed. Any method available in the art for detecting the expression of a biomarker is included herein. The expression, presence, or amount of the biomarker of the present invention can be detected at the nucleic acid level (e.g., as an RNA transcript) or at the protein level. "Detecting or determining the expression of a biomarker" is intended to include determining the amount or presence of a protein or its RNA transcript for the biomarkers disclosed herein. Thus, "detecting the expression" includes cases where it is determined that the biomarker is not expressed, not detectably expressed, expressed at a low level, expressed at a normal level, or overexpressed.

[0166] In certain embodiments, DNA, RNA, and protein-based diagnostic methods for directly or indirectly detecting the biomarkers described herein are provided herein. The present invention also provides compositions, reagents, and kits for such diagnostic purposes. The diagnostic methods described herein can be qualitative or quantitative. Quantitative diagnostic methods include, for example, comparing the detected biomarker levels to a cut-off level or threshold level. In certain embodiments, DNA, RNA, and protein-based diagnostic methods for directly or indirectly detecting the biomarkers described herein are provided herein. The present invention also provides compositions, reagents, and kits for such diagnostic purposes. The diagnostic methods described herein can be qualitative or quantitative. Quantitative diagnostic methods include, for example, comparing the detected biomarker levels to a cut-off level or threshold level. In certain embodiments, DNA, RNA, and protein-based diagnostic methods for directly or indirectly detecting the biomarkers described herein are provided herein. The present invention also provides compositions, reagents, and kits for such diagnostic purposes. The diagnostic methods described herein can be qualitative or quantitative. Quantitative diagnostic methods include, for example, comparing the detected biomarker levels to a cut-off level or threshold level. In certain embodiments, DNA, RNA, and protein-based diagnostic methods for directly or indirectly detecting the biomarkers described herein are provided herein. The present invention also provides compositions, reagents, and kits for such diagnostic purposes. The diagnostic methods described herein can be qualitative or quantitative. Quantitative diagnostic methods include, for example, comparing the detected biomarker levels to a cut-off level or threshold level. In certain embodiments, DNA, RNA, and protein-based diagnostic methods for directly or indirectly detecting the biomarkers described herein are provided herein. The present invention also provides compositions, reagents, and kits for such diagnostic purposes. The diagnostic methods described herein can be qualitative or quantitative. Quantitative diagnostic methods include, for example, comparing the detected biomarker levels to a cut-off level or threshold level. It can be used for. Where applicable, qualitative or quantitative diagnostic methods may also include amplifying a target, signal, or intermediate.

[0167] In certain embodiments, the biomarker is detected at the nucleic acid (e.g., RNA) level . For example, the amount of biomarker RNA (e.g., mRNA) present in a sample is determined (e.g g., to determine the level of biomarker expression). Biomarker nucleic acids (e.g., RNA, amplified cDNA, etc.) can be detected / quantified using a variety of nucleic acid techniques known to those skilled in the art, including but not limited to quantitative polymerase chain reaction (qPC R), nucleic acid hybridization, and nucleic acid amplification. In one embodiment, PCR primers, including qPCR primers, are selected from the group consisting of SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 33, SEQ ID NO: 34, SEQ ID NO: 36, SEQ ID NO: 37, SEQ ID NO: 39, SEQ ID NO: 40, SEQ ID NO: 42, SEQ ID NO: 4 3, SEQ ID NO: 45, SEQ ID NO: 46, SEQ ID NO: 48, SEQ ID NO: 49, SEQ ID NO: 51, and SEQ ID NO: 52.

[0168] In certain embodiments, a microarray is used to detect the biomarker. Microarrays can include, for example, DNA microarrays, protein microarrays, tissue micro arrays, cell microarrays, chemical compound microarrays, and antibody microarrays . A DNA microarray, commonly referred to as a gene chip, is used to detect thousands The expression levels of multiple genes can be monitored simultaneously using microarrays. By comparing expression in disease versus normal states, disease genes can be identified. Microarrays can also be used for diagnostic purposes, i.e., to diagnose disease. The pattern of gene expression levels can be examined in the pre-transcription sample, and then These patterns can be used to predict the occurrence of disease states in healthy subjects Microarrays can be used to detect disease states in a subject prior to and / or concurrently with diagnosis. By detecting patterns in gene expression levels over time, it is possible to predict the response to a given therapeutic treatment. The response of the subject may also be predicted.

[0169] In certain embodiments, the expression products are proteins corresponding to the biomarkers of the panel. In certain embodiments, detecting the level of an expression product is a biomarker of the panel. In certain embodiments, the method further comprises exposing the sample to an antibody against a protein corresponding to In certain embodiments, the antibody is covalently attached to a solid surface. Detecting can include exposing the sample to a mass spectrometry technique (eg, mass spectrometry).

[0170] In certain embodiments, reagents for the detection and / or quantification of biomarker proteins are The reagents include a primary antibody that binds to a protein biomarker, secondary antibodies that bind to protein biomarkers, affibodies that bind to protein biomarkers, or aptamers that bind to nucleic acid biomarkers (e.g., RNA or DNA), and / or can include a nucleic acid that binds to a nucleic acid biomarker (e.g., RNA or DNA). is not limited to these. The detection reagent may be labeled (e.g., fluorescently), or may not be labeled. Additionally, the detection reagent may be free in solution or immobilized and may be fixed.

[0171] In certain embodiments, when quantifying the level of a biomarker present in a sample , the level can be determined based on an absolute or relative standard. When determined based on a relative standard , a comparison may be made with a control, which can include a past sample from the same patient (e.g., a series of samples over a specific period), a subject without a disease or disorder (e.g., IBD), or the levels, thresholds, and acceptable ranges found in a population of subjects, but is not limited to these. In some embodiments, 1 to 13 biomarkers are used to predict a patient's response. Any range therein is also contemplated. In one embodiment, 1 biomarker is used to predict a patient's response. In one embodiment, 2 biomarkers are used to

[0172] predict a patient's response. In one embodiment, 3 biomarkers are used to predict a patient's response. In one embodiment, 4 biomarkers are used to predict a patient's response. In one embodiment, 5 biomarkers are used to predict a patient's response. In another embodiment , 6 biomarkers are used to predict a patient's response. In another embodiment, 7 biomarkers are used to predict a patient's response. In yet another embodiment, 8 biomarkers are used to predict a patient's response. In yet another embodiment, 9 biomarkers are used to predict a patient's response. In yet another embodiment, 11 biomarkers are used to predict a patient's response. In yet another embodiment, 13 biomarkers are used to predict a patient's response. biomarkers are used to predict a patient's response. In yet another embodiment, 8 biomarkers are used to predict a patient's response. In yet another embodiment, 9 biomarkers are used to predict a patient's response. In yet another embodiment, 11 biomarkers are used to to predict the patient's response. In yet another embodiment, 12 biomarkers are used to predict the patient's response. In another embodiment, 13 biomarkers are used to predict the patient 's response.

[0173] In some embodiments, one or more biomarkers independently are CKLF-like MARVEL transmembrane domain-containing 2 (CMTM2), complement C5a receptor 1 (C5AR1), fibroblast growth factor 2 (FGF2), glycerol kinase (GK), hepatocyte growth factor (HGF ), interleukin 1 receptor antagonist (IL1RN), leukocyte immunoglobulin-like receptor A2 (LILRA2), nicotinamide phosphoribosyltransferase (N AMPT), pappalysin 1 (PAPPA), synuclein alpha (SNCA), superoxide dismutase 2, mitochondrial (SOD2), STEAP4 metalloreductase (STEAP4), and zinc finger BED-type containing 3 (ZBED3) and are selected from the group consisting of ). In one embodiment, the biomarker is CMTM2. In one embodiment the biomarker is C5AR1. In one embodiment, the biomarker is FGF 2. In one embodiment, the biomarker is GK. In one embodiment, the biomarker is HGF. In one embodiment, the biomarker is IL1RN. In one embodiment, the biomarker is LILRA2. In one embodiment, the biomarker is NAMPT. In one embodiment, the biomarker is PAPPA. In one embodiment, the biomarker is SNCA. In one embodiment, the biomarker is SOD2. In one embodiment, the biomarker is STEAP4. In one embodiment the biomarker is ZBED3. In one embodiment, the biomarker is CMTM2. In one embodiment the biomarker is C5AR1. In one embodiment, the biomarker is FGF 2. In one embodiment, the biomarker is GK. In one embodiment, the biomarker is HGF. In one embodiment, the biomarker is IL1RN. In one In this case, the biomarker is ZBED3.

[0174] In one embodiment, the pattern of the biomarker panel is determined using a method that includes determining the baseline gene expression levels of each biomarker in the panel. In one embodiment, the pattern of the biomarker panel is determined using a method that includes determining the signature score for each sample using the baseline gene expression levels of each biomarker. As used herein, a "signature score" is a unique risk score that is calculated individually for each sample based on the gene expression levels of the biomarker panel. Exemplary methods for determining the signature score are shown in Example 8. In some embodiments, the signature score can be determined by other techniques known in the art.

[0175] In certain embodiments, if the signature score of the biomarker panel exceeds a predetermined threshold indicating a response, the subject is predicted to be a responder to anti-inflammatory therapy for IBD. In one embodiment, if the signature score of the biomarker panel exceeds a predetermined threshold indicating a response, the subject is predicted to be a responder to anti-IL therapy for IBD. In another embodiment, if the signature score of the biomarker panel exceeds a predetermined threshold indicating a response, the subject is predicted to be a responder to JAKi therapy for IBD. In certain embodiments, if the signature score of the biomarker panel is below a predetermined threshold indicating non-response, the subject is predicted to be a non-responder to anti-inflammatory therapy for IBD. In one embodiment, if the signature score of the biomarker panel is below a predetermined threshold indicating non-response, If below the threshold value, the subject is predicted to be a non-responder to anti-IL therapy for IBD. . In another embodiment, if the signature score of a panel of biomarkers is below a predetermined threshold value, the subject is predicted to be a non-responder to JAKi therapy for IBD .

[0176] In another embodiment, a method for predicting a negative response of a subject diagnosed with inflammatory bowel disease (IBD) to anti-inflammatory treatment for IBD, comprising: a. Detecting a set of probes capable of detecting a panel of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 biomarkers selected from the group consisting of CKLF-like MARVEL transmembrane domain-containing 2 (CMTM2), complement C5a receptor 1 (C5AR1), fibroblast growth factor 2 (FGF2), glycerol kinase (GK), hepatocyte growth factor (HGF), interleukin 1 receptor antagonist (IL1RN), leukocyte immunoglobulin-like receptor A2 (LILRA2), nicotinamide phosphoribosyl transferase (NAMPT), pappalysin 1 (PAPPA), synuclein alpha (SNCA), superoxide dismutase 2, mitochondrial (SOD2), STEAP4 metalloreductase (STEAP4), and zinc finger BED-type containing 3 (ZBED3), and contacting the set of probes with a sample from the subject; b. Determining the baseline gene expression levels of the panel of biomarkers in the sample; c. Determining a signature score for each sample; and wherein the signature score of the panel of biomarkers is below a predetermined threshold value indicating non-response. ​ the subject is predicted to be a non-responder to anti-inflammatory treatment for IBD if , provided herein.

[0177] In another embodiment, an anti-inflammatory treatment for inflammatory bowel disease (IBD) is provided in a subject diagnosed with IBD. 1. A method for predicting a negative response to a therapy, comprising: a. CKLF-like MARVEL transmembrane domain-containing 2 (CMTM2), complement C5a receptor 1 (C5AR1), fibroblast growth factor 2 (FGF2), glycerol kinase (GK) , hepatocyte growth factor (HGF), interleukin 1 receptor antagonist (IL1RN) , leukocyte immunoglobulin-like receptor A2 (LILRA2), nicotinamide phosphoribosyl Transferase (NAMPT), Paparisin 1 (PAPPA), Synnuclein Al Fa (SNCA), superoxide dismutase 2, mitochondrial (SOD2), S TEAP4 metalloreductase (STEAP4), and zinc finger BED-type containing 3 (ZBED3) A set of probes capable of detecting the panel is contacted with a sample from the subject. And, b. Determine the baseline gene expression levels of the panel of biomarkers in the sample. To decide, and c. Determining a signature score for each sample; Including, The signature score of the panel of biomarkers is below a predetermined threshold indicating non-response. the subject is predicted to be a non-responder to anti-inflammatory treatment for IBD if , provided herein.

[0178] In another embodiment, a method for predicting a negative response of a subject diagnosed with inflammatory bowel disease (IBD) to anti-inflammatory treatment of IBD, comprising: a. Detecting a set of probes capable of detecting a panel of biomarkers comprising two biomarkers selected from the group consisting of CKLF-like MARVEL transmembrane domain-containing 2 (CMTM2), complement C5a receptor 1 (C5AR1), fibroblast growth factor 2 (FGF2), glycerol kinase (GK), hepatocyte growth factor (HGF), interleukin 1 receptor antagonist (IL1RN), leukocyte immunoglobulin-like receptor A2 (LILRA2), nicotinamide phosphoribosyl transferase (NAMPT), pappalysin 1 (PAPPA), synuclein alpha (SNCA), superoxide dismutase 2, mitochondrial (SOD2), S TEAP4 metalloreductase (STEAP4), and zinc finger BED-type containing 3 (ZBED3) in a sample from the subject; b. Determining the baseline gene expression levels of the panel of biomarkers in the sample; and c. Determining a signature score for each sample, wherein if the signature score of the panel of biomarkers is below a predetermined threshold indicating non-response, the subject is predicted to be a non-responder to anti-inflammatory treatment of IBD, as provided herein. In another embodiment, a method for predicting a negative response of a subject diagnosed with inflammatory bowel disease (IBD) to anti-inflammatory treatment of IBD, comprising: a. CKLF-like MARVEL transmembrane domain-containing 2 (CMTM2), complement C5a receptor 1 (C). is provided herein.

[0179] In another embodiment, a method for predicting a negative response of a subject diagnosed with inflammatory bowel disease (IBD) to anti-inflammatory treatment of IBD, comprising: a. CKLF-like MARVEL transmembrane domain-containing 2 (CMTM2), complement C5a receptor 1 (C5AR1), fibroblast growth factor 2 (FGF2), glycerol kinase (GK) , hepatocyte growth factor (HGF), interleukin 1 receptor antagonist (IL1RN) , leukocyte immunoglobulin-like receptor A2 (LILRA2), nicotinamide phosphoribosyl transferase (NAMPT), pappalysin 1 (PAPPA), synuclein alpha (SNCA), superoxide dismutase 2, mitochondrial (SOD2), S TEAP4 metalloreductase (STEAP4), and zinc finger BED-type containing 3 (ZBED3) A set of probes capable of detecting a panel of biomarkers comprising three biomarkers selected from the group consisting of is contacted with a sample from a subject and b. determining the baseline gene expression levels of the panel of biomarkers in the sample and c. determining a signature score for each sample comprising wherein if the signature score of the panel of biomarkers is below a predetermined threshold indicating non-response the subject is predicted to be a non-responder to anti-inflammatory treatment for IBD, a method is provided herein

[0180] In another embodiment, a method for predicting a negative response to anti-inflammatory treatment of IBD in a subject diagnosed with inflammatory bowel disease (IBD), comprising a. CKLF-like MARVEL transmembrane domain-containing 2 (CMTM2), complement C5a receptor 1 (C5AR1), fibroblast growth factor 2 (FGF2), glycerol kinase (GK) , hepatocyte growth factor (HGF), interleukin 1 receptor antagonist (IL1RN) , leukocyte immunoglobulin-like receptor A2 (LILRA2), nicotinamide phosphoribosyl , leukocyte immunoglobulin-like receptor A2 (LILRA2), nicotinamide phosphoribosyl transferase (NAMPT), pappalysin 1 (PAPPA), synuclein alpha (SNCA), superoxide dismutase 2, mitochondrial (SOD2), S TEAP4 metalloreductase (STEAP4), and zinc finger BED-type containing 3 (ZBED3), a set of probes capable of detecting a panel of 4 biomarkers selected from the group consisting of is contacted with a sample from a subject, and b. determining the baseline gene expression levels of the panel of biomarkers in the sample and c. determining a signature score for each sample, comprising wherein if the signature score of the panel of biomarkers is below a predetermined threshold indicating non-response, the subject is predicted to be a non-responder to anti-inflammatory treatment for IBD, a method is provided herein.

[0181] In another embodiment, a method for predicting a negative response to anti-inflammatory treatment for IBD in a subject diagnosed with inflammatory bowel disease (IBD), comprising a. CKLF-like MARVEL transmembrane domain-containing 2 (CMTM2), complement C5a receptor 1 (C5AR1), fibroblast growth factor 2 (FGF2), glycerol kinase (GK) , hepatocyte growth factor (HGF), interleukin 1 receptor antagonist (IL1RN) , leukocyte immunoglobulin-like receptor A2 (LILRA2), nicotinamide phosphoribosyl transferase (NAMPT), pappalysin 1 (PAPPA), synuclein alpha alpha-synuclein (SNCA), superoxide dismutase 2, mitochondrial (SOD2), S Transmembrane Epithelial Antigen of the Prostate 4 metalloreductase (STEAP4), and zinc finger BED type containing 3 (ZBED3), a set of probes capable of detecting a panel of 5 biomarkers selected from the group consisting of is contacted with a sample from a subject and b. determining the baseline gene expression levels of the panel of biomarkers in the sample and c. determining a signature score for each sample comprising wherein if the signature score of the panel of biomarkers is below a predetermined threshold indicating non-response, the subject is predicted to be a non-responder to anti-inflammatory treatment for IBD a method is provided herein

[0182] In another embodiment, a method of predicting a negative response to anti-inflammatory treatment for inflammatory bowel disease (IBD) in a subject diagnosed with IBD, comprising a. CKLF-like MARVEL transmembrane domain containing 2 (CMTM2), complement C5a receptor 1 (C5AR1), fibroblast growth factor 2 (FGF2), glycerol kinase (GK) hepatocyte growth factor (HGF), interleukin 1 receptor antagonist (IL1RN) leukocyte immunoglobulin-like receptor A2 (LILRA2), nicotinamide phosphoribosyltransferase (NAMPT), pappalysin 1 (PAPPA), alpha-synuclein (SNCA), superoxide dismutase 2, mitochondrial (SOD2), S Transmembrane Epithelial Antigen of the Prostate 4 metalloreductase (STEAP4), and zinc finger BED type containing 3 ZBED3 from the group consisting of alpha-synuclein (SNCA), superoxide dismutase 2, mitochondrial (SOD2), S Transmembrane Epithelial Antigen of the Prostate 4 metalloreductase (STEAP4), and zinc finger BED type containing 3 ​A biomarker panel comprising 6 biomarkers selected from the group consisting of (ZBED3) Contacting a set of probes capable of detecting the panel with a sample from a subject and b. Determining the baseline gene expression levels of the biomarker panel in the sample and c. Determining a signature score for each sample comprising wherein if the signature score of the biomarker panel is below a predetermined threshold indicating non - response, the subject is predicted to be a non - responder to anti - inflammatory treatment for IBD, a method is provided herein.

[0183] In another embodiment, a method for predicting a negative response to anti - inflammatory treatment for inflammatory bowel disease (IBD) in a subject diagnosed with IBD, comprising a. CKLF - like MARVEL transmembrane domain - containing 2 (CMTM2), complement C5a receptor 1 (C5AR1), fibroblast growth factor 2 (FGF2), glycerol kinase (GK) , hepatocyte growth factor (HGF), interleukin 1 receptor antagonist (IL1RN) , leukocyte immunoglobulin - like receptor A2 (LILRA2), nicotinamide phosphoribosyltransferase (NAMPT) , pappalysin 1 (PAPPA), synuclein alpha (SNCA), superoxide dismutase 2, mitochondrial (SOD2), S TEAP4 metalloreductase (STEAP4), and zinc finger BED - type containing 3 (ZBED3) A biomarker panel comprising 7 biomarkers selected from the group consisting of Contacting a set of probes capable of detecting the panel with a sample from a subject (ZBED3) and and b. determining the baseline gene expression levels of the panel of biomarkers in the sample and c. determining a signature score for each sample comprising wherein if the signature score of the panel of biomarkers is below a predetermined threshold indicating non - response the subject is predicted to be a non - responder to anti - inflammatory treatment for IBD, a method is provided herein.

[0184] In another embodiment, a method for predicting a negative response to anti - inflammatory treatment for inflammatory bowel disease (IBD) in a subject diagnosed with IBD, comprising a. contacting a set of probes capable of detecting a panel of biomarkers comprising CKLF - like MARVEL transmembrane domain - containing 2 (CMTM2), complement C5a receptor 1 (C5AR1), fibroblast growth factor 2 (FGF2), glycerol kinase (GK) , hepatocyte growth factor (HGF), interleukin 1 receptor antagonist (IL1RN) , leukocyte immunoglobulin - like receptor A2 (LILRA2), nicotinamide phosphoribosyltransferase (NAMPT), pappalysin 1 (PAPPA), synuclein alpha (SNCA) , superoxide dismutase 2, mitochondrial (SOD2), STEAP4 metalloreductase (STEAP4), and zinc finger BED - type containing 3 (ZBED3) with a sample from the subject b. determining the baseline gene expression levels of the panel of biomarkers in the sample c. determining a signature score for each sample comprising wherein if the signature score of the panel of biomarkers is below a predetermined threshold indicating non - response the subject is predicted to be a non - responder to anti - inflammatory treatment for IBD a set of probes capable of detecting a panel of biomarkers comprising CKLF - like MARVEL transmembrane domain - containing 2 (CMTM2), complement C5a receptor 1 (C5AR1), fibroblast growth factor 2 (FGF2), glycerol kinase (GK) and b. determining the baseline gene expression levels of the panel of biomarkers in the sample and c. determining a signature score for each sample comprising When the signature score of the panel of biomarkers is below a predetermined threshold indicating non - response there is provided herein a method for predicting that the subject is a non - responder to anti - inflammatory treatment for IBD

[0185] In another embodiment, a method for predicting a negative response of a subject diagnosed with inflammatory bowel disease (IBD) to anti - inflammatory treatment for IBD, comprising a. Detecting a set of probes capable of detecting a panel of 9 biomarkers selected from the group consisting of CKLF - like MARVEL transmembrane domain - containing 2 (CMTM2), complement C5a receptor 1 (C5AR1), fibroblast growth factor 2 (FGF2), glycerol kinase (GK) , hepatocyte growth factor (HGF), interleukin 1 receptor antagonist (IL1RN) , leukocyte immunoglobulin - like receptor A2 (LILRA2), nicotinamide phosphoribosyltransferase (NAMPT) , pappalysin 1 (PAPPA), alpha - synuclein (SNCA) , superoxide dismutase 2, mitochondrial (SOD2), STEAP4 metalloreductase (STEAP4), and zinc finger BED - type containing 3 (ZBED3) by contacting the set of probes with a sample from the subject b. Determining the baseline gene expression levels of the panel of biomarkers in the sample c. Determining a signature score for each sample wherein when the signature score of the panel of biomarkers is below a predetermined threshold indicating non - response there is provided herein a method for predicting that the subject is a non - responder to anti - inflammatory treatment for IBD ​​​​​​​​​

[0186] In another embodiment, a method for predicting a negative response of a subject diagnosed with inflammatory bowel disease (IBD) to anti-inflammatory treatment of IBD, comprising: a. Detecting a set of probes capable of detecting a panel of 10 biomarkers selected from the group consisting of CKLF-like MARVEL transmembrane domain-containing 2 (CMTM2), complement C5a receptor 1 (C5AR1), fibroblast growth factor 2 (FGF2), glycerol kinase (GK), hepatocyte growth factor (HGF), interleukin 1 receptor antagonist (IL1RN), leukocyte immunoglobulin-like receptor A2 (LILRA2), nicotinamide phosphoribosyltransferase (NAMPT), pappalysin 1 (PAPPA), synuclein alpha (SNCA), superoxide dismutase 2, mitochondrial (SOD2), STEAP4 metalloreductase (STEAP4), and zinc finger BED-type containing 3 (ZBED3), by contacting the set of probes with a sample from the subject; b. Determining the baseline gene expression levels of the panel of biomarkers in the sample; c. Determining a signature score for each sample; wherein if the signature score of the panel of biomarkers is below a predetermined threshold indicating non-response, the subject is predicted to be a non-responder to anti-inflammatory treatment of IBD, as provided herein.

[0187] In another embodiment, a method for predicting a negative response of a subject diagnosed with inflammatory bowel disease (IBD) to anti-inflammatory treatment of IBD, comprising: ​​​​​​​​​​​​​​a. CKLF-like MARVEL transmembrane domain-containing 2 (CMTM2), complement C5a receptor 1 (C5AR1), fibroblast growth factor 2 (FGF2), glycerol kinase (GK) , hepatocyte growth factor (HGF), interleukin 1 receptor antagonist (IL1RN) , leukocyte immunoglobulin-like receptor A2 (LILRA2), nicotinamide phosphoribosyl transferase (NAMPT), pappalysin 1 (PAPPA), synuclein alpha (SNCA), superoxide dismutase 2, mitochondrial (SOD2), S TEAP4 metalloreductase (STEAP4), and zinc finger BED-type containing 3 (ZBED3), a panel of 11 biomarkers selected from the group consisting of contacting a set of probes capable of detecting the panel of biomarkers with a sample from a subject thereby, b. determining a baseline gene expression level of the panel of biomarkers in the sample thereby, c. determining a signature score for each sample comprising wherein when the signature score of the panel of biomarkers is below a predetermined threshold indicating non-response, the subject is predicted to be a non-responder to anti-inflammatory therapy for IBD, a method is provided herein.

[0188] In another embodiment, a method for predicting a negative response to anti-inflammatory treatment of IBD in a subject diagnosed with inflammatory bowel disease (IBD), comprising: a. CKLF-like MARVEL transmembrane domain-containing 2 (CMTM2), complement C5a receptor 1 (C5AR1), fibroblast growth factor 2 (FGF2), glycerol kinase (GK) 1 (C5AR1), fibroblast growth factor 2 (FGF2), glycerol kinase (GK) , hepatocyte growth factor (HGF), interleukin 1 receptor antagonist (IL1RN) , leukocyte immunoglobulin-like receptor A2 (LILRA2), nicotinamide phosphoribosyl transferase (NAMPT), pappalysin 1 (PAPPA), synuclein alpha (SNCA), superoxide dismutase 2, mitochondrial (SOD2), S TEAP4 metalloreductase (STEAP4), and zinc finger BED-type containing 3 (ZBED3), a set of probes capable of detecting a panel of 12 biomarkers selected from the group consisting of is contacted with a sample from a subject and b. determining the baseline gene expression levels of the panel of biomarkers in the sample and c. determining a signature score for each sample including where the signature score of the panel of biomarkers is below a predetermined threshold indicating non-response the subject is predicted to be a non-responder to anti-inflammatory treatment for IBD, a method is provided herein

[0189] In one embodiment, a method for predicting a negative response to anti-inflammatory treatment for IBD in a subject diagnosed with inflammatory bowel disease (IBD), comprising a. contacting a probe capable of detecting a biomarker including STEAP4 metalloreductase (STEAP4) with a sample from a subject and b. determining the baseline gene expression levels of the panel of biomarkers in the sample and c. determining a signature score for each sample including and When the signature score of the biomarker is below a predetermined threshold indicating non-response, the subject is predicted to be a non-responder to anti-inflammatory treatment for IBD, a method is provided in this specification .

[0190] In another embodiment, a method for predicting a negative response to anti-inflammatory treatment for IBD in a subject diagnosed with inflammatory bowel disease (IBD), comprising: a. Detecting a panel of biomarkers comprising 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 biomarkers selected from the group consisting of STEAP4 metalloreductase (STEAP4), CKLF-like MARVEL transmembrane domain-containing 2 (CMTM2), complement C5a receptor 1 (C5AR1), fibroblast growth factor 2 (FGF2), glycerol kinase (GK), hepatocyte growth factor (HGF), interleukin 1 receptor antagonist (IL1RN), leukocyte immunoglobulin-like receptor A2 (LILRA2), nicotinamide phosphoribosyltransferase (NAMPT ), pappalysin 1 (PAPPA), synuclein alpha (SNCA), superoxide dismutase 2, mitochondrial (SOD2), and zinc finger BED-type containing 3 (ZBED3) with a set of probes capable of detecting the panel of biomarkers, contacting the set of probes with a sample from the subject, b. Determining the baseline gene expression levels of the panel of biomarkers in the sample, c. Determining a signature score for each sample, wherein when the signature score of the panel of biomarkers is below a predetermined threshold indicating non-response, the subject is predicted to be a non-responder to anti-inflammatory treatment for IBD, a method is provided. ​​​​​​​​, is provided herein.

[0191] In another embodiment, a method for predicting a negative response of a subject diagnosed with inflammatory bowel disease (IBD) to anti-inflammatory treatment of IBD, comprising: a. detecting a set of probes capable of detecting a panel of biomarkers comprising one biomarker selected from the group consisting of STEAP4 metalloreductase (STEAP4), CKLF-like MARVEL transmembrane domain-containing 2 (CMTM2), complement C5a receptor 1 (C5AR1), fibroblast growth factor 2 (FGF2), glycerol kinase (GK), hepatocyte growth factor (HGF), interleukin 1 receptor antagonist (IL1RN), leukocyte immunoglobulin-like receptor A2 (LILRA2), nicotinamide phosphoribosyltransferase (NAMPT ), pappalysin 1 (PAPPA), synuclein alpha (SNCA), superoxide dismutase 2, mitochondrial (SOD2), and zinc finger BED-type containing 3 (ZBED3) with a sample from the subject; b. determining a baseline gene expression level of the panel of biomarkers in the sample; c. determining a signature score for each sample; wherein if the signature score of the panel of biomarkers is below a predetermined threshold indicating non-response, the subject is predicted to be a non-responder to anti-inflammatory treatment of IBD. A method is provided herein. In one embodiment, a method for predicting a negative response of a subject diagnosed with inflammatory bowel disease (IBD) to anti-inflammatory treatment of IBD, comprising: a. contacting a set of probes capable of detecting a panel of biomarkers comprising one biomarker selected from the group consisting of STEAP4 metalloreductase (STEAP4), CKLF-like MARVEL transmembrane domain-containing 2 (CMTM2), complement C5a receptor 1 (C5AR1), fibroblast growth factor 2 (FGF2), glycerol kinase (GK), hepatocyte growth factor (HGF), interleukin 1 receptor antagonist (IL1RN), leukocyte immunoglobulin-like receptor A2 (LILRA2), nicotinamide phosphoribosyltransferase (NAMPT ), pappalysin 1 (PAPPA), synuclein alpha (SNCA), superoxide dismutase 2, mitochondrial (SOD2), and zinc finger BED-type containing 3 (ZBED3) with a sample from the subject; b. determining a baseline gene expression level of the panel of biomarkers in the sample; c. determining a signature score for each sample; wherein if the signature score of the panel of biomarkers is below a predetermined threshold indicating non-response, the subject is predicted to be a non-responder to anti-inflammatory treatment of IBD. Including: If the signature score of the panel of biomarkers is below a predetermined threshold indicating non-response, the subject is predicted to be a non-responder to anti-inflammatory treatment of IBD. A method is provided herein. , is provided herein.

[0192] In one embodiment, a method for predicting a negative response of a subject diagnosed with inflammatory bowel disease (IBD) to anti-inflammatory treatment of IBD, comprising: a. A panel of biomarkers comprising two biomarkers selected from the group consisting of STEAP4 metalloreductase (STEAP4), CKLF-like MARVEL transmembrane domain-containing 2 (CMTM2), complement C5a receptor 1 (C5AR1), fibroblast growth factor 2 (FGF2), glycerol kinase (GK), hepatocyte growth factor (HGF), interleukin 1 receptor antagonist (IL1RN), leukocyte immunoglobulin-like receptor A2 (LILRA2), nicotinamide phosphoribosyltransferase (NAMPT), pappalysin 1 (PAPPA), synuclein alpha (SNCA), superoxide dismutase 2, mitochondrial (SOD2), and zinc finger BED-type containing 3 (ZBED3), is contacted with a sample derived from a subject, b. the baseline gene expression levels of the panel of biomarkers in the sample are determined, c. a signature score for each sample is determined, and if the signature score of the panel of biomarkers is below a predetermined threshold indicating non-response, the subject is predicted to be a non-responder to anti-inflammatory treatment for IBD, a method is provided herein. In another embodiment, a method for predicting a negative response to anti-inflammatory treatment for inflammatory bowel disease (IBD) in a subject diagnosed with IBD, comprising: a. STEAP4 metalloreductase (STEAP4) and CKLF-like MARVEL transmembrane domain-containing 2 (CMTM2), complement C5a receptor 1 (C5AR1), fibroblast growth factor 2 (FGF2), glycerol kinase (GK), hepatocyte growth factor (HGF), interleukin 1 receptor antagonist (IL1RN), leukocyte immunoglobulin-like receptor A2 (LILRA2), nicotinamide phosphoribosyltransferase (NAMPT), pappalysin 1 (PAPPA), synuclein alpha (SNCA), superoxide dismutase 2, mitochondrial (SOD2), and zinc finger BED-type containing 3 (ZBED3), a panel of biomarkers comprising two biomarkers selected from the group consisting of is contacted with a sample derived from a subject, b. the baseline gene expression levels of the panel of biomarkers in the sample are determined, c. a signature score for each sample is determined, comprising, wherein if the signature score of the panel of biomarkers is below a predetermined threshold indicating non-response, the subject is predicted to be a non-responder to anti-inflammatory treatment for IBD. is provided herein.

[0193] In another embodiment, a method for predicting a negative response to anti-inflammatory treatment for inflammatory bowel disease (IBD) in a subject diagnosed with IBD, comprising: a. STEAP4 metalloreductase (STEAP4) and CKLF-like MARVEL transmembrane domain-containing 2 (CMTM2), complement C5a receptor 1 (C5AR1), fibroblast growth factor 2 (FGF2), glycerol kinase (GK), hepatocyte growth factor (HGF), interleukin 1 receptor antagonist (IL1RN), leukocyte immunoglobulin-like receptor A2 (LILRA2), nicotinamide phosphoribosyltransferase (NAMPT), complement C5a receptor 1 (C5AR1), fibroblast growth factor 2 (FGF2), glycerol kinase (GK), hepatocyte growth factor (HGF), interleukin 1 receptor antagonist (IL1RN), leukocyte immunoglobulin-like receptor A2 (LILRA2), nicotinamide phosphoribosyltransferase (NAMPT), ​​​Growth factor 2 (FGF2), glycerol kinase (GK), hepatocyte growth factor (HGF), Interleukin 1 receptor antagonist (IL1RN), leukocyte immunoglobulin-like receptor A2 (LILRA2), nicotinamide phosphoribosyltransferase (NAMPT ), Pappalysin 1 (PAPPA), Synnuclein alpha (SNCA), Superox SOD2, mitochondrial (SOD2), and zinc finger BED-type containing and three biomarkers selected from the group consisting of ZBED3 (ZBED4). A set of probes capable of detecting a panel of antibodies is contacted with a sample from a subject. To be able to do so, b. Determine the baseline gene expression levels of the panel of biomarkers in the sample. To decide and c. Determining a signature score for each sample; Including, The signature score of the panel of biomarkers is below a predetermined threshold indicating non-response. the subject is predicted to be a non-responder to anti-inflammatory treatment for IBD if , provided herein.

[0194] In one embodiment, an anti-inflammatory treatment of inflammatory bowel disease (IBD) in a subject diagnosed with IBD. 1. A method for predicting a negative response to a testosterone-dependent steroid drug, comprising: a. STEAP4 metalloreductase (STEAP4) and CKLF-like MARVEL membrane Transmembrane domain-containing 2 (CMTM2), complement C5a receptor 1 (C5AR1), fibroblast proliferation Growth factor 2 (FGF2), glycerol kinase (GK), hepatocyte growth factor (HGF), Interleukin 1 receptor antagonist (IL1RN), leukocyte immunoglobulin-like receptor A2 (LILRA2), nicotinamide phosphoribosyltransferase (NAMPT ), pappalysin 1 (PAPPA), synuclein alpha (SNCA), superoxide dismutase 2, mitochondrial (SOD2), and zinc finger BED type containing 3 (ZBED3), a set of probes capable of detecting a panel of four biomarkers selected from the group consisting of is contacted with a sample from a subject, and b. determining the baseline gene expression levels of the panel of biomarkers in the sample and c. determining a signature score for each sample including where the signature score of the panel of biomarkers is below a predetermined threshold indicating non - response, the subject is predicted to be a non - responder to anti - inflammatory treatment for IBD, a method is provided herein.

[0195] In one embodiment, a method for predicting a negative response of a subject diagnosed with inflammatory bowel disease (IBD) to anti - inflammatory treatment for IBD, comprising a. STEAP4 metalloreductase (STEAP4) and CKLF - like MARVEL transmembrane domain - containing 2 (CMTM2), complement C5a receptor 1 (C5AR1), fibroblast growth factor 2 (FGF2), glycerol kinase (GK), hepatocyte growth factor (HGF), interleukin 1 receptor antagonist (IL1RN), leukocyte immunoglobulin - like receptor A2 (LILRA2), nicotinamide phosphoribosyltransferase (NAMPT ), pappalysin 1 (PAPPA), synuclein alpha (SNCA), superoxide dismutase 2, mitochondrial (SOD2), and zinc finger BED type containing 3 (ZBED3), Superoxide dismutase 2, mitochondrial (SOD2), and zinc finger BED type containing 3 (ZBED3) A set of probes capable of detecting a panel of 5 biomarkers selected from the group consisting of is contacted with a sample from a subject and b. determining the baseline gene expression levels of the panel of biomarkers in the sample and c. determining a signature score for each sample comprising wherein if the signature score of the panel of biomarkers is below a predetermined threshold indicating non - response, the subject is predicted to be a non - responder to anti - inflammatory treatment for IBD A method is provided herein

[0196] In other embodiments, a method of predicting a negative response to anti - inflammatory treatment for inflammatory bowel disease (IBD) in a subject diagnosed with IBD comprising a. STEAP4 metalloreductase (STEAP4) and CKLF - like MARVEL transmembrane domain containing 2 (CMTM2), complement C5a receptor 1 (C5AR1), fibroblast growth factor 2 (FGF2), glycerol kinase (GK), hepatocyte growth factor (HGF), interleukin 1 receptor antagonist (IL1RN), leukocyte immunoglobulin - like receptor A2 (LILRA2), nicotinamide phosphoribosyltransferase (NAMPT ), pappalysin 1 (PAPPA), synuclein alpha (SNCA), superoxide dismutase 2, mitochondrial (SOD2), and zinc finger BED type containing 3 (ZBED3) A panel of 6 biomarkers selected from the group consisting of ) Superoxide dismutase 2, mitochondrial (SOD2), and zinc finger BED type containing 3 (ZBED3) A panel of 6 biomarkers selected from the group consisting of ​​​A set of probes capable of detecting a panel of biomarkers is contacted with a sample from a subject and b. determining the baseline gene expression levels of the panel of biomarkers in the sample and c. determining a signature score for each sample comprising wherein when the signature score of the panel of biomarkers is below a predetermined threshold indicating non - response, the subject is predicted to be a non - responder to anti - inflammatory treatment for IBD A method as provided herein .

[0197] In one embodiment, a method for predicting a negative response of a subject diagnosed with inflammatory bowel disease (IBD) to anti - inflammatory treatment for IBD comprising a. a set of probes capable of detecting a panel of 7 biomarkers selected from the group consisting of STEAP4 metalloreductase (STEAP4), CKLF - like MARVEL transmembrane domain - containing 2 (CMTM2), complement C5a receptor 1 (C5AR1), fibroblast growth factor 2 (FGF2), glycerol kinase (GK), hepatocyte growth factor (HGF), interleukin 1 receptor antagonist (IL1RN), leukocyte immunoglobulin - like receptor A2 (LILRA2), nicotinamide phosphoribosyltransferase (NAMPT ), complement C5a receptor 1 (C5AR1), fibroblast growth factor 2 (FGF2), glycerol kinase (GK), hepatocyte growth factor (HGF), interleukin 1 receptor antagonist (IL1RN), leukocyte immunoglobulin - like receptor A2 (LILRA2), nicotinamide phosphoribosyltransferase (NAMPT ), pappalysin 1 (PAPPA), synuclein alpha (SNCA), superoxide dismutase 2, mitochondrial (SOD2), and zinc finger BED - type containing 3 (ZBED3) is contacted with a sample from a subject and b. determining the baseline gene expression levels of the panel of biomarkers in the sample and c. determining a signature score for each sample comprising A set of probes capable of detecting a panel of biomarkers is contacted with a sample from a subject and b. determining the baseline gene expression levels of the panel of biomarkers in the sample and c. determining a signature score for each sample; including wherein if the signature score of the panel of biomarkers is below a predetermined threshold indicating non - response, the subject is predicted to be a non - responder to anti - inflammatory treatment for IBD, a method is provided herein.

[0198] In another embodiment, a method for predicting a negative response of a subject diagnosed with inflammatory bowel disease (IBD) to anti - inflammatory treatment for IBD, comprising: a. detecting a set of probes capable of detecting a panel of 8 biomarkers selected from the group consisting of STEAP4 metalloreductase (STEAP4), CKLF - like MARVEL transmembrane domain - containing 2 (CMTM2), complement C5a receptor 1 (C5AR1), fibroblast growth factor 2 (FGF2), glycerol kinase (GK), hepatocyte growth factor (HGF), interleukin 1 receptor antagonist (IL1RN), leukocyte immunoglobulin - like receptor A2 (LILRA2), nicotinamide phosphoribosyltransferase (NAMPT ), pappalysin 1 (PAPPA), synuclein alpha (SNCA), superoxide dismutase 2, mitochondrial (SOD2), and zinc finger BED - type containing 3 (ZBED3) in a sample from the subject; b. determining the baseline gene expression levels of the panel of biomarkers in the sample; c. determining a signature score for each sample; including wherein if the signature score of the panel of biomarkers is below a predetermined threshold indicating non - response, the subject is predicted to be a non - responder to anti - inflammatory treatment for IBD; contacting the sample from the subject with the set of probes; b. determining the baseline gene expression levels of the panel of biomarkers in the sample; c. determining a signature score for each sample; including wherein if the signature score of the panel of biomarkers is below a predetermined threshold indicating non - response, ​​In the case where the subject is predicted to be a non-responder to anti-inflammatory treatment for IBD, a method is provided herein.

[0199] In one embodiment, a method for predicting a negative response to anti-inflammatory treatment for inflammatory bowel disease (IBD) in a subject diagnosed with IBD, comprising: a. detecting a set of probes capable of detecting a panel of 9 biomarkers selected from the group consisting of STEAP4 metalloreductase (STEAP4), CKLF-like MARVEL transmembrane domain-containing 2 (CMTM2), complement C5a receptor 1 (C5AR1), fibroblast growth factor 2 (FGF2), glycerol kinase (GK), hepatocyte growth factor (HGF), interleukin 1 receptor antagonist (IL1RN), leukocyte immunoglobulin-like receptor A2 (LILRA2), nicotinamide phosphoribosyltransferase (NAMPT ), pappalysin 1 (PAPPA), synuclein alpha (SNCA), superoxide dismutase 2, mitochondrial (SOD2), and zinc finger BED-type containing 3 (ZBED3) in a sample derived from the subject; [[ID=!4]]b. determining the baseline gene expression levels of the panel of biomarkers in the sample; c. determining a signature score for each sample; wherein when the signature score of the panel of biomarkers is below a predetermined threshold indicating non-response, the subject is predicted to be a non-responder to anti-inflammatory treatment for IBD, a method is ) provided herein.

[0200] ​​​​​​​​​​​In certain embodiments, an anti-inflammatory of inflammatory bowel disease (IBD) in a subject diagnosed with IBD A method for predicting a negative response to treatment, comprising: a. Detecting a set of probes capable of detecting a panel of biomarkers comprising STEAP4 metalloreductase (STEAP4), CKLF-like MARVEL transmembrane domain-containing 2 (CMTM2), complement C5a receptor 1 (C5AR1), fibroblast growth factor 2 (FGF2), glycerol kinase (GK), hepatocyte growth factor (HGF), interleukin 1 receptor antagonist (IL1RN), leukocyte immunoglobulin-like receptor A2 (LILRA2), nicotinamide phosphoribosyltransferase (NAMPT ), pregnancy-associated plasma protein A (PAPPA), alpha-synuclein (SNCA), superoxide dismutase 2, mitochondrial (SOD2), and zinc finger BED-type containing 3 (ZBED3), which are selected from the group consisting of 10 biomarkers, by contacting the set of probes with a sample derived from the subject; b. Determining the baseline gene expression levels of the panel of biomarkers in the sample; c. Determining a signature score for each sample; wherein when the signature score of the panel of biomarkers is below a predetermined threshold indicating non-response, the subject is predicted to be a non-responder to anti-inflammatory treatment for IBD, as provided herein. In one embodiment, a method for predicting a negative response to anti-inflammatory treatment of inflammatory bowel disease (IBD) in a subject diagnosed with IBD, comprising: a. Detecting a set of probes capable of detecting a panel of biomarkers comprising STEAP4 metalloreductase (STEAP4), CKLF-like MARVEL transmembrane domain-containing 2 (CMTM2), complement C5a receptor 1 (C5AR1), fibroblast growth factor 2 (FGF2), glycerol kinase (GK), hepatocyte growth factor (HGF), interleukin 1 receptor antagonist (IL1RN), leukocyte immunoglobulin-like receptor A2 (LILRA2), nicotinamide phosphoribosyltransferase (NAMPT ), pregnancy-associated plasma protein A (PAPPA), alpha-synuclein (SNCA), superoxide dismutase 2, mitochondrial (SOD2), and zinc finger BED-type containing 3 (ZBED3), which are selected from the group consisting of 10 biomarkers, by contacting the set of probes with a sample derived from the subject; b. Determining the baseline gene expression levels of the panel of biomarkers in the sample; c. Determining a signature score for each sample; wherein when the signature score of the panel of biomarkers is below a predetermined threshold indicating non-response, the subject is predicted to be a non-responder to anti-inflammatory treatment for IBD. The method is provided herein. In one embodiment, a method for predicting a negative response to anti-inflammatory treatment of inflammatory bowel disease (IBD) in a subject diagnosed with IBD, comprising: a. Detecting a set of probes capable of detecting a panel of biomarkers comprising STEAP4 metalloreductase (STEAP4), CKLF-like MARVEL transmembrane domain-containing 2 (CMTM2), complement C5a receptor 1 (C5AR1), fibroblast growth factor 2 (FGF2), glycerol kinase (GK), hepatocyte growth factor (HGF), interleukin 1 receptor antagonist (IL1RN), leukocyte immunoglobulin-like receptor A2 (LILRA2), nicotinamide phosphoribosyltransferase (NAMPT ), pregnancy-associated plasma protein A (PAPPA), alpha-synuclein (SNCA), superoxide dismutase 2, mitochondrial (SOD2), and zinc finger BED-type containing 3 (ZBED3), which are selected from the group consisting of 10 biomarkers, by contacting the set of probes with a sample derived from the subject; b. Determining the baseline gene expression levels of the panel of biomarkers in the sample; c. Determining a signature score for each sample;

[0201] In one embodiment, a method for predicting a negative response to anti-inflammatory treatment of inflammatory bowel disease (IBD) in a subject diagnosed with IBD, comprising: a. Detecting a set of probes capable of detecting a panel of biomarkers comprising STEAP4 metalloreductase (STEAP4), CKLF-like MARVEL transmembrane domain-containing 2 (CMTM2), complement C5a receptor 1 (C5AR1), fibroblast growth factor 2 (FGF2), glycerol kinase (GK), hepatocyte growth factor (HGF), interleukin 1 receptor antagonist (IL1RN), leukocyte immunoglobulin-like receptor A2 (LILRA2), nicotinamide phosphoribosyltransferase (NAMPT ), pregnancy-associated plasma protein A (PAPPA), alpha-synuclein (SNCA), superoxide dismutase 2, mitochondrial (SOD2), and zinc finger BED-type containing 3 (ZBED3), which are selected from the group consisting of 10 biomarkers, by contacting the set of probes with a sample derived from the subject; Six transmembrane epithelial antigen of prostate 4 (STEAP4), CKLF-like MARVEL transmembrane domain-containing 2 (CMTM2), complement C5a receptor 1 (C5AR1), fibroblast growth factor 2 (FGF2), glycerol kinase (GK), hepatocyte growth factor (HGF), interleukin 1 receptor antagonist (IL1RN), leukocyte immunoglobulin-like receptor A2 (LILRA2), nicotinamide phosphoribosyltransferase (NAMPT), pappalysin 1 (PAPPA), synuclein alpha (SNCA), superoxide dismutase 2, mitochondrial (SOD2), and zinc finger BED-type containing 3 (ZBED3), a set of probes capable of detecting a panel of biomarkers comprising 11 biomarkers selected from the group consisting of: is contacted with a sample from a subject, b. determining a baseline gene expression level of the panel of biomarkers in the sample, c. determining a signature score for each sample, wherein if the signature score of the panel of biomarkers is below a predetermined threshold indicating non-response, the subject is predicted to be a non-responder to anti-inflammatory treatment for IBD, is provided herein. In one embodiment, a method of predicting a negative response to anti-inflammatory treatment for inflammatory bowel disease (IBD) in a subject diagnosed with IBD, the method comprising: a. STEAP4 metalloreductase (STEAP4) and CKLF-like MARVEL transmembrane domain-containing ] 2 (CMTM2), complement C5a receptor 1 (C5AR1), fibroblast growth factor 2 (FGF 2), glycerol kinase (GK), hepatocyte growth factor (HGF), interleukin 1 receptor antagonist (IL1RN), leukocyte immunoglobulin-like receptor A2 (LILRA2), nicotinamide phosphoribosyltransferase (NAMPT), pappalysin 1 (PAPPA), synuclein alpha (SNCA), superoxide dismutase 2, mitochondrial (SOD2), and zinc finger BED-type containing 3 (ZBED3), a set of probes capable of detecting a panel of biomarkers comprising 11 biomarkers selected from the group consisting of:

[0202] is contacted with a sample from the subject, b. determining a baseline gene expression level of the panel of biomarkers in the sample, c. determining a signature score for each sample, wherein if the signature score of the panel of biomarkers is below a predetermined threshold indicating non-response, the subject is predicted to be a non-responder to anti-inflammatory treatment for IBD. a set of probes capable of detecting a panel of biomarkers comprising 11 biomarkers selected from the group consisting of: Interleukin 1 receptor antagonist (IL1RN), leukocyte immunoglobulin-like receptor A2 (LILRA2), nicotinamide phosphoribosyltransferase (NAMPT ), pappalysin 1 (PAPPA), synuclein alpha (SNCA), superoxide dismutase 2, mitochondrial (SOD2), and zinc finger BED-type containing 3 (ZBED3), a set of probes capable of detecting a panel of biomarkers comprising all biomarkers selected from the group consisting of is contacted with a sample from a subject, b. determining the baseline gene expression levels of the panel of biomarkers in the sample; c. determining a signature score for each sample; and wherein when the signature score of the panel of biomarkers is below a predetermined threshold indicating non-response, the subject is predicted to be a non-responder to anti-inflammatory treatment for IBD, a method is provided herein. In one embodiment, a method for predicting a negative response of a subject diagnosed with inflammatory bowel disease (IBD) to anti-inflammatory treatment for IBD, comprising: a. CKLF-like MARVEL transmembrane domain-containing 2 (CMTM2), complement C5a receptor

[0203] 1 (C5AR1), fibroblast growth factor 2 (FGF2), glycerol kinase (GK) , hepatocyte growth factor (HGF), interleukin 1 receptor antagonist (IL1RN) , leukocyte immunoglobulin-like receptor A2 (LILRA2), nicotinamide phosphoribosyl transferase (NAMPT), pappalysin 1 (PAPPA), synuclein alpha , and zinc finger BED-type containing 3 (ZBED3); Fascin (SNCA), superoxide dismutase 2, mitochondrial (SOD2), S TEAP4 metalloreductase (STEAP4), and zinc finger BED-type containing 3 (ZBED3), a probe set capable of detecting a panel of biomarkers, is contacted with a sample from a subject, and b. determining the baseline gene expression levels of the panel of biomarkers in the sample by quantitative polymerase chain reaction (qPCR); and c. determining a signature score for each sample, comprising wherein when the signature score of the panel of biomarkers is below a predetermined threshold indicating non-response, the subject is predicted to be a non-responder to anti-inflammatory treatment for IBD, a method is provided herein.

[0204] In some embodiments, the level of the predetermined threshold is selected from the group consisting of -3.9000 to 1.1000. All ranges from -3.9000 to 1.1000 are contemplated. In other embodiments, the level of the predetermined threshold is selected from the group consisting of -3.8500 to 1.0500. In certain embodiments, the level of the predetermined threshold is -3.8250 to 1.0250 selected from the group consisting of. In another embodiment, the level of the predetermined threshold is -3.8234 to 1.0000 selected from the group consisting of. In another embodiment, the level of the predetermined threshold is -3.8000 to 0.9000 selected from the group consisting of. In other embodiments, the predetermined threshold level is selected from the group consisting of -3.5000 to 0.6000. In other embodiments the level of the predetermined threshold is selected from the group consisting of -3.0000 to 0.2000 selected from the group consisting of ​. In another embodiment, the level of the predetermined threshold is selected from the group consisting of -2.5000 to 1.0000 . In other embodiments, the level of the predetermined threshold is selected from the group consisting of -2.5000 to 0.60 00. In other embodiments, the level of the predetermined threshold is selected from the group consisting of -2.50 00 to 0.2000. In another embodiment, the level of the predetermined threshold is selected from the group consisting of -1.5000 to 1.0000. In other embodiments, the predetermined threshold level is selected from the group consisting of -1.5000 to 0.6000. In other embodiments , the level of the predetermined threshold is selected from the group consisting of -1.5000 to 0.2000 . In one embodiment, the level of the predetermined threshold is -3.8234. In another embodiment , the level of the predetermined threshold is 1.0000.

[0205] . In certain embodiments, the threshold level of the signature score can be determined to represent the maximum sum of sensitivity and specificity. . In other embodiments, the threshold level of the signature score can be determined to represent the maximum positive predictive value. . In other embodiments, the threshold level of the signature score can be determined to represent the maximum negative predictive value.

[0206] . In certain embodiments, non-responder subjects have one or more of the characteristics selected from the group consisting of high disease burden, microbial dysbiosis, and high levels of inflammatory activity. In one embodiment, non-responder subjects have a high disease burden. . In another embodiment, non-responder subjects have microbial dysbiosis. . In one embodiment, non-responder subjects have gastrointestinal microbial dysbiosis. . In another embodiment, non-responder subjects have small intestine microbial dysbiosis. has dysbiosis. In another embodiment, the non-responder subject has a microbial dysbiosis of the large intestine. In other embodiments, the non-responder subject has a high level of inflammatory activity .

[0207] In certain embodiments, a method is provided for determining a treatment regimen for a subject diagnosed with inflammatory bowel disease (IBD). The method includes: (a) contacting a set of the isolated probes of the present invention with a sample obtained from a subject to detect a panel of biomarkers of the present invention in the sample; and (b) detecting a pattern of the panel of biomarkers that determines a treatment regimen appropriate for the subject. As an example, when detecting a pattern of the panel of biomarkers, a first pattern in which the baseline gene expression level of a specific biomarker gene is increased or decreased relative to a baseline gene expression level in a control, such as a healthy subject, or a predetermined threshold indicating a positive response or non-response to treatment is determined, one of ordinary skill in the art will understand that IBD can be successfully treated using a specific treatment regimen . When a second pattern in which the expression of a different set of biomarkers is increased or decreased is determined , one of ordinary skill in the art will understand that IBD can be successfully treated using a different treatment regimen . .

[0208] In certain embodiments, a method is provided for monitoring responsiveness to a treatment regimen in a subject being treated for inflammatory bowel disease (IBD). The method includes: (a) obtaining a first sample from a subject undergoing treatment for IBD; (b) obtaining a second sample from a subject undergoing treatment for IBD; (c) the isolated probes of the present invention ​​​​Contacting the set of probes with the sample to obtain a panel of biomarkers in the sample detecting, and (c) detecting a difference in the pattern of the panel of biomarkers between two samples, wherein detecting the difference in the pattern of the panel of biomarkers between the two samples indicates responsiveness to a treatment regimen in a subject including. As an example, a subject undergoing treatment for IBD exhibits a specific pattern of a panel of biomarkers of the present invention at the start of the treatment regimen. During the course of treatment, samples or multiple samples can be obtained from the subject, and these samples can be used to determine the difference in the pattern of the panel of biomarkers. In one embodiment, the pattern of the panel of biomarkers includes the gene expression levels of the biomarkers in the panel. An increase or decrease in the expression of the panel of biomarkers can indicate that the treatment regimen is successfully treating IBD. The expression levels of a second set of biomarkers can also be used to indicate whether the treatment regimen has been successful in treating IBD. In certain embodiments, when determining a treatment regimen or monitoring the response to a treatment regimen, multiple samples can be obtained from the subject, and the pattern of biomarkers can be determined for each sample obtained from the subject. Over time, monitoring the pattern of biomarkers that respond to the treatment regimen can provide the skilled person with the information necessary to determine the treatment regimen, maintain the same treatment regimen, or change the treatment regimen. For example, a subject undergoing treatment for IBD exhibits a specific pattern of a panel of biomarkers of the present invention at the start of the treatment regimen. During the course of treatment, samples or multiple samples can be obtained from the subject, and these samples can be used to determine the difference in the pattern of the panel of biomarkers. In one embodiment, the pattern of the panel of biomarkers includes the gene expression levels of the biomarkers in the panel. An increase or decrease in the expression of the panel of biomarkers can indicate that the treatment regimen is successfully treating IBD. The expression levels of a second set of biomarkers can also be used to indicate whether the treatment regimen has been successful in treating IBD. In certain embodiments, when determining a treatment regimen or monitoring the response to a treatment regimen, multiple samples can be obtained from the subject, and the pattern of biomarkers can be determined for each sample obtained from the subject. Over time, monitoring the pattern of biomarkers that respond to the treatment regimen can provide the skilled person with the information necessary to determine the treatment regimen, maintain the same treatment regimen, or change the treatment regimen. In one embodiment, the pattern of the panel of biomarkers includes the gene expression levels of the biomarkers in the panel. An increase or decrease in the expression of the panel of biomarkers can indicate that the treatment regimen is successfully treating IBD. The expression levels of a second set of biomarkers can also be used to indicate whether the treatment regimen has been successful in treating IBD. In certain embodiments, when determining a treatment regimen or monitoring the response to a treatment regimen, multiple samples can be obtained from the subject, and the pattern of biomarkers can be determined for each sample obtained from the subject.

[0209] Over time, monitoring the pattern of biomarkers that respond to the treatment regimen can provide the skilled person with the information necessary to determine the treatment regimen, maintain the same treatment regimen, or change the treatment regimen. For example, a subject undergoing treatment for IBD exhibits a specific pattern of a panel of biomarkers of the present invention at the start of the treatment regimen. During the course of treatment, samples or multiple samples can be obtained from the subject, and these samples can be used to determine the difference in the pattern of the panel of biomarkers. In one embodiment, the pattern of the panel of biomarkers includes the gene expression levels of the biomarkers in the panel. An increase or decrease in the expression of the panel of biomarkers can indicate that the treatment regimen is successfully treating IBD. The expression levels of a second set of biomarkers can also be used to indicate whether the treatment regimen has been successful in treating IBD. In certain embodiments, when determining a treatment regimen or monitoring the response to a treatment regimen, multiple samples can be obtained from the subject, and the pattern of biomarkers can be determined for each sample obtained from the subject. Over time, monitoring the pattern of biomarkers that respond to the treatment regimen can provide the skilled person with the information necessary to determine the treatment regimen, maintain the same treatment regimen, or change the treatment regimen.

[0210] In some embodiments, a subject diagnosed with inflammatory bowel disease (IBD) is administered an anti-IBD drug. A method for predicting response to inflammatory treatment, comprising administering one or more anti-inflammatory treatments for IBD. In a further embodiment, the present invention provides a method for treating a subject, the method further comprising administering to the subject a therapeutically effective amount of ... Anti-inflammatory treatments provided in the specification include aminosalicylates, corticosteroids, anti-tumor necrotic agents, These include tumor necrosis factor (TNF) agents, anti-integrin agents, JAK inhibitors, and anti-interleukin agents. In one embodiment, the anti-inflammatory treatment includes, but is not limited to, one or more aminosalicylic acid In one embodiment, the aminosalicylic acid is sulfasalazine. In one embodiment, the aminosalicylic acid is mesalamine. is olsalazine. In one embodiment, the aminosalicylic acid is balsalazide. In one embodiment, the anti-inflammatory treatment is one or more corticosteroids. In one embodiment, the corticosteroid is prednisone. In one embodiment, the corticosteroid is methylprednisolone. In one embodiment, the anti-inflammatory treatment is budesonide. The treatment is one or more anti-tumor necrosis factor (TNF) agents. In one embodiment, the anti-inflammatory agent is: In one embodiment, the anti-inflammatory agent is infliximab (Remicade). In one embodiment, the anti-inflammatory agent is golimumab (Simpson). i). In one embodiment, the anti-inflammatory treatment is one or more anti-integrin agents. In one embodiment, the anti-inflammatory agent is vedolizumab. In one embodiment, the anti-inflammatory treatment is one or more JAK inhibitors. In an embodiment, the JAK inhibitor is an inhibitor against one or more of the four JAK members: JAK1, JAK2, JAK 3, and TYK2. In one embodiment, the JAK inhibitor is filgotinib. In one embodiment, the JAK inhibitor is peficitinib . In one embodiment, the JAK inhibitor is tofacitinib (Xeljanz / Jakvinus ). In one embodiment, the JAK inhibitor is upadacitinib. In one embodiment , the anti-inflammatory treatment is one or more anti-interleukin agents. In some embodiments, the anti interleukin (IL) agents include anti-IL-1 agents, anti-IL-6 agents, anti-IL-10 agents, anti-IL-13 agents, anti-IL-17 agents, anti-IL-12 / 23 agents, or anti-IL-23 agents, among others, but are not limited thereto. In one embodiment, the anti-IL agent is BI6 55066. In one embodiment, the anti-IL agent is briakinumab. In one embodiment the anti-IL agent is guselkumab. In one embodiment, the anti-IL agent is tildrakizumab . In one embodiment, the anti-IL agent is ustekinumab (Stelara).

[0211] In some embodiments, non-responder subjects are identified as candidates for combination therapy. In certain embodiments, the combination therapy includes two or more treatments selected from the group consisting of anti-inflammatory treatment, antibiotics, immunomodulators, antidiarrheal agents, analgesics, iron supplementation, and calcium and vitamin D supplementation . In certain embodiments, the combination therapy includes administering an inhibitor of NKG2D to the subject .

[0212] In certain embodiments, the combination therapy includes using two or more anti-inflammatory drugs. Two Exemplary combination therapies with anti-inflammatory drugs include administration of aminosalicylate and corticosteroid, administration of aminosalicylate and anti-TNF agent, administration of aminosalicylate and JAK inhibitor, administration of aminosalicylate and anti-interleukin agent, administration of corticosteroid and anti-TNF agent, administration of corticosteroid and JAK inhibitor, administration of corticosteroid and anti-interleukin agent, administration of anti-TNF agent and JAK inhibitor, administration of anti-TNF agent and anti-interleukin agent, administration of JAK inhibitor and anti-interleukin agent, administration of anti-integrin agent and aminosalicylate, administration of anti-integrin agent and corticosteroid, administration of anti-integrin agent and anti-TNF agent, administration of anti-integrin agent and JAK inhibitor, and administration of anti-integrin agent and anti-interleukin agent to the same patient, but are not limited thereto. Administration to the same patient, administration of aminosalicylate and anti-TNF agent, administration of aminosalicylate and JAK inhibitor, administration of aminosalicylate and anti-interleukin agent, administration of corticosteroid and anti-TNF agent, administration of corticosteroid and JAK inhibitor, administration of corticosteroid and anti-interleukin agent, administration of anti-TNF agent and JAK inhibitor, administration of anti-TNF agent and anti-interleukin agent, administration of JAK inhibitor and anti-interleukin agent, administration of anti-integrin agent and aminosalicylate, administration of anti-integrin agent and corticosteroid, administration of anti-integrin agent and anti-TNF agent, administration of anti-integrin agent and JAK inhibitor, Administration of aminosalicylate and JAK inhibitor to the same patient, administration of aminosalicylate and anti-interleukin agent, administration of corticosteroid and anti-TNF agent, administration of corticosteroid and JAK inhibitor, administration of corticosteroid and anti-interleukin agent, administration of anti-TNF agent and JAK inhibitor, administration of anti-TNF agent and anti-interleukin agent, administration of JAK inhibitor and anti-interleukin agent, administration of anti-integrin agent and aminosalicylate, administration of anti-integrin agent and corticosteroid, administration of anti-integrin agent and anti-TNF agent, administration of anti-integrin agent and JAK inhibitor, Administration of aminosalicylate and anti-interleukin agent, administration of corticosteroid and anti-TNF agent, administration of corticosteroid and JAK inhibitor, administration of corticosteroid and anti-interleukin agent, administration of anti-TNF agent and JAK inhibitor, administration of anti-TNF agent and anti-interleukin agent, administration of JAK inhibitor and anti-interleukin agent, administration of anti-integrin agent and aminosalicylate, administration of anti-integrin agent and corticosteroid, administration of anti-integrin agent and anti-TNF agent, administration of anti-integrin agent and JAK inhibitor, Administration of corticosteroid and anti-TNF agent, administration of corticosteroid and JAK inhibitor, administration of corticosteroid and anti-interleukin agent, administration of anti-TNF agent and JAK inhibitor, administration of anti-TNF agent and anti-interleukin agent, administration of JAK inhibitor and anti-interleukin agent, administration of anti-integrin agent and aminosalicylate, administration of anti-integrin agent and corticosteroid, administration of anti-integrin agent and anti-TNF agent, administration of anti-integrin agent and JAK inhibitor, Administration of corticosteroid and JAK inhibitor, administration of corticosteroid and anti-interleukin agent, administration of anti-TNF agent and JAK inhibitor, administration of anti-TNF agent and anti-interleukin agent, administration of JAK inhibitor and anti-interleukin agent, administration of anti-integrin agent and aminosalicylate, administration of anti-integrin agent and corticosteroid, administration of anti-integrin agent and anti-TNF agent, administration of anti-integrin agent and JAK inhibitor, Administration of corticosteroid and anti-interleukin agent, administration of anti-TNF agent and JAK inhibitor, administration of anti-TNF agent and anti-interleukin agent, administration of JAK inhibitor and anti-interleukin agent, administration of anti-integrin agent and aminosalicylate, administration of anti-integrin agent and corticosteroid, administration of anti-integrin agent and anti-TNF agent, administration of anti-integrin agent and JAK inhibitor, Administration of anti-TNF agent and JAK inhibitor, administration of anti-TNF agent and anti-interleukin agent, administration of JAK inhibitor and anti-interleukin agent, administration of anti-integrin agent and aminosalicylate, administration of anti-integrin agent and corticosteroid, administration of anti-integrin agent and anti-TNF agent, administration of anti-integrin agent and JAK inhibitor, Administration of anti-TNF agent and anti-interleukin agent, administration of JAK inhibitor and anti-interleukin agent, administration of anti-integrin agent and aminosalicylate, administration of anti-integrin agent and corticosteroid, administration of anti-integrin agent and anti-TNF agent, administration of anti-integrin agent and JAK inhibitor, Administration of JAK inhibitor and anti-interleukin agent, administration of anti-integrin agent and aminosalicylate, administration of anti-integrin agent and corticosteroid, administration of anti-integrin agent and anti-TNF agent, administration of anti-integrin agent and JAK inhibitor, And administration of anti-integrin agent and anti-interleukin agent to the same patient, but are not limited thereto. These are not limited thereto.

[0213] In other embodiments, the combination therapy includes using one or more anti-inflammatory drugs in combination with one or more antibiotics. Exemplary combination therapies with one anti-inflammatory drug in combination with an antibiotic include administration of aminosalicylate and metronidazole, administration of corticosteroid and metronidazole, administration of anti-TNF agent and metronidazole, administration of anti-integrin agent and metronidazole, administration of JAK inhibitor and metronidazole, administration of anti-interleukin agent and metronidazole, administration of aminosalicylate and ciprofloxacin, Administration of aminosalicylate and metronidazole, administration of corticosteroid and metronidazole, administration of anti-TNF agent and metronidazole, administration of anti-integrin agent and metronidazole, administration of JAK inhibitor and metronidazole, administration of anti-interleukin agent and metronidazole, administration of aminosalicylate and ciprofloxacin, Administration of corticosteroid and metronidazole, administration of anti-TNF agent and metronidazole, administration of anti-integrin agent and metronidazole, administration of JAK inhibitor and metronidazole, administration of anti-interleukin agent and metronidazole, administration of aminosalicylate and ciprofloxacin, Administration of anti-TNF agent and metronidazole, administration of anti-integrin agent and metronidazole, administration of JAK inhibitor and metronidazole, administration of anti-interleukin agent and metronidazole, administration of aminosalicylate and ciprofloxacin, Administration of anti-integrin agent and metronidazole, administration of JAK inhibitor and metronidazole, administration of anti-interleukin agent and metronidazole, administration of aminosalicylate and ciprofloxacin, Administration of JAK inhibitor and metronidazole, administration of anti-interleukin agent and metronidazole, administration of aminosalicylate and ciprofloxacin, Administration of anti-interleukin agent and metronidazole, administration of aminosalicylate and ciprofloxacin, , administration of corticosteroids and ciprofloxacin to the same patient, administration of anti-TNF agents and ciprofloxacin to the same patient, administration of anti-integrin agents and ciprofloxacin to the same patient, administration of JAK inhibitors and ciprofloxacin to the same patient, and administration of anti-interleukin agents and ciprofloxacin to the same patient are included, but are not limited thereto. , administration of anti-TNF agents and ciprofloxacin to the same patient, administration of anti-integrin agents and ciprofloxacin to the same patient, administration of JAK inhibitors and ciprofloxacin to the same patient, and administration of anti-interleukin agents and ciprofloxacin to the same patient are included, but are not limited thereto. , administration of JAK inhibitors and ciprofloxacin to the same patient, and administration of anti-interleukin agents and ciprofloxacin to the same patient are included, but are not limited thereto. , and administration of anti-interleukin agents and ciprofloxacin to the same patient are included, but are not limited thereto.

[0214] In some embodiments, the combination therapy includes using one or more anti-inflammatory drugs in combination with one or more immunomodulatory agents. Exemplary combination therapies with one anti-inflammatory drug in combination with an immunomodulatory agent include administration of aminosalicylate and azathioprine (AZA) to the same patient, administration of corticosteroids and AZA to the same patient, administration of anti-TNF agents and AZA to the same patient, administration of anti-integrin agents and AZA to the same patient, administration of JAK inhibitors and AZA to the same patient, administration of anti-interleukin agents and AZA to the same patient, administration of aminosalicylate and cyclosporine to the same patient, administration of corticosteroids and cyclosporine to the same patient, administration of anti-TNF agents and cyclosporine to the same patient, administration of anti-integrin agents and cyclosporine to the same patient, administration of JAK inhibitors and cyclosporine to the same patient, administration of anti-interleukin agents and cyclosporine to the same patient, administration of aminosalicylate and 6-mercaptopurine (6MP) to the same patient, administration of corticosteroids and 6MP to the same patient, administration of anti-TNF agents and 6MP to the same patient, administration of anti-integrin agents and 6MP to the same patient, administration of JAK inhibitors and 6MP to the same patient, administration of anti-interleukin agents and 6MP to the same patient, administration of aminosalicylate and methotrexate to the same patient, administration of corticosteroids and methotrexate to the same patient. , administration of anti-TNF agents and AZA to the same patient, administration of anti-integrin agents and AZA to the same patient, administration of JAK inhibitors and AZA to the same patient, and administration of anti-interleukin agents and AZA to the same patient are included, but are not limited thereto. , administration of anti-TNF agents and AZA to the same patient, administration of anti-integrin agents and AZA to the same patient, administration of JAK inhibitors and AZA to the same patient, and administration of anti-interleukin agents and AZA to the same patient are included, but are not limited thereto. , administration of anti-TNF agents and AZA to the same patient, administration of anti-integrin agents and AZA to the same patient, administration of JAK inhibitors and AZA to the same patient, and administration of anti-interleukin agents and AZA to the same patient are included, but are not limited thereto. , administration of anti-integrin agents and AZA to the same patient, administration of JAK inhibitors and AZA to the same patient, and administration of anti-interleukin agents and AZA to the same patient are included, but are not limited thereto. , administration of anti-interleukin agents and AZA to the same patient are included, but are not limited thereto. , administration of corticosteroids and cyclosporine to the same patient, administration of anti-TNF agents and cyclosporine to the same patient, administration of anti-integrin agents and cyclosporine to the same patient, administration of JAK inhibitors and cyclosporine to the same patient, and administration of anti-interleukin agents and cyclosporine to the same patient are included, but are not limited thereto. , administration of anti-TNF agents and cyclosporine to the same patient, administration of anti-integrin agents and cyclosporine to the same patient, administration of JAK inhibitors and cyclosporine to the same patient, and administration of anti-interleukin agents and cyclosporine to the same patient are included, but are not limited thereto. , administration of anti-TNF agents and cyclosporine to the same patient, administration of anti-integrin agents and cyclosporine to the same patient, administration of JAK inhibitors and cyclosporine to the same patient, and administration of anti-interleukin agents and cyclosporine to the same patient are included, but are not limited thereto. , administration of anti-TNF agents and cyclosporine to the same patient, administration of anti-integrin agents and cyclosporine to the same patient, administration of JAK inhibitors and cyclosporine to the same patient, and administration of anti-interleukin agents and cyclosporine to the same patient are included, but are not limited thereto. , administration of corticosteroids and 6MP to the same patient, administration of anti-TNF agents and 6MP to the same patient, administration of anti-integrin agents and 6MP to the same patient, administration of JAK inhibitors and 6MP to the same patient, and administration of anti-interleukin agents and 6MP to the same patient are included, but are not limited thereto. , administration of anti-TNF agents and 6MP to the same patient, administration of anti-integrin agents and 6MP to the same patient, administration of JAK inhibitors and 6MP to the same patient, and administration of anti-interleukin agents and 6MP to the same patient are included, but are not limited thereto. , administration of anti-TNF agents and 6MP to the same patient, administration of anti-integrin agents and 6MP to the same patient, administration of JAK inhibitors and 6MP to the same patient, and administration of anti-interleukin agents and 6MP to the same patient are included, but are not limited thereto. , administration of anti-TNF agents and 6MP to the same patient, administration of anti-integrin agents and 6MP to the same patient, administration of JAK inhibitors and 6MP to the same patient, and administration of anti-interleukin agents and 6MP to the same patient are included, but are not limited thereto. ​administration of corticosteroids and methotrexate to the same patient; administration of corticosteroids and methotrexate to the same patient administration of anti-TNF agents and methotrexate to the same patient; administration of anti-integrin agents and methotrexate to the same patient; administration of methotrexate to the same patient; administration of a JAK inhibitor and methotrexate to the same patient; and administration of anti-interleukins and methotrexate to the same patient, Not limited to these.

[0215] In some embodiments, the combination therapy comprises one or more antibiotics in combination with one or more antibiotics. This includes using an immunomodulator in combination with an antibiotic. Exemplary combination therapies include administration of AZA and metronidazole to the same patient, cyclosporine, and cyclosporine. administration of 6MP and metronidazole to the same patient; administration of methotrexate and metronidazole to the same patient; AZA and Administration of ciprofloxacin to the same patient, administration of cyclosporine and ciprofloxacin to the same patient administration of 6MP and ciprofloxacin to the same patient; administration of a JAK inhibitor and ciprofloxacin to the same patient; administration of ciprofloxacin to the same patient, and methotrexate and ciprofloxacin Examples of suitable therapeutic agents include, but are not limited to, administration of a therapeutic agent to the same patient.

[0216] In some embodiments, the combination therapy includes one or more antibiotics and one or more anti-inflammatory drugs. This includes the use of one or more immunomodulatory agents in combination. Exemplary such combinations include: Examples include administration of anti-TNF agents, ciprofloxacin, and AZA in the same patient, and anti-IL agents. , metronidazole and 6MP administration to the same patient, JAKi, ciprofloxacin and Administration of ciclosporin to the same patient, aminosalicylate, metronidazole and methotrexate Administration of to the same patient, and corticosteroids, ciprofloxacin and AZ Administration to the same patient of is included, but is not limited thereto.

[0217] In some embodiments, the combination therapy includes using two or more antibiotics. In other embodiments, the combination therapy includes using two or more immunomodulators.

[0218] In other embodiments, the combination therapy includes using one or more anti-inflammatory drugs in combination with one or more antidiarrheal drugs In some embodiments, the combination therapy includes using one or more anti-inflammatory drugs in combination with one or more analgesics In other embodiments, the combination therapy includes using one or more anti-inflammatory drugs in combination with one or more iron supplements In some embodiments, the combination therapy includes using one or more anti-inflammatory drugs in combination with one or more calcium and vitamin D supplements

[0219] In other embodiments, the combination therapy includes using one or more antibiotics in combination with one or more antidiarrheal drugs In some embodiments, the combination therapy includes using one or more antibiotics in combination with one or more analgesics In other embodiments, the combination therapy includes using one or more antibiotics in combination with one or more iron supplements In some embodiments, the combination therapy includes using one or more antibiotics in combination with one or more calcium and vitamin D supplements

[0220] In other embodiments, the combination therapy includes using one or more immunomodulators in combination with one or more antidiarrheal drugs including using an agent. In some embodiments, the combination therapy comprises using one or more immunomodulatory agents in combination with one or more analgesics. In other embodiments, the combination therapy comprises using one or more immunomodulatory agents in combination with one or more iron supplements. In some embodiments, the combination therapy comprises using one or more immunomodulatory agents in combination with one or more calcium and vitamin D supplements. In some embodiments, the combination therapy comprises using one or more antidiarrheal agents in combination with one or more analgesics. In other embodiments, the combination therapy comprises using one or more antidiarrheal agents in combination with one or more iron supplements.

[0221] In some embodiments, the combination therapy comprises using one or more antidiarrheal agents in combination with one or more calcium and vitamin D supplements. In other embodiments, the combination therapy comprises using one or more analgesics in combination with one or more iron supplements. In some embodiments, the combination therapy comprises using one or more analgesics in combination with one or more calcium and vitamin D supplements. In some embodiments, the combination therapy comprises using one or more iron supplements in combination with one or more calcium and vitamin D supplements. In other embodiments, the combination therapy comprises using one or more analgesics in combination with one or more iron supplements. In some embodiments, the combination therapy comprises using one or more analgesics in combination with one or more calcium and vitamin D supplements. In some embodiments, the combination therapy comprises using one or more iron supplements in combination with one or more calcium and vitamin D supplements. In some embodiments, the combination therapy comprises using one or more iron supplements in combination with one or more calcium and vitamin D supplements. In other embodiments, the combination therapy comprises roles of granulocyte adhesion and extravasation, agranulocyte adhesion and extravasation, the osteoarthritis pathway, macrophages, fibroblasts and endothelial cells in rheumatoid arthritis, liver fibrosis and hepatic stellate cell activation, inhibition of matrix metalloproteinases, atherosclerotic signal transduction, bladder cancer signal transduction, and patterns in the recognition of bacteria and viruses.

[0222] In other embodiments, the combination therapy comprises roles of granulocyte adhesion and extravasation, agranulocyte adhesion and extravasation, the osteoarthritis pathway, macrophages, fibroblasts and endothelial cells in rheumatoid arthritis, liver fibrosis and hepatic stellate cell activation, inhibition of matrix metalloproteinases, atherosclerotic signal transduction, bladder cancer signal transduction, and patterns in the recognition of bacteria and viruses. In other embodiments, the combination therapy comprises roles of granulocyte adhesion and extravasation, agranulocyte adhesion and extravasation, the osteoarthritis pathway, macrophages, fibroblasts and endothelial cells in rheumatoid arthritis, liver fibrosis and hepatic stellate cell activation, inhibition of matrix metalloproteinases, atherosclerotic signal transduction, bladder cancer signal transduction, and patterns in the recognition of bacteria and viruses. [[ID=!36]]In other embodiments, the combination therapy comprises roles of granulocyte adhesion and extravasation, agranulocyte adhesion and extravasation, the osteoarthritis pathway, macrophages, fibroblasts and endothelial cells in rheumatoid arthritis, liver fibrosis and hepatic stellate cell activation, inhibition of matrix metalloproteinases, atherosclerotic signal transduction, bladder cancer signal transduction, and patterns in the recognition of bacteria and viruses. In other embodiments, the combination therapy comprises roles of granulocyte adhesion and extravasation, agranulocyte adhesion and extravasation, the osteoarthritis pathway, macrophages, fibroblasts and endothelial cells in rheumatoid arthritis, liver fibrosis and hepatic stellate cell activation, inhibition of matrix metalloproteinases, atherosclerotic signal transduction, bladder cancer signal transduction, and patterns in the recognition of bacteria and viruses. administering to a subject one or more agents that target one or more standard pathways selected from the group consisting of the role of pattern recognition receptors and HMGB1 signaling including.

[0223] In some embodiments, the combination therapy is granulocyte adhesion and leakage, agranulocyte adhesion and leakage out, the osteoarthritis pathway, macrophages, fibroblasts and endothelial cells in rheumatoid arthritis role, liver fibrosis and activation of hepatic stellate cells, inhibition of matrix metalloproteinases, atherosclerosis signaling, bladder cancer signaling, the role of pattern recognition receptors in the recognition of bacteria and viruses, and HMGB1 signaling, and one or more agents that target one or more standard pathways selected from the group consisting of using one or more anti-inflammatory drugs in combination. including. In other embodiments, the combination therapy comprises using one or more anti-inflammatory drugs in combination with one or more agents that target granulocyte adhesion and leakage. In certain embodiments, the combination therapy

[0224] comprises using one or more anti-inflammatory drugs in combination with one or more agents that target agranulocyte adhesion and leakage. In other embodiments, the combination therapy comprises using one or more anti-inflammatory drugs in combination with one or more agents that target the osteoarthritis pathway including. In some embodiments, the combination therapy comprises using one or more anti-inflammatory drugs in combination with one or more agents that target the role of macrophages, fibroblasts, and endothelial cells in rheumatoid arthritis including. In other embodiments, the combination therapy comprises using one or more anti-inflammatory drugs in combination with one or more agents that target liver fibrosis and activation of hepatic stellate cells. In other embodiments, including. In some embodiments, the combination therapy comprises using one or more anti-inflammatory drugs in combination with one or more agents that target the role of macrophages, fibroblasts, and endothelial cells in rheumatoid arthritis including. In other embodiments, the combination therapy comprises using one or more anti-inflammatory drugs in combination with one or more agents that target liver fibrosis and activation of hepatic stellate cells. In other embodiments, including. comprises using one or more anti-inflammatory drugs in combination with one or more agents that target liver fibrosis and activation of hepatic stellate cells. In other embodiments, The combination therapy involves using one or more anti-inflammatory agents in combination with one or more agents that target the inhibition of matrix metalloproteinases. In some embodiments, the combination therapy involves using one or more anti-inflammatory agents in combination with one or more agents that target atherosclerotic signaling. In other embodiments, the combination therapy involves using one or more anti-inflammatory agents in combination with one or more agents that target bladder cancer signaling. In certain embodiments, the combination therapy involves using one or more anti-inflammatory agents in combination with one or more agents that target the role of pattern recognition receptors in the recognition of bacteria and viruses. In other embodiments, the combination therapy involves using one or more anti-inflammatory agents in combination with one or more agents that target HMGB1 signaling. In other embodiments, the combination therapy involves using one or more anti-TNF agents in combination with one or more agents that target granulocyte adhesion and extravasation. In certain embodiments, the combination therapy involves using one or more anti-TNF agents in combination with one or more agents that target agranulocyte adhesion and extravasation. In other embodiments, the combination therapy involves using one or more anti-TNF agents in combination with one or more agents that target the osteoarthritis pathway.

[0225] In some embodiments, the combination therapy involves using one or more anti-TNF agents in combination with one or more agents that target the role of macrophages, fibroblasts, and endothelial cells in rheumatoid arthritis. In other embodiments, the combination therapy involves using one or more anti-TNF agents in combination with one or more agents that target liver fibrosis and the activation of hepatic stellate cells. In other embodiments, the combination therapy involves using one or more anti-TN F agents in combination with one or more agents that target the role of macrophages, fibroblasts, and endothelial cells in rheumatoid arthritis. In some embodiments, the combination therapy involves using one or more anti-TNF agents in combination with one or more agents that target the role of macrophages, fibroblasts, and endothelial cells in rheumatoid arthritis. In some embodiments, the combination therapy involves using one or more anti-TNF agents in combination with one or more agents that target the role of macrophages, fibroblasts, and endothelial cells in rheumatoid arthritis. In other embodiments, the combination therapy involves using one or more anti-TNF agents in combination with one or more agents that target liver fibrosis and the activation of hepatic stellate cells. In other embodiments, the combination therapy involves using one or more anti-TNF agents in combination with one or more agents that target liver fibrosis and the activation of hepatic stellate cells. In other embodiments, the combination therapy involves using one or more anti-TNF agents in combination with one or more agents that target liver fibrosis and the activation of hepatic stellate cells. In one form, the combination therapy comprises using one or more anti-TNF drugs in combination with one or more agents that target the inhibition of matrix metalloproteinases. In some embodiments , the combination therapy comprises using one or more anti-TNF drugs in combination with one or more agents that target atherosclerotic signaling. In other embodiments, the combination therapy comprises using one or more anti-TNF drugs in combination with one or more agents that target bladder cancer signaling. In certain embodiments, the combination therapy comprises using one or more anti-TNF drugs in combination with one or more agents that target the role of pattern recognition receptors in the recognition of bacteria and viruses. In other embodiments, the combination therapy comprises using one or more anti-TNF drugs in combination with one or more agents that target the role of HMGB1 signaling. In other embodiments, the combination therapy comprises using golimumab in combination with one or more agents that target granulocyte adhesion and extravasation. In certain embodiments, the combination therapy comprises using golimumab in combination with one or more

[0226] agents that target neutrophil adhesion and extravasation. In other embodiments, the combination therapy comprises using golimumab in combination with one or more agents that target the osteoarthritis pathway. In some embodiments, the combination therapy comprises using golimumab in combination with one or more agents that target the role of macrophages, fibroblasts, and endothelial cells in rheumatoid arthritis. In other embodiments, the combination therapy comprises using golimumab in combination with one or more agents that target hepatic fibrosis and the activation of hepatic stellate cells. In other embodiments, the combination therapy comprises using matrix metalloprotease In some embodiments, the combination therapy comprises using golimumab in combination with one or more agents that target the role of macrophages, fibroblasts, and endothelial cells in rheumatoid arthritis. In other embodiments, the combination therapy comprises using golimumab in combination with one or more agents that target hepatic fibrosis and the activation of hepatic stellate cells. In other embodiments, the combination therapy comprises using matrix metalloprotease In other embodiments, the combination therapy comprises using golimumab in combination with one or more agents that target hepatic fibrosis and the activation of hepatic stellate cells. In other embodiments, the combination therapy comprises using matrix metalloprotease In other embodiments, the combination therapy comprises using golimumab in combination with one or more agents that target hepatic fibrosis and the activation of hepatic stellate cells. In other embodiments, the combination therapy comprises using matrix metalloprotease Comprising using golimumab in combination with one or more agents targeting inhibition of zero. In some embodiments, the combination therapy comprises using golimumab in combination with one or more agents targeting atherosclerotic signaling. In other embodiments, the combination therapy comprises using golimumab in combination with one or more agents targeting bladder cancer signaling. In other embodiments, the combination therapy comprises using golimumab in combination with one or more agents targeting the role of pattern recognition receptors in the recognition of bacteria and viruses. In certain embodiments, the combination therapy comprises using golimumab in combination with one or more agents targeting HMGB1 signaling. In other embodiments, the combination therapy comprises using golimumab in combination with one or more agents targeting the role of pattern recognition receptors in the recognition of bacteria and viruses. In other embodiments, the combination therapy comprises using golimumab in combination with one or more agents targeting HMGB1 signaling. In other embodiments, the combination therapy comprises using one or more anti-IL agents in combination with one or more agents targeting granulocyte adhesion and extravasation.

[0227] In other embodiments, the combination therapy comprises using one or more anti-IL agents in combination with one or more agents targeting granulocyte adhesion and extravasation. In certain embodiments, the combination therapy comprises using one or more anti-IL agents in combination with one or more agents targeting agranulocyte adhesion and extravasation. In other embodiments, the combination therapy comprises using one or more anti-IL agents in combination with one or more agents targeting the osteoarthritis pathway. In some embodiments, the combination therapy comprises using one or more anti-IL agents in combination with one or more agents targeting the role of macrophages, fibroblasts, and endothelial cells in rheumatoid arthritis. In some embodiments, the combination therapy comprises using one or more anti-IL agents in combination with one or more agents targeting the role of macrophages, fibroblasts, and endothelial cells in rheumatoid arthritis. In other embodiments, the combination therapy comprises using one or more anti-IL agents in combination with one or more agents targeting the role of macrophages, fibroblasts, and endothelial cells in rheumatoid arthritis. In other embodiments, the combination therapy comprises using one or more anti-IL agents in combination with one or more agents targeting the role of macrophages, fibroblasts, and endothelial cells in rheumatoid arthritis. In other embodiments, the combination therapy comprises using one or more anti-IL agents in combination with one or more agents targeting liver fibrosis and activation of hepatic stellate cells. In other embodiments, the combination therapy comprises using one or more anti-IL agents in combination with one or more agents targeting liver fibrosis and activation of hepatic stellate cells. In other embodiments, the combination therapy comprises using one or more anti-IL agents in combination with one or more agents targeting inhibition of matrix metalloproteinases. including using one or more anti-IL drugs. In some embodiments, the combination therapy includes using one or more anti-IL drugs in combination with one or more agents that target atherosclerotic signaling . In other embodiments, the combination therapy includes using one or more anti-IL drugs in combination with one or more agents that target bladder cancer signaling . In certain embodiments, the combination therapy includes using one or more anti-IL drugs in combination with one or more agents that target the role of pattern recognition receptors in the recognition of bacteria and viruses . In other embodiments, the combination therapy includes using one or more anti-IL drugs in combination with one or more agents that target HMGB1 signaling . In other embodiments, the combination therapy includes using ustekinumab in combination with one or more agents that target granulocyte adhesion and extravasation . In certain embodiments, the combination therapy includes using ustekinumab in combination with one or more agents that target non-granulocyte adhesion and extravasation . In other embodiments, the combination therapy includes using ustekinumab in combination with one or more agents that target the osteoarthritis pathway

[0228] . In some embodiments, the combination therapy includes using ustekinumab in combination with one or more agents that target the role of macrophages, fibroblasts, and endothelial cells in rheumatoid arthritis . In other embodiments, the combination therapy includes using ustekinumab in combination with one or more agents that target liver fibrosis and the activation of hepatic stellate cells . In other embodiments, the combination therapy includes using ustekinumab in combination with one or more agents that target the inhibition of matrix metalloproteinases . In other embodiments, the combination therapy includes using ustekinumab in combination with one or more agents that target the role of macrophages, fibroblasts, and endothelial cells in rheumatoid arthritis . In some embodiments, the combination therapy includes using ustekinumab in combination with one or more agents that target the role of macrophages, fibroblasts, and endothelial cells in rheumatoid arthritis . In other embodiments, the combination therapy includes using ustekinumab in combination with one or more agents that target the role of macrophages, fibroblasts, and endothelial cells in rheumatoid arthritis . In other embodiments, the combination therapy includes using ustekinumab in combination with one or more agents that target the role of macrophages, fibroblasts, and endothelial cells in rheumatoid arthritis . In other embodiments, the combination therapy includes using ustekinumab in combination with one or more agents that target liver fibrosis and the activation of hepatic stellate cells . In other embodiments, the combination therapy includes using ustekinumab in combination with one or more agents that target the inhibition of matrix metalloproteinases . In other embodiments, the combination therapy includes using ustekinumab in combination with one or more agents that target the inhibition of matrix metalloproteinases including using. In some embodiments, the combination therapy includes using ustekinumab in combination with one or more agents that target atherosclerotic signaling pathways. In other embodiments, the combination therapy includes using ustekinumab in combination with one or more agents that target bladder cancer signaling pathways. In certain embodiments, the combination therapy includes using ustekinumab in combination with one or more agents that target the role of pattern recognition receptors in the recognition of bacteria and viruses pathways. In other embodiments, the combination therapy includes using ustekinumab in combination with one or more agents that target HMGB1 signaling pathways. In other embodiments, the combination therapy includes using one or more JAK inhibitors in combination with one or more agents that target granulocyte adhesion and extravasation. In certain embodiments, the combination therapy includes using one or more JAK inhibitors in combination with one or more agents that target neutrophil adhesion and extravasation. In other embodiments, the combination therapy includes using one or more JAK inhibitors in combination with one or more agents that target the osteoarthritis pathway. In some embodiments, the combination therapy includes using one or more JAK inhibitors in combination with one or more agents that target the role of macrophages, fibroblasts, and endothelial cells in rheumatoid arthritis pathways. In other embodiments, the combination therapy includes using one or more JAK inhibitors in combination with one or more agents that target liver fibrosis and hepatic stellate cell activation pathways. In other embodiments, the combination therapy includes using one or more JAK inhibitors in combination with one or more agents that target the inhibition of matrix metalloproteinases. In some

[0229] embodiments, the combination therapy includes using one or more JAK inhibitors in combination with one or more agents that target the role of macrophages, fibroblasts, and endothelial cells in rheumatoid arthritis. In other embodiments, the combination therapy includes using one or more JAK inhibitors in combination with one or more agents that target liver fibrosis and hepatic stellate cell activation pathways. In certain embodiments, the combination therapy includes using one or more JAK inhibitors in combination with one or more agents that target the role of macrophages, fibroblasts, and endothelial cells in rheumatoid arthritis. In other embodiments, the combination therapy includes using one or more JAK inhibitors in combination with one or more agents that target liver fibrosis and hepatic stellate cell activation pathways. In other embodiments, the combination therapy includes using one or more JAK inhibitors in combination with one or more agents that target the role of macrophages, fibroblasts, and endothelial cells in rheumatoid arthritis. In other embodiments, the combination therapy includes using one or more JAK inhibitors in combination with one or more agents that target liver fibrosis and hepatic stellate cell activation pathways. In other embodiments, the combination therapy includes using one or more JAK inhibitors in combination with one or more agents that target the role of macrophages, fibroblasts, and endothelial cells in rheumatoid arthritis. In other embodiments, the combination therapy includes using one or more JAK inhibitors in combination with one or more agents that target liver fibrosis and hepatic stellate cell activation pathways. In some embodiments, the combination therapy includes using one or more JAK inhibitors in combination with one or more agents that target the role of macrophages, fibroblasts, and endothelial cells in rheumatoid arthritis. In other embodiments, the combination therapy includes using one or more JAK inhibitors in combination with one or more agents that target liver fibrosis and hepatic stellate cell activation pathways. In some embodiments, the combination therapy includes using one or more JAK inhibitors in combination with one or more agents that target the role of macrophages, fibroblasts, and endothelial cells in rheumatoid arthritis. In other embodiments, the combination therapy includes using one or more JAK inhibitors in combination with one or more agents that target liver fibrosis and hepatic stellate cell activation pathways. In other embodiments, the combination therapy includes using one or more JAK inhibitors in combination with one or more agents that target liver fibrosis and hepatic stellate cell activation pathways. In other embodiments, the combination therapy includes using one or more JAK inhibitors in combination with one or more agents that target liver fibrosis and hepatic stellate cell activation pathways. In other embodiments, the combination therapy includes using one or more JAK inhibitors in combination with one or more agents that target the inhibition of matrix metalloproteinases. In some embodiments, the combination therapy includes using one or more JAK inhibitors in combination with one or more agents that target the inhibition of matrix metalloproteinases. In some embodiments, the combination therapy includes using one or more JAK inhibitors in combination with one or more agents that target the inhibition of matrix metalloproteinases. In some In an embodiment, the combination therapy comprises using one or more JAK inhibitors in combination with one or more agents that target atherosclerotic signaling. In other embodiments, the combination therapy comprises using one or more JAK inhibitors in combination with one or more agents that target bladder cancer signaling. In certain embodiments, the combination therapy comprises using one or more JAK inhibitors in combination with one or more agents that target the role of pattern recognition receptors in the recognition of bacteria and viruses. In other embodiments, the combination therapy

[0230] comprises using one or more JAK inhibitors in combination with one or more agents that target HMGB1 signaling. In other embodiments, the combination therapy comprises using one or more antibiotics in combination with one or more agents that target one or more canonical pathways selected from the group consisting of granulocyte adhesion and extravasation, agranulocyte adhesion and extravasation, the osteoarthritis pathway, the role of macrophages, fibroblasts and endothelial cells in rheumatoid arthritis, hepatic fibrosis and activation of hepatic stellate cells, inhibition of matrix metalloproteinases, atherosclerotic signaling, bladder cancer signaling, the role of pattern recognition receptors in the recognition of bacteria and viruses, and HMGB1 signaling. In an embodiment, the combination therapy uses one or more antibiotics in combination with one or more agents that target the roles of macrophages, fibroblasts, and endothelial cells in rheumatoid arthritis. In other embodiments, the combination therapy includes using one or more antibiotics in combination with one or more agents that target hepatic fibrosis and the activation of hepatic stellate cells. In other embodiments, the combination therapy includes using one or more antibiotics in combination with one or more agents that target the inhibition of matrix metalloproteinases. In some embodiments, the combination therapy includes using one or more antibiotics in combination with one or more agents that target atherosclerotic signaling. In other embodiments, the combination therapy includes using one or more antibiotics in combination with one or more agents that target bladder cancer signaling. In certain embodiments, the combination therapy includes using one or more antibiotics in combination with one or more agents that target the role of pattern recognition receptors in the recognition of bacteria and viruses. In other embodiments, the combination therapy includes using one or more antibiotics in combination with one or more agents that target HMGB1 signaling.

[0231] In certain embodiments, the combination therapy is selected from the group consisting of granulocyte adhesion and extravasation, agranulocyte adhesion and extravasation, the osteoarthritis pathway, the roles of macrophages, fibroblasts, and endothelial cells in rheumatoid arthritis, hepatic fibrosis and the activation of hepatic stellate cells, the inhibition of matrix metalloproteinases, atherosclerotic signaling, bladder cancer signaling, the role of pattern recognition receptors in the recognition of bacteria and viruses, and HMGB1 signaling. <s Using one or more immunomodulatory agents in combination with one or more agents that target the above standard pathway including. In other embodiments, the combination therapy includes using one or more immunomodulatory agents in combination with one or more agents that target granulocyte adhesion and leakage. In certain embodiments the combination therapy includes using one or more immunomodulatory agents in combination with one or more agents that target agranulocyte adhesion and leakage. In certain embodiments the combination therapy includes using one or more immunomodulatory agents in combination with one or more agents that target macrophage, fibroblast and endothelial cell roles in rheumatoid arthritis. In other embodiments, the combination therapy includes using one or more immunomodulatory agents in combination with one or more agents that target the osteoarthritis pathway including. In some embodiments, the combination therapy includes using one or more immunomodulatory agents in combination with one or more agents that target the roles of macrophages, fibroblasts and endothelial cells in rheumatoid arthritis. In other embodiments, the combination therapy includes using one or more immunomodulatory agents in combination with one or more agents that target hepatic fibrosis and hepatic stellate cell activation including. In other embodiments, the combination therapy includes using one or more immunomodulatory agents in combination with one or more agents that target the inhibition of matrix metalloproteinases including. In some embodiments, the combination therapy includes using one or more immunomodulatory agents in combination with one or more agents that target atherosclerotic signaling including. In other embodiments, the combination therapy includes using one or more immunomodulatory agents in combination with one or more agents that target bladder cancer signaling including. In other embodiments, the combination therapy includes using one or more immunomodulatory agents in combination with one or more agents that target the role of pattern recognition receptors in the recognition of bacteria and viruses including. In some embodiments, the combination therapy includes using one or more immunomodulatory agents in combination with one or more agents that target HMGB1 signaling including. In other embodiments, the combination therapy includes using one or more immunomodulatory agents in combination with one or more agents that target the role of pattern recognition receptors in the recognition of bacteria and viruses including. In other embodiments, the combination therapy includes using one or more immunomodulatory agents in combination with one or more agents that target HMGB1 signaling including. In certain embodiments, the combination therapy includes using one or more immunomodulatory agents in combination with one or more agents that target the role of pattern recognition receptors in the recognition of bacteria and viruses including. In other embodiments, the combination therapy includes using one or more immunomodulatory agents in combination with one or more agents that target HMGB1 signaling including. In other embodiments, the combination therapy includes using one or more immunomodulatory agents in combination with one or more agents that target the role of pattern recognition receptors in the recognition of bacteria and viruses including. In other embodiments, the combination therapy includes using one or more immunomodulatory agents in combination with one or more agents that target HMGB1 signaling including. In other embodiments, the combination therapy includes using one or more immunomodulatory agents in combination with one or more agents that target HMGB1 signaling 。

[0232] In another aspect, provided is a method of treating, managing, and / or preventing inflammatory bowel disease (IBD), comprising administering to a patient in need of such treatment, management, or prevention a therapeutically or prophylactically effective amount of an anti-inflammatory treatment for IBD, such as an anti-tumor necrosis factor (TNF ) agent. In one embodiment, the method is a method of treating an inflammatory disease or related disorder. In one embodiment, the method is a method of managing an inflammatory disease or related disorder. In one embodiment, the method is a method of preventing an inflammatory disease or related disorder. In one embodiment, the inflammatory bowel disease (IBD) is Crohn's disease. In one embodiment, the inflammatory bowel disease (IBD) is ulcerative colitis. In some embodiments, provided herein is a method of treating a subject diagnosed with inflammatory bowel disease (IBD) with one or more of the anti-inflammatory treatments provided herein. In one embodiment of the various methods provided herein, the method comprises administering one or more anti-inflammatory treatments to a subject diagnosed with inflammatory bowel disease (IBD). In another embodiment of the various methods provided herein, the method comprises administering one or more anti-inflammatory treatments to a subject determined to be likely to respond to anti-inflammatory treatment using the methods provided herein. Accordingly, in other embodiments, provided is a method of treating a subject diagnosed with inflammatory bowel disease (IBD), comprising: (a) predicting the response of the subject to an anti-inflammatory treatment for IBD, wherein:

[0233] (i) CKLF-like MARVEL transmembrane domain-containing 2 (CMTM2), complement C5a receptor one or more of the anti-inflammatory treatments provided herein. In one embodiment of the various methods provided herein, the method comprises administering one or more anti-inflammatory treatments to a subject diagnosed with inflammatory bowel disease (IBD). In another embodiment of the various methods provided herein, the method comprises administering one or more anti-inflammatory treatments to a subject determined to be likely to respond to anti-inflammatory treatment using the methods provided herein. Accordingly, in other embodiments, provided is a method of treating a subject diagnosed with inflammatory bowel disease (IBD), comprising: (a) predicting the response of the subject to an anti-inflammatory treatment for IBD, wherein:

[0234] (i) CKLF-like MARVEL transmembrane domain-containing 2 (CMTM2), complement C5a receptor is a method of treating a subject diagnosed with inflammatory bowel disease (IBD), comprising: (a) predicting the response of the subject to an anti-inflammatory treatment for IBD, Complement C5a receptor 1 (C5AR1), fibroblast growth factor 2 (FGF2), glycerol kinase (GK ), hepatocyte growth factor (HGF), interleukin 1 receptor antagonist (IL1RN ), leukocyte immunoglobulin-like receptor A2 (LILRA2), nicotinamide phosphoribosyl transferase (NAMPT), pappalysin 1 (PAPPA), synuclein alpha (SNCA), superoxide dismutase 2, mitochondrial (SOD2), STEAP4 metalloreductase (STEAP4), and zinc finger BED-type containing 3 (ZBED3 ), and detecting a panel of biomarkers comprising 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 , 11, 12, or 13 biomarkers selected from the group consisting of , by contacting a set of probes capable of detecting the panel of biomarkers with a sample from a subject, and (ii) determining a pattern of the panel of biomarkers, wherein the pattern of the panel of biomarkers predicts a response to anti-inflammatory treatment in the subject, and b. administering to the subject a therapeutically effective amount of one or more anti-inflammatory therapeutic agents, is provided herein. In some embodiments, a method of treating a subject diagnosed with inflammatory bowel disease (IBD), comprising

[0235] a. predicting the response of the subject to anti-inflammatory treatment of IBD, wherein (i) STEAP4 metalloreductase (STEAP4) and CKLF-like MARVEL transmembrane domain-containing 2 (CMTM2), complement C5a receptor 1 (C5AR1), fibroblast growth factor 2 (FGF2), glycerol kinase (GK), hepatocyte growth factor (HGF), complement C5a receptor 1 (C5AR1), fibroblast growth factor 2 (FGF2), glycerol kinase (GK ), hepatocyte growth factor (HGF), interleukin 1 receptor antagonist (IL1RN Interleukin 1 receptor antagonist (IL1RN), leukocyte immunoglobulin-like receptor A2 (LILRA2), nicotinamide phosphoribosyltransferase (NAMPT), pappalysin 1 (PAPPA), synuclein alpha (SNCA), superoxide dismutase 2, mitochondrial (SOD2), and zinc finger BED-type containing 3 (ZBED3) from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 1 0, 11, or 12 biomarkers and detecting a panel of biomarkers comprising the same, contacting a set of probes with a sample derived from a subject, (ii) determining a pattern of the panel of biomarkers, wherein the pattern of the panel of biomarkers predicts a response to anti-inflammatory treatment in the subject, predicting, and b. administering to the subject a therapeutically effective amount of one or more anti-inflammatory therapeutic agents, is provided herein. (ii) determining a pattern of the panel of biomarkers, comprising, wherein the pattern of the panel of biomarkers predicts a response to anti-inflammatory treatment in the subject, predicting, and b. administering to the subject a therapeutically effective amount of one or more anti-inflammatory therapeutic agents, is provided herein. In another embodiment, a method of treating a subject determined to be likely non-responsive to anti-inflammatory treatment of IBD with one or more of the anti-inflammatory treatments is provided herein.

[0236] In one embodiment of the various methods provided herein, the method comprises administering one or more anti-inflammatory treatments to a subject determined to be likely non-responsive to anti-inflammatory treatment using the methods provided herein. Accordingly, in another embodiment, a method of treating a subject diagnosed with inflammatory bowel disease (IBD) is provided, wherein the method comprises: a. predicting that the subject is a non-responder to anti-inflammatory treatment of IBD, comprising administering one or more anti-inflammatory treatments to the subject.

[0237] In one embodiment of the various methods provided herein, the method comprises administering one or more anti-inflammatory treatments to a subject determined to be likely non-responsive to anti-inflammatory treatment using the methods provided herein. Accordingly, in another embodiment, a method of treating a subject diagnosed with inflammatory bowel disease (IBD) is provided, wherein the method comprises: hand, (i) CKLF-like MARVEL transmembrane domain-containing 2 (CMTM2), complement C5a receptor C5AR1 (C5AR1), fibroblast growth factor 2 (FGF2), glycerol kinase (GK ), hepatocyte growth factor (HGF), interleukin-1 receptor antagonist (IL1RN ), leukocyte immunoglobulin-like receptor A2 (LILRA2), nicotinamide phosphoribosyl NAMPT, paparzyme 1 (PAPPA), synnuclein A Lufa (SNCA), superoxide dismutase 2, mitochondrial (SOD2), STEAP4 metalloreductase (STEAP4) and zinc finger BED type containing 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 selected from the group consisting of ZBED3 Detecting a panel of biomarkers containing 11, 12, or 13 biomarkers contacting a set of probes capable of detecting the above-mentioned mutations with a sample from a subject; (ii) the baseline gene expression levels of the panel of biomarkers in the sample; determining the rule; (iii) determining a signature score for each sample; and Including, The signature score of the panel of biomarkers is below a predetermined threshold indicating non-response. If the subject is predicted to be a non-responder to anti-inflammatory treatment for IBD, And, b. administering to the subject a therapeutically effective amount of one or more anti-inflammatory therapeutic agents. Methods are provided herein, including:

[0238] In some embodiments, a method of treating a subject diagnosed with inflammatory bowel disease (IBD) And, a. predict that the subject will be a non-responder to anti-inflammatory treatment for IBD hand, (i) STEAP4 metalloreductase (STEAP4) and CKLF-like MARVEL Transmembrane domain-containing 2 (CMTM2), complement C5a receptor 1 (C5AR1), fibroblasts Growth factor 2 (FGF2), glycerol kinase (GK), hepatocyte growth factor (HGF), Interleukin 1 receptor antagonist (IL1RN), leukocyte immunoglobulin-like receptor Lipoprotein A2 (LILRA2), nicotinamide phosphoribosyltransferase (NAMP T), paparzyme 1 (PAPPA), synnuclein alpha (SNCA), superoxide oxide dismutase 2, mitochondrial (SOD2), and zinc finger BED-type 1, 2, 3, 4, 5, 6, 7, 8, 9, 1 selected from the group consisting of ZBED3 Detecting a panel of biomarkers comprising 0, 11, or 12 biomarkers contacting a set of probes capable of: (ii) the baseline gene expression levels of the panel of biomarkers in the sample; determining the rule; (iii) determining a signature score for each sample; and Including, The signature score of the panel of biomarkers is below a predetermined threshold indicating non-response. If the subject is predicted to be a non-responder to anti-inflammatory treatment for IBD, And, b. administering to the subject a therapeutically effective amount of one or more anti-inflammatory therapeutic agents. Methods are provided herein, including:

[0239] In further embodiments, the biomarkers for the methods of treating a subject provided herein are The car panel includes CMTM2, C5AR1, FGF2, GK, HGF, IL1RN, and LI LRA2, NAMPT, PAPPA, SNCA, SOD2, STEAP4, and ZBED In some embodiments, the sample is collected before the subject is treated with the anti-inflammatory treatment. In certain embodiments, the probes provided herein are aptamers, antibodies, In one embodiment, the protease is selected from the group consisting of an affibody, a peptide, and a nucleic acid. In other embodiments, the probe is a nucleic acid. SEQ ID NO: 20, SEQ ID NO: 23, SEQ ID NO: 26, SEQ ID NO: 29, SEQ ID NO: 32, SEQ ID NO: 3 5, SEQ ID NO: 38, SEQ ID NO: 41, SEQ ID NO: 44, SEQ ID NO: 47, and SEQ ID NO: 50 In light of the teachings and guidance provided herein, one of ordinary skill in the art will be able to The disclosure in the document provides a method for administering to a subject diagnosed with inflammatory bowel disease (IBD) an anti-inflammatory treatment for IBD. a method of treating a subject with a probe or set of probes as disclosed above, It is understood that the present invention is intended to include methods that involve contacting a sample from a body It would be.

[0240] In some embodiments, the pattern of a panel of biomarkers provided herein is (a) determining the baseline gene expression levels of the panel of biomarkers in the subject; and (b) determining a signature score for each sample. In certain embodiments, gene expression levels are measured using quantitative polymerase chain reaction (qPCR). In another embodiment, the qPCR primers are determined by SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34, SEQ ID NO: 35, SEQ ID NO: 36, SEQ ID NO: 37, SEQ ID NO: 38, SEQ ID NO: 39, SEQ ID NO: 40, SEQ ID NO: 41 No. 16, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 24, selected from the group consisting of SEQ ID NO: 25, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 33, SEQ ID NO: 34, SEQ ID NO: 36, SEQ ID NO: 37, SEQ ID NO: 39, SEQ ID NO: 40, SEQ ID NO: 42, SEQ ID NO: 43, SEQ ID NO: 45, SEQ ID NO: 46, SEQ ID NO: 48, SEQ ID NO: 49, SEQ NO: 51, and SEQ ID NO: 52. In view of the teachings and guidelines provided herein, one of ordinary skill in the art will understand that the disclosure herein is a method of treating a subject diagnosed with inflammatory bowel disease (IBD) by anti-inflammatory treatment of IBD, which includes determining a pattern of a panel of biomarkers using any one of the above techniques.

[0241] In a further embodiment, the predicted non-responder subject is identified as a candidate for combination therapy. In another aspect, a method of treating a subject diagnosed with inflammatory bowel disease (IBD) includes predicting that the subject is a non-responder to anti-inflammatory treatment of IBD and administering to the subject a combination therapy including two or more treatments selected from the group consisting of anti-inflammatory treatment, antibiotics, immunomodulators, antidiarrheals, analgesics, iron supplementation, and calcium and vitamin D supplementation. In a further embodiment, the combination therapy targets granulocyte adhesion and extravasation, agranulocyte adhesion and extravasation, the osteoarthritis pathway, the role of macrophages, fibroblasts and endothelial cells in rheumatoid arthritis, liver fibrosis and activation of administering to a subject one or more agents that target one or more canonical pathways selected from the group consisting of including. In view of the teachings and guidance provided herein, one of ordinary skill in the art will understand that the disclosure herein is intended to include methods of treating predicted non-responder subjects with various combinations of one or more of the above treatments. will understand.

[0242] In some embodiments, a method of treating a subject diagnosed with inflammatory bowel disease (IBD) further comprising administering to the subject one or more of the anti-inflammatory treatments for IBD is provided herein. In further embodiments, the anti-inflammatory treatment provided herein is amino salicylic acid, corticosteroids, anti-tumor necrosis factor (TNF) agents, anti-integrin agents, JAK inhibitors, and anti-interleukin agents, including but not limited to these. In one embodiment, the anti-inflammatory treatment is one or more amino salicylic acids. In one embodiment, the amino salicylic acid is sulfasalazine. In one embodiment, the amino salicylic acid is mesalazine. In one embodiment, the amino salicylic acid is olsalazine. In one embodiment, the amino salicylic acid is balsalazide. In one embodiment, the anti-inflammatory treatment is one or more corticosteroids. In one embodiment, the corticosteroid is prednisone. In one embodiment, the corticosteroid is prednisolone. In one embodiment, the corticosteroid is methylprednisolone. In one embodiment, the anti-inflammatory treatment is budesonide. In one embodiment, the anti-inflammatory treatment is one or more anti-tumor necrosis factor ( TNF) agents. In one embodiment, the anti-inflammatory agent is infliximab (Remicade ). In one embodiment, the anti-inflammatory agent is adalimumab (Humira). In one embodiment, TNF) agents. In one embodiment, the anti-inflammatory agent is infliximab (Remicade ) is. In one embodiment, the anti-inflammatory agent is adalimumab (Humira). In one embodiment, In one form, the anti-inflammatory agent is golimumab (Simponi). In one embodiment, the anti-inflammatory treatment is one or more anti-integrin agents. In one embodiment, the anti-inflammatory agent is vedolizumab . In one embodiment, the anti-inflammatory agent is natalizumab. In one embodiment, the anti-inflammatory treatment is one or more JAK inhibitors. In some embodiments, the JAK inhibitor is one or more of the four JAK members: JAK1, JAK2, JAK3, and TYK2 . In one embodiment, the JAK inhibitor is filgotinib. In one embodiment, the JAK inhibitor is peficitinib. In one embodiment, the JAK inhibitor is tofacitinib (Xeljanz / Jakvinus). In one embodiment, the JAK inhibitor is upadacitinib. In one embodiment, the anti-inflammatory treatment is one or more anti-inter leukin agents. In some embodiments, the anti-interleukin (IL) agents include, but are not limited to, anti-IL-1 agents, anti-IL-6 agents, anti-IL-10 agents, anti-IL-13 agents, anti-IL-17 agents, anti- IL-12 / 23 agents, or anti-IL-23 agents. In one embodiment, the anti-IL agent is BI-655066. In one embodiment, the anti-IL agent is briakinumab. In one embodiment, the anti-IL agent is guselkumab . In one embodiment, the anti-IL agent is tildrakizumab. In one embodiment, the anti-IL agent is ustekinumab (Stelara).

[0243] In some embodiments, the methods provided herein further include predicting the response based on one or more other characteristics of the subject. In one embodiment, the characteristic is at the protein level In another embodiment, the feature is the gut microbiota. In other embodiments, the feature is the histological findings of the subject. In another embodiment, the feature is the clinical features of the subject. In certain embodiments, the methods provided herein further comprise measuring the response of a subject to IBD treatment at least 6 weeks after the IBD treatment. In another embodiment, the methods provided herein further comprise measuring the response of a subject to IBD treatment more than 6 weeks after the IBD treatment. In certain embodiments, the methods provided herein further comprise measuring the response of a subject to IBD treatment 30 weeks after the IBD treatment.

[0244] In certain embodiments, the methods provided herein further comprise measuring the response of a subject to IBD treatment more than 30 weeks after the IBD treatment. In other embodiments, the methods provided herein further comprise measuring the response of a subject to IBD treatment 50 weeks after the IBD treatment. In certain embodiments, the methods provided herein further comprise measuring the response of a subject to IBD treatment more than 50 weeks after the IBD treatment. In some embodiments, the subject has previously failed or been intolerant to at least one treatment selected from the group consisting of vedolizumab, corticosteroids, azathioprine (AZA), and 6-mercaptopurine (6MP), or the subject has shown corticosteroid dependence. In some embodiments, the subject has previously failed or been intolerant to anti-integrin treatment.

[0245] In some embodiments, the subject has previously failed or been intolerant to at least one treatment selected from the group consisting of vedolizumab, corticosteroids, azathioprine (AZA), and 6-mercaptopurine (6MP), or the subject has shown corticosteroid dependence. In some embodiments, the subject has previously failed or been intolerant to anti-integrin treatment. In some embodiments, the subject has previously failed or been intolerant to at least one treatment selected from the group consisting of vedolizumab, corticosteroids, azathioprine (AZA), and 6-mercaptopurine (6MP), or the subject has shown corticosteroid dependence. In some embodiments, the subject has previously failed or been intolerant to anti-integrin treatment. ​​​​​​​​​​​​​In an embodiment, the subject has previously failed or been intolerant to vedolizumab In another embodiment, the subject has previously failed or been intolerant to natalizumab In one embodiment, the subject has previously failed or been intolerant to corticosteroids In one embodiment, the subject has previously failed or been intolerant to prednisone In another embodiment, the subject has previously failed or been intolerant to prednisolone In another embodiment, the subject has previously failed or been intolerant to methylprednisolone In one embodiment, the subject has previously shown corticosteroid dependence In another embodiment, the subject has previously shown prednisone dependence In one embodiment, the subject has previously shown prednisolone dependence In other embodiments, the subject has previously shown methylprednisolone dependence In some embodiments, the subject has previously failed or been intolerant to immunomodulators In one embodiment, the subject has previously failed or been intolerant to AZA In one embodiment, the subject has previously failed or been intolerant to 6MP In one embodiment, the subject has previously failed or been intolerant to cyclosporine In other embodiments, the subject has previously failed or been intolerant to methotrexate A panel of biomarkers can identify subsets of patients with different responses to different IBD treatments, which reduces the number of patients receiving ineffective treatments and leads to higher response

[0246] rates [[ID=�6]]rates Alternative therapies to avoid foot-dragging through achieving response rates and treating patients predicted to be non-responders with ineffective therapies can be beneficial in many ways, including being able to treat patients predicted to be non-responsive (NR). Biomarker panels can also be used for other purposes, such as reducing the sample size in proof-of-concept studies by stratifying patients in clinical trials and excluding predicted non-responder (NR) patients, and

[0247] ensuring an equal number of non-responders in both arms of a clinical trial to balance the treatment arms. Compositions for use in the methods disclosed herein include, but are not limited to, probes, antibodies, aptamers, nucleic acids, and / or aptamers. In some embodiments, the composition can detect the expression level

[0248] of a panel of biomarkers (e.g., mRNA or protein level) from a biological sample. Any of the compositions can be provided in the form of a kit or reagent mixture. As an example, a labeled probe can be provided in a kit for detecting a panel of biomarkers. The kit can contain all the components necessary or sufficient for the assay, including detection reagents (e.g., probes), buffers, control reagents (e.g., positive and negative controls), amplification reagents, solid supports, labels, instructions, etc., but are not including reagents for doing so (e.g., reagents for isolating proteins or nucleic acids from a sample) including

[0249] In one embodiment, the present specification includes a kit for predicting a response to treatment in a subject diagnosed with inflammatory bowel disease (IBD). In other embodiments, the kit is C KLF-like MARVEL transmembrane domain-containing 2 (CMTM2), complement C5a receptor 1 (C5AR1), fibroblast growth factor 2 (FGF2), glycerol kinase (G K), hepatocyte growth factor (HGF), interleukin 1 receptor antagonist (IL1RN ), leukocyte immunoglobulin-like receptor A2 (LILRA2), nicotinamide phosphoribosyl transferase (NAMPT), pappalysin 1 (PAPPA), synuclein alpha (SNCA), superoxide dismutase 2, mitochondrial (SOD2) ), STEAP4 metalloreductase (STEAP4), and zinc finger BED-type containing 3 (ZBED3), and includes a set of isolated probes capable of detecting at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 biomarkers selected from the group consisting of In another embodiment, the kit is STEAP4, and CKLF-like MARVEL transmembrane domain-containing 2 (CMTM2), complement C5a receptor 1 (C5AR1), fibroblast growth factor 2 (FGF2), glycerol kinase (GK), hepatocyte growth factor (HGF), interleukin 1 receptor antagonist (IL1RN), leukocyte immunoglobulin-like receptor A2 (LILRA2), nicotinamide phosphoribosyltransferase (NAMPT), pappalysin 1 (PAPPA), syn (SNCA), superoxide dismutase 2, mitochondrial (SOD2), STEAP4 metalloreductase (STEAP4), and zinc finger BED-type containing 3 (ZBED3), and includes a set of isolated probes capable of detecting at least 1, 2, 3, 4, 5, 6, 7, Nuclein alpha (SNCA), superoxide dismutase 2, mitochondria ( SOD2), and zinc finger BED type containing 3 (ZBED3) selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 biomarkers, and An isolated probe set capable of detecting a panel of biomarkers comprising at least is included.

[0250] In another embodiment, the kit is CKLF-like MARVEL transmembrane domain containing 2 (CMT M2), complement C5a receptor 1 (C5AR1), fibroblast growth factor 2 (FGF2), gly cerol kinase (GK), hepatocyte growth factor (HGF), interleukin 1 receptor ant agonist (IL1RN), leukocyte immunoglobulin-like receptor A2 (LILRA2), nico tinamide phosphoribosyltransferase (NAMPT), papalysin 1 (PAPP A), synuclein alpha (SNCA), superoxide dismutase 2, mito chondria (SOD2), STEAP4 metalloreductase (STEAP4), and zinc finger BED type containing 3 (ZBED3), and includes an isolated probe set capable of detecting all biomarkers selected from the group consisting of . In certain embodiments, the kit further comprises a therapeutic agent.

Example

[0251] Example 1: Identification and Refinement of predictive gene expression signatures for anti-TNF responses in IBD patients In this example, first, in the ACT1 infliximab trial (Remicade, a chimeric monoclonal antibody against tumor necrosis factor alpha (TNFα)), the predictive genetic ​Identified gene expression signatures and validated them in the PURSUIT golimumab trial (Simu poni®, a human monoclonal antibody against TNFα), and then densified them.

[0252] The gene expression signatures were first identified in the ACT1 infliximab trial through comparative analysis from a subset of 22 patients who consented to participate in an optional biopsy substudy (Arijs, et al., Gut., 2009, 58:1612-161 9). Total RNA was extracted and then analyzed on Affymetrix Human Genome U133 Plus 2.0 Arrays (Thermo Fisher Scien tific’s Affymetrix, Santa Clara, CA). Baseline gene expression was evaluated for its ability to distinguish non-responders (n = 10) from week 8 responders (n = 12). A set of 109 probe sets was significantly differentially expressed at baseline between responders and non-responders (fold change > 2, P <.05). The panel of 109 probe sets was able to predict week 8 response with > 90% sensitivity and specificity.

[0253] Next, the predictive panel of 109 probe sets mapped to 81 unique genes was subsequently validated retrospectively in the PURSUIT golimumab trial (Sandborn, et a ) l., Gastroenterology 2014, 146:85-95), an independent cohort, using gene expression from biopsy samples of 59 patients collected at baseline. Golimumab has multiple glyco forms with a molecular weight of approximately 150-151 kD. A human IgG1κ monoclonal antibody specific for human tumor necrosis factor α (TNF-α) that shows a form. A nal antibody. The 109-probe set panel was able to predict the mucosal healing response at week 6 in PURSUIT (n = 59), and the area under the curve (AUC ) was 0.7 ROC 62.

[0254] Next, in the same PURSUIT golimumab trial, the prediction panel of 109 probe sets was refined. A 13-gene signature (Table 1) achieved the area under the curve value of the maximum receiver operating characteristic (ROC) curve (AUC ) for predicting the mucosal healing response at week 6 (AUC C ROC ) of 0.768. The 13-gene signature is referred to as the molecular prediction signature (MPS). These genes represent biological processes related to the inflammatory response, oxidative stress, and cell motility, and the baseline expression of these genes is higher in mucosal healing non-responders compared to mucosal healing responders. ROC )

[0255]

Table 1

[0256] Example 2: Gene expression signature for predicting golimumab response in a phase 2a open-label trial of patients with ulcerative colitis A phase 2a open-label trial (P ROgECT) (Telesco SE, et al., Gastroenterolo gy, 2018 Oct., 155(4):1008-1011.e8; Clinica lTrials.gov number is NCT01988961) of 103 golimumab-treated patients with moderate to severe UC, and the disclosure of each reference is, as such (which is incorporated herein by reference in its entirety) was designed and conducted to determine which patients can achieve mucosal healing, clinical response, and clinical remission at 6 weeks and 30 weeks of treatment using MPS. The secondary objective was to confirm the accuracy of MPS for predicting sustained mucosal healing, sustained clinical response, and sustained clinical remission (sustained assessment items were defined as meeting the respective response criteria at 6 weeks and 30 weeks). To confirm that it is possible to predict which patients will achieve mucosal healing, clinical response, and clinical remission at 6 weeks and 30 weeks of treatment using MPS, the study was designed and conducted. The secondary objective was to confirm the accuracy of MPS for predicting sustained mucosal healing, sustained clinical response, and sustained clinical remission (sustained assessment items were defined as meeting the respective response criteria at 6 weeks and 30 weeks). To confirm that it is possible to predict which patients will achieve mucosal healing, clinical response, and clinical remission at 6 weeks and 30 weeks of treatment using MPS, the study was designed and conducted. The secondary objective was to confirm the accuracy of MPS for predicting sustained mucosal healing, sustained clinical response, and sustained clinical remission (sustained assessment items were defined as meeting the respective response criteria at 6 weeks and 30 weeks). To confirm that it is possible to predict which patients will achieve mucosal healing, clinical response, and clinical remission at 6 weeks and 30 weeks of treatment using MPS, the study was designed and conducted. The secondary objective was to confirm the accuracy of MPS for predicting sustained mucosal healing, sustained clinical response, and sustained clinical remission (sustained assessment items were defined as meeting the respective response criteria at 6 weeks and 30 weeks). (Sustained assessment items were defined as meeting the respective response criteria at 6 weeks and 30 weeks, respectively). .

[0257] Materials and Methods Study Design: Eligible patients had established diagnoses of UC (for at least 3 months) and moderate to severe disease activity defined as having a Mayo score core of 6 or more and 12 or less and an endoscopic subscore of ≥2 (based on the endoscopic score assigned by the facility's adjudicator). Patients had an inadequate response or were unable to tolerate one or more of the following conventional treatments: oral 5-aminosalicylic acid, oral corticosteroids, azathioprine, and / or 6-mercaptopurine; or were corticosteroid-dependent (i.e., unable to taper corticosteroids without recurrence of UC symptoms). Study Design: Eligible patients had established diagnoses of UC (for at least 3 months) and moderate to severe disease activity defined as having a Mayo score core of 6 or more and 12 or less and an endoscopic subscore of ≥2 (based on the endoscopic score assigned by the facility's adjudicator). Patients had an inadequate response or were unable to tolerate one or more of the following conventional treatments: oral 5-aminosalicylic acid, oral corticosteroids, azathioprine, and / or 6-mercaptopurine; or were corticosteroid-dependent (i.e., unable to taper corticosteroids without recurrence of UC symptoms). Study Design: Eligible patients had established diagnoses of UC (for at least 3 months) and moderate to severe disease activity defined as having a Mayo score core of 6 or more and 12 or less and an endoscopic subscore of ≥2 (based on the endoscopic score assigned by the facility's adjudicator). Patients had an inadequate response or were unable to tolerate one or more of the following conventional treatments: oral 5-aminosalicylic acid, oral corticosteroids, azathioprine, and / or 6-mercaptopurine; or were corticosteroid-dependent (i.e., unable to taper corticosteroids without recurrence of UC symptoms). All patients enrolled in the study received the approved induction dosing regimen of subcutaneous (SC) golimumab: 200 mg at week 0 (baseline) and 100 mg at week 2. From week 6 through week 50, patients received the maintenance dose of SC golimumab (100 mg every 4 weeks [q4w] or 50 mg q4w) approved for UC in the country where the treatment was administered. In countries where golimumab was not approved for UC patients, a maintenance dose of 100 mg q4w was used. All patients enrolled in the study received the approved induction dosing regimen of subcutaneous (SC) golimumab: 200 mg at week 0 (baseline) and 100 mg at week 2. From week 6 through week 50, patients received the maintenance dose of SC golimumab (100 mg every 4 weeks [q4w] or 50 mg q4w) approved for UC in the country where the treatment was administered. In countries where golimumab was not approved for UC patients, a maintenance dose of 100 mg q4w was used. All patients enrolled in the study received the approved induction dosing regimen of subcutaneous (SC) golimumab: 200 mg at week 0 (baseline) and 100 mg at week 2. From week 6 through week 50, patients received the maintenance dose of SC golimumab (100 mg every 4 weeks [q4w] or 50 mg q4w) approved for UC in the country where the treatment was administered. In countries where golimumab was not approved for UC patients, a maintenance dose of 100 mg q4w was used. All patients enrolled in the study received the approved induction dosing regimen of subcutaneous (SC) golimumab: 200 mg at week 0 (baseline) and 100 mg at week 2. From week 6 through week 50, patients received the maintenance dose of SC golimumab (100 mg every 4 weeks [q4w] or 50 mg q4w) approved for UC in the country where the treatment was administered. In countries where golimumab was not approved for UC patients, a maintenance dose of 100 mg q4w was used. (i.e., unable to taper corticosteroids without recurrence of UC symptoms).

[0258] All patients enrolled in the study received the approved induction dosing regimen of subcutaneous (SC) golimumab: 200 mg at week 0 (baseline) and 100 mg at week 2. From week 6 through week 50, patients received the maintenance dose of SC golimumab (100 mg every 4 weeks [q4w] or 50 mg q4w) approved for UC in the country where the treatment was administered. In countries where golimumab was not approved for UC patients, a maintenance dose of 100 mg q4w was used. All patients enrolled in the study received the approved induction dosing regimen of subcutaneous (SC) golimumab: 200 mg at week 0 (baseline) and 100 mg at week 2. From week 6 through week 50, patients received the maintenance dose of SC golimumab (100 mg every 4 weeks [q4w] or 50 mg q4w) approved for UC in the country where the treatment was administered. In countries where golimumab was not approved for UC patients, a maintenance dose of 100 mg q4w was used. All patients enrolled in the study received the approved induction dosing regimen of subcutaneous (SC) golimumab: 200 mg at week 0 (baseline) and 100 mg at week 2. From week 6 through week 50, patients received the maintenance dose of SC golimumab (100 mg every 4 weeks [q4w] or 50 mg q4w) approved for UC in the country where the treatment was administered. In countries where golimumab was not approved for UC patients, a maintenance dose of 100 mg q4w was used. All patients enrolled in the study received the approved induction dosing regimen of subcutaneous (SC) golimumab: 200 mg at week 0 (baseline) and 100 mg at week 2. From week 6 through week 50, patients received the maintenance dose of SC golimumab (100 mg every 4 weeks [q4w] or 50 mg q4w) approved for UC in the country where the treatment was administered. In countries where golimumab was not approved for UC patients, a maintenance dose of 100 mg q4w was used. In countries where golimumab was not approved for UC patients, a maintenance dose of 100 mg q4w was used. were used. After 8 weeks of screening, the treatment phase of the trial was 50 weeks, followed by 8 weeks of safety follow-up, with the last safety visit at week 58 (Figure 1). At the time of registration for the trial, patients who were receiving oral 5-aminosalicylic acid or immunomodulators (6-mercaptopurine, azathioprine, and methotrexate) maintained a stable predetermined dose throughout the trial (unless a dose reduction or interruption was necessary due to toxicity or medical necessity). Patients who were receiving oral corticosteroids (maximum dose 40 mg) maintained a stable predetermined dose until week 6, after which the dose could be tapered at the discretion of the principal investigator.

[0259] Trial evaluation: To assess disease activity, Mayo scores were calculated at baseline, week 6, and week 30. Analysis of patient eligibility at baseline and treatment efficacy at weeks 6 and 30 was provided by a panel of adjudicator(s) from 3 independent facilities who were blinded to patient number and visit, based on endoscopic subscores. The assigned endoscopic evaluation was based on the worst findings identified in the intestine during the endoscopic procedure. Patients at high risk of colorectal cancer were evaluated by colonoscopy, and sigmoidoscopy was acceptable for all other patients. For scoring of rectal bleeding and frequency of bowel movements, the mean subscore over the most recent consecutive 3 days before the

[0260] Trial visit was used. Biopsy sample processing for predictive analysis: Using biopsy samples collected using the QuantStudio qPCR platform (Thermo Fish er Scientific, Waltham, MA) to measure the expression level of MPS Each patient had a signature score based on ...

Claims

1. A method for predicting the response of a subject diagnosed with inflammatory bowel disease (IBD) to anti-interleukin (IL) therapy for the IBD, comprising: a. contacting a set of probes capable of detecting a panel of biomarkers comprising 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 biomarkers selected from the group consisting of CKLF-like MARVEL transmembrane domain-containing 2 (CMTM2), complement C5a receptor 1 (C5AR1), fibroblast growth factor 2 (FGF2), glycerol kinase (GK), hepatocyte growth factor (HGF), interleukin 1 receptor antagonist (IL1RN), leukocyte immunoglobulin-like receptor A2 (LILRA2), nicotinamide phosphoribosyl transferase (NAMPT), pappalysin 1 (PAPPA), synuclein alpha (SNCA), superoxide dismutase 2, mitochondrial (SOD2), STEAP4 metalloreductase (STEAP4), and zinc finger BED type-containing 3 (Zbed3) with a sample from the subject; and b. determining the pattern of the panel of biomarkers; wherein the pattern of the biomarker panel predicts the response of the subject to anti-IL therapy.

2. The method of claim 1, wherein the panel of biomarkers comprises CMTM2, C5AR1, FGF2, GK, HGF, IL1RN, LILRA2, NAMPT, PAPPA, SNCA, SOD2, STEAP4, and Zbed3.

3. The method of claim 1 or 2, wherein the sample is obtained before the subject is treated with the anti-IL therapy.

4. The method according to any one of claims 1 to 3, wherein the probe is selected from the group consisting of an aptamer, an antibody, an affibody, a peptide, and a nucleic acid.

5. The method of claim 4, wherein the probe is a nucleic acid.

6. The method according to claim 4 or 5, wherein the probe is selected from the group consisting of SEQ ID NO: 1 to 14, SEQ ID NO: 17, SEQ ID NO: 20, SEQ ID NO: 23, SEQ ID NO: 26, SEQ ID NO: 29, SEQ ID NO: 32, SEQ ID NO: 35, SEQ ID NO: 38, SEQ ID NO: 41, SEQ ID NO: 44, SEQ ID NO: 47, and SEQ ID NO:

50.

7. The pattern of the panel of biomarkers is (a) the expression level of the biomarkers in the subject; ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ Determine the baseline gene expression levels of the marker panel, and (b) for each sample The method according to any one of claims 1 to 6, determined by determining the signature score of .

8. The method according to claim 7, wherein the gene expression level is determined by quantitative polymerase chain reaction (qPCR). .

9. The primers for the qPCR are selected from the group consisting of SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 33, SEQ ID NO: 34, SEQ ID NO: 36, SEQ ID NO: 37, SEQ ID NO: 39, SEQ ID NO: 40, SEQ ID NO: 42, SEQ ID NO: 43, SEQ ID NO: 4 5, SEQ ID NO: 46, SEQ ID NO: 48, SEQ ID NO: 49, SEQ ID NO: 51, and SEQ ID NO: 52, the method according to claim 8.

10. When the signature score of the biomarker panel exceeds a predetermined threshold indicating a response, the subject is predicted to be a responder to the anti-interleukin (IL) treatment for the IBD, the method according to any one of claims 7 to 9.

11. The method according to claim 10, wherein the level of the predetermined threshold is selected from the group consisting of -3.9000 to 1.1000.

12. The method according to claim 10, wherein the level of the predetermined threshold is -3.8234.

13. The method according to claim 10, wherein the level of the predetermined threshold is 1.0000.

14. A method for predicting the response of a subject diagnosed with inflammatory bowel disease (IBD) to treatment with a Janus kinase inhibitor (JALI) for the IBD, comprising: a. CKLF-like MARVEL transmembrane domain-containing 2 (CMTM2), complement C5a receptor 1 (C5AR1), fibroblast growth factor 2 (FGF2), glycerol kinase (GK) , hepatocyte growth factor (HGF), interleukin 1 receptor antagonist (IL1RN) , leukocyte immunoglobulin-like receptor A2 (LILRA2), nicotinamide phosphoribosyl transferase (NAMPT), pappalysin 1 (PAPPA), synuclein alpha synuclein (SNCA), superoxide dismutase 2, mitochondrial (SOD2), S TEAP4 metalloreductase (STEAP4), and zinc finger BED type-containing 3 ​ ​ ​ ​ ​ 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 biomarkers selected from the group consisting of (ZBED3), contacting a set of probes capable of detecting a panel of biomarkers with a sample from a subject, and b. determining the pattern of the panel of biomarkers, comprising, wherein the pattern of the panel of biomarkers predicts the response of the subject to JALI treatment, Method.

15. The panel of biomarkers comprises CMTM2, C5AR1, FGF2, GK, HGF, IL1RN, LILRA2, NAMPT, PAPP A, SNCA, SOD2, STEAP 4, and ZBED3, the method according to claim 14.

16. The sample is obtained before the subject is treated with JALI treatment, claim 1 4 or 15 method described.

17. The probe is selected from the group consisting of aptamers, antibodies, affibodies, peptides, and nucleic acids, The method according to any one of claims 14 to 16.

18. The probe is a nucleic acid, the method according to claim 17.

19. The probe is selected from the group consisting of SEQ ID NO: 1 to 14, SEQ ID NO: 17, SEQ ID NO: 20, SEQ ID NO: 23, SEQ ID NO: 26, SEQ ID NO: 29, SEQ ID NO: 32, SEQ ID NO: 35, SEQ ID NO: 38, SEQ ID NO: 41 , SEQ ID NO: 44, SEQ ID NO: 47, and SEQ ID NO: 50, the method according to claim 1 7 or 18 described.

20. The pattern of the panel of biomarkers is determined by (a) determining the baseline gene expression levels of the panel of biomarkers in the subject, and (b) determining the signature score for each sample, The method according to any one of claims 14 to 19. The method according to any one of claims 14 to 19. The method according to any one of claims 14 to 19.

21. The gene expression level is determined by quantitative polymerase chain reaction (qPCR), The method according to claim 20.

22. The primers for the qPCR are SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 33, SEQ ID NO: 34, SEQ ID NO: 36, SEQ ID NO: 37, SEQ ID NO: 39, SEQ ID NO: 40, SEQ ID NO: 42, SEQ ID NO: 43, SEQ ID NO: 4 5. The method according to claim 21, selected from the group consisting of SEQ ID NO: 46, SEQ ID NO: 48, SEQ ID NO: 49, SEQ ID NO: 51, and SEQ ID NO:

52. **Claim 23** When the signature score of the panel of biomarkers exceeds a predetermined threshold indicating a response, the subject is predicted to be a responder to the JALI treatment of the IBD. The method according to any one of claims 20 to 22. **Claim 24** The level of the predetermined threshold is selected from the group consisting of -3.9000 to 1.1000. The method according to claim 23. **Claim 25** The level of the predetermined threshold is -3.8234. The method according to claim 23. **Claim 26** The level of the predetermined threshold is 1.0000. The method according to claim 23. **Claim 27** A method for predicting a negative response of a subject diagnosed with inflammatory bowel disease (IBD) to anti-inflammatory treatment of the IBD, comprising: a. Detecting a set of probes capable of detecting a panel of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 biomarkers selected from the group consisting of CKLF-like MARVEL transmembrane domain-containing 2 (CMTM2), complement C5a receptor 1 (C5AR1), fibroblast growth factor 2 (FGF2), glycerol kinase (GK), hepatocyte growth factor (HGF), interleukin 1 receptor antagonist (IL1RN), leukocyte immunoglobulin-like receptor A2 (LILRA2), nicotinamide phosphoribosyltransferase (NAMPT), pappalysin 1 (PAPPA), synuclein alpha (SNCA), superoxide dismutase 2, mitochondrial (SOD2), STEAP4 metalloreductase (STEAP4), and zinc finger BED-type containing 3 (Zbed3), contacting the set of probes with a sample from the subject; b. Determining the baseline gene expression levels of the panel of biomarkers in the sample; c. Determining a signature score for each sample; wherein when the signature score of the panel of biomarkers is below a predetermined threshold indicating non-response, the subject is predicted to be a non-responder to the anti-inflammatory treatment of the IBD. **Claim 28** The method according to claim 27, wherein the sample is obtained before the subject is treated with the anti-inflammatory treatment. **Claim 29** The method according to claim 27 or 28, wherein the probe is selected from the group consisting of an aptamer, an antibody, an affibody, a peptide, and a nucleic acid. The method according to claim 27 or 28, wherein the probe is selected from the group consisting of an aptamer, an antibody, an affibody, a peptide, and a nucleic acid. **Claim 30** The method according to claim 29, wherein the probe is a nucleic acid. **Claim 31** The method according to claim 29 or 30, wherein the probe is selected from the group consisting of SEQ ID NO: 1 to 14, SEQ ID NO: 17, SEQ ID NO: 20, SEQ ID NO: 23, SEQ ID NO: 26, SEQ ID NO: 29, SEQ ID NO: 32, SEQ ID NO: 35, SEQ ID NO: 38, SEQ ID NO: 41 , SEQ ID NO: 44, SEQ ID NO: 47, and SEQ ID NO:

50. The method according to claim 29 or 30, wherein the probe is selected from the group consisting of SEQ ID NO: 1 to 14, SEQ ID NO: 17, SEQ ID NO: 20, SEQ ID NO: 23, SEQ **Claim 32** The method according to any one of claims 27 to 31, wherein the gene expression level is determined by quantitative polymerase chain reaction (qPCR). The method according to any one of claims 27 to 31, wherein the gene expression level is determined by quantitative polymerase chain reaction (qPCR). **Claim 33** The method according to claim 32, wherein the primers for the qPCR are selected from the group consisting of SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 33, SEQ ID NO: 34, SEQ ID NO: 36, SEQ ID NO: 37, SEQ ID NO: 39, SEQ ID NO: 40, SEQ ID NO: 42, SEQ ID NO: 43, SEQ ID NO: 4 5, SEQ ID NO: 46, SEQ ID NO: 48, SEQ ID NO: 49, SEQ ID NO: 51, and SEQ ID NO:

52. The method according to claim 32, wherein the primers for the qPCR are selected from the group consisting of SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 18, SEQ ID NO: **Claim 34** The method according to any one of claims 27 to 33, wherein the level of the predetermined threshold is selected from the group consisting of -3.9000 to 1.1000. The method according to any one of claims 27 to 33, wherein the level of the predetermined threshold is selected from the group consisting of -3.9000 to 1.1000. **Claim 35** The method according to any one of claims 27 to 34, wherein the level of the predetermined threshold is -3.8234. The method according to any one of claims 27 to 34, wherein the level of the predetermined threshold is -3.8234. **Claim 36** The method according to any one of claims 27 to 34, wherein the level of the predetermined threshold is 1.0000. The method according to any one of claims 27 to 34, wherein the level of the predetermined threshold is 1.0000. **Claim 37** A method for predicting a negative response to anti-inflammatory treatment of inflammatory bowel disease (IBD) in a subject diagnosed with IBD, comprising: a. CKLF-like MARVEL transmembrane domain-containing 2 (CMTM2), complement C5a receptor 1 (C5AR1), fibroblast growth factor 2 (FGF2), glycerol kinase (GK) , hepatocyte growth factor (HGF), interleukin 1 receptor antagonist (IL1RN) , leukocyte immunoglobulin-like receptor A2 (LILRA2), nicotinamide phosphoribosyl transferase (NAMPT), pappalysin 1 (PAPPA), synuclein alpha transferase (NAT), and tissue inhibitor of metalloproteinase 1 (TIMP1) in a sample obtained from the subject are detected; Fascin (SNCA), superoxide dismutase 2, mitochondrial (SOD2), STEAP4 metalloreductase (STEAP4), and zinc finger BED type containing 3 A set of probes capable of detecting a panel of biomarkers consisting of (ZBED3) Contacting with a sample from a subject, b. Determining the baseline gene expression levels of the panel of biomarkers in the sample by quantitative polymerase chain reaction (qPCR); c. Determining a signature score for each sample, Including, When the signature score of the panel of biomarkers is below a predetermined threshold indicating non-response, the subject is predicted to be a non-responder to the anti-inflammatory treatment of the IBD Method.

38. The method according to claim 37, wherein the sample is obtained before the subject is treated with the anti-inflammatory treatment.

39. The method according to claim 37 or 38, wherein the probe is selected from the group consisting of SEQ ID NO: 14, SEQ ID NO: 17, SEQ ID NO: 20, SEQ ID NO: 23, SEQ ID NO: 26, SEQ ID NO: 29, SEQ ID NO: 32, SEQ ID NO: 35, SEQ ID NO: 38, SEQ ID NO: 41, SEQ ID NO: 44, SEQ ID NO: 47, and SEQ ID NO:

50.

40. The method according to any one of claims 37 to 39, wherein the primers for the qPCR are selected from the group consisting of SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 33, SEQ ID NO: 34, SEQ ID NO: 36, SEQ ID NO: 37, SEQ ID NO: 39, SEQ ID NO: 40, SEQ ID NO: 42, SEQ ID NO: 43, SEQ ID NO: 45, SEQ ID NO: 46, SEQ ID NO: 48, SEQ ID NO: 49, SEQ ID NO: 51, and SEQ ID NO:

52.

41. The method according to any one of claims 37 to 40, wherein the level of the predetermined threshold is selected from the group consisting of -3.9000 to 1.1000.

42. The method according to any one of claims 37 to 41, wherein the level of the predetermined threshold is -3.8234.

43. The method according to any one of claims 37 to 41, wherein the level of the predetermined threshold is 1.0000.

44. The method according to any one of claims 1 to 43, further comprising administering to the subject one or more of the anti-inflammatory treatments for the IBD. ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​

45. The method according to any one of claims 27 to 43, wherein the non-responder subject has one or more of the characteristics selected from the group consisting of high disease burden, microbial dysbiosis, and high levels of inflammatory activity.

46. The method according to any one of claims 27 to 43, wherein the non-responder subject is identified as a candidate for combination therapy.

47. The method according to claim 46, wherein the combination therapy comprises two or more treatments selected from the group consisting of anti-inflammatory therapy, antibiotics, immunomodulators, antidiarrheal agents, analgesics, iron supplementation, and calcium and vitamin D supplementation.

48. The method according to claim 46, comprising administering to the subject one or more agents that target one or more standard pathways selected from the group consisting of granulocyte adhesion and extravasation, agranulocyte adhesion and extravasation, the osteoarthritis pathway, the role of macrophages, fibroblasts, and endothelial cells in rheumatoid arthritis, liver fibrosis and activation of hepatic stellate cells, inhibition of matrix metalloproteinases, atherosclerotic signal transduction, bladder cancer signal transduction, the role of pattern recognition receptors in the recognition of bacteria and viruses, and HMGB1 signal transduction.

49. The method according to any one of claims 27 to 48, wherein the anti-inflammatory therapy is anti-tumor necrosis factor (TNF) therapy, JAK inhibitor (JAKi) therapy, or anti-interleukin (IL) therapy.

50. The method according to any one of claims 27 to 49, wherein the anti-inflammatory therapy is anti-IL-23 or anti-IL-12 / 23 therapy.

51. The method according to claim 50, wherein the anti-IL therapy is ustekinumab.

52. The method according to any one of claims 27 to 49, wherein the anti-inflammatory therapy is the JAK inhibitor therapy.

53. The method according to any one of claims 27 to 49, wherein the anti-inflammatory therapy is the anti-TNF therapy.

54. The method according to claim 53, wherein the anti-TNF therapy is golimumab.

55. A method of treating a subject diagnosed with inflammatory bowel disease (IBD), comprising: a. predicting the response of the subject to anti-inflammatory therapy for the IBD, comprising: (i) CKLF-like MARVEL transmembrane domain-containing 2 (CMTM2), complement C5a receptor 1 (C5AR1), fibroblast growth factor 2 (FGF2), glycerol kinase (G ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ K), hepatocyte growth factor (HGF), interleukin 1 receptor antagonist (IL1RN) N), leukocyte immunoglobulin-like receptor A2 (LILRA2), nicotinamide phosphoribosyl transferase (NAMPT), pappalysin 1 (PAPPA), synuclein alpha (SNCA), superoxide dismutase 2, mitochondrial (SOD2) , STEAP4 metalloreductase (STEAP4), and zinc finger BED type containing 3 (Zbed3) selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 1 0, 11, 12, or 13 biomarkers, contacting a set of probes capable of detecting the biomarker panel with a sample from a subject, and (ii) determining the pattern of the biomarker panel, including , predicting that the pattern of the biomarker panel predicts a response to anti-inflammatory treatment in the subject, and b. administering to the subject a therapeutically effective amount of one or more anti-inflammatory therapeutic agents. A method comprising .

56. The biomarker panel is CMTM2, C5AR1, FGF2, GK, HGF, IL1RN, LILRA2, NAMPT, PAPPA, SNCA, SOD2, STEAP 4, and ZBED3. The method according to claim 55

57. The sample is obtained before the subject is treated with the anti-inflammatory treatment. The method according to claim 55 Or 56

58. The probe is selected from the group consisting of aptamers, antibodies, affibodies, peptides, and nucleic acids . The method according to any one of claims 55 to 57

59. The probe is a nucleic acid. The method according to claim 58

60. The probe is selected from the group consisting of SEQ ID NOs: 1 to 14, SEQ ID NO: 17, SEQ ID NO: 20, SEQ ID NO: 23, SEQ ID NO: 26, SEQ ID NO: 29, SEQ ID NO: 32, SEQ ID NO: 35, SEQ ID NO: 38, SEQ ID NO: 41 , SEQ ID NO: 44, SEQ ID NO: 47, and SEQ ID NO:

50. The method according to claim 5 8 or 59

61. The pattern of the biomarker panel is determined by (a) determining the baseline gene expression level of the biomarker panel in the subject and (b) determining the signature score for each sample . The method according to any one of claims 55 to 60 Item .

62. The method according to claim 61, wherein the gene expression level is determined by quantitative polymerase chain reaction (qPCR). The method according to claim 61.

63. The method according to claim 63, wherein the primers for the qPCR are selected from the group consisting of SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 33, SEQ ID NO: 34, SEQ ID NO: 36, SEQ ID NO: 37, SEQ ID NO: 39, SEQ ID NO: 40, SEQ ID NO: 42, SEQ ID NO: 43, SEQ ID NO: 4 5, SEQ ID NO: 46, SEQ ID NO: 48, SEQ ID NO: 49, SEQ ID NO: 51, and SEQ ID NO:

52. The method according to claim 63.

64. When the signature score of the panel of biomarkers exceeds a predetermined threshold indicating a response, the subject is predicted to be a responder to the anti-inflammatory treatment for the IBD, according to the method according to any one of claims 61 to 63. The method according to any one of claims 61 to 63, wherein when the signature score of the panel of biomarkers exceeds a predetermined threshold indicating a response, the subject is predicted to be a responder to the anti-inflammatory treatment for the IBD. The method according to any one of claims 61 to 63.

65. The method according to claim 64, wherein the level of the predetermined threshold is selected from the group consisting of -3.9000 to 1.1000. The method according to claim 64.

66. The method according to claim 64, wherein the level of the predetermined threshold is -3.8234.

67. The method according to claim 64, wherein the level of the predetermined threshold is 1.0000.

68. A method of treating a subject diagnosed with inflammatory bowel disease (IBD), comprising: a. predicting that the subject is a non-responder to the anti-inflammatory treatment for the IBD, wherein (i) detecting a panel of biomarkers comprising 1, 2, 3, 4, 5, 6, 7, 8, 9, 1 0, 11, 12, or 13 biomarkers selected from the group consisting of CKLF-like MARVEL transmembrane domain-containing 2 (CMTM2), complement C5a receptor 1 (C5AR1), fibroblast growth factor 2 (FGF2), glycerol kinase (G K), hepatocyte growth factor (HGF), interleukin 1 receptor antagonist (IL1R N), leukocyte immunoglobulin-like receptor A2 (LILRA2), nicotinamide phosphorib osyltransferase (NAMPT), pappalysin 1 (PAPPA), synuclein alpha (SNCA), superoxide dismutase 2, mitochondrial (SOD2) , STEAP4 metalloreductase (STEAP4), and zinc finger BED-type containing 3 (Zbed3). The method according to claim 68, wherein (i) detecting a panel of biomarkers comprising 1, 2, 3, 4, 5, 6, 7, 8, 9, 1 0, 11, 12, or 13 biomarkers selected from the group consisting of CKLF-like MARVEL transmembrane domain-containing 2 (CMTM2), complement C5a receptor 1 (C5AR1), fibroblast growth factor 2 (FGF2), glycerol kinase (G K), hepatocyte growth factor (HGF), interleukin 1 receptor antagonist (IL1R N), leukocyte immunoglobulin-like receptor A2 (LILRA2), nicotinamide phosphorib osyltransferase (NAMPT), pappalysin 1 (PAPPA), synuclein alpha (SNCA), superoxide dismutase 2, mitochondrial (SOD2) , STEAP4 metalloreductase (STEAP4), and zinc finger BED-type containing 3 (Zbed3). The method according to claim 68, wherein (i) detecting a panel of biomarkers comprising 1, 2, 3, 4, 5, 6, 7, 8, 9, 1 0, 11, 12, or 13 biomarkers selected from the group consisting of CKLF-like MARVEL transmembrane domain-containing 2 (CMTM2), complement C5a receptor 1 (C5AR1), fibroblast growth factor 2 (FGF2), glycerol kinase (G K), hepatocyte growth factor (HGF), interleukin 1 receptor antagonist (IL1R N), leukocyte immunoglobulin-like receptor A2 (LILRA2), nicotinamide phosphorib osyltransferase (NAMPT), pappalysin 1 (PAPPA), synuclein alpha (SNCA), superoxide dismutase 2, mitochondrial (SOD2) , STEAP4 metalloreductase (STEAP4), and zinc finger BED-type containing 3 (Zbed3). The method according to claim 68, wherein (i) detecting a panel of biomarkers comprising 1, 2, 3, 4, 5, 6, 7, 8, 9, 1 0, 11, 12, or 13 biomarkers selected from the group consisting of CKLF-like MARVEL transmembrane domain-containing 2 (CMTM2), complement C5a receptor 1 (C5AR1), fibroblast growth factor 2 (FGF2), glycerol kinase (G K), hepatocyte growth factor (HGF), interleukin 1 receptor antagonist (IL1R N), leukocyte immunoglobulin-like receptor A2 (LILRA2), nicotinamide phosphorib osyltransferase (NAMPT), pappalysin 1 (PAPPA), synuclein alpha (SNCA), superoxide dismutase 2, mitochondrial (SOD2) , STEAP4 metalloreductase (STEAP4), and zinc finger BED-type containing 3 (Zbed3). The method according to claim 68, wherein (i) detecting a panel of biomarkers comprising 1, 2, 3, 4, 5, 6, 7, 8, 9, contacting a set of probes capable of doing so with a sample from a subject; (ii) determining a baseline gene expression level of the panel of biomarkers in the sample; (iii) determining a signature score for each sample; including: wherein when the signature score of the panel of biomarkers is below a predetermined threshold indicating non - response, predicting that the subject is a non - responder to the anti - inflammatory treatment for the IBD; b. administering to the subject a therapeutically effective amount of one or more anti - inflammatory therapeutic agents; A method, comprising:

69. The method according to claim 68, wherein the sample is obtained before the subject is treated with the anti - inflammatory treatment.

70. The method according to claim 68 or 69, wherein the probe is selected from the group consisting of aptamers, antibodies, affibodies, peptides, and nucleic acids.

71. The method according to claim 70, wherein the probe is a nucleic acid.

72. The method according to claim 70 or 71, wherein the probe is selected from the group consisting of SEQ ID NO: 1 - 14, SEQ ID NO: 17, SEQ ID NO: 20, SEQ ID NO: 23, SEQ ID NO: 26, SEQ ID NO: 29, SEQ ID NO: 32, SEQ ID NO: 35, SEQ ID NO: 38, SEQ ID NO: 41, SEQ ID NO: 44, SEQ ID NO: 47, and SEQ ID NO:

50.

73. The method according to any one of claims 68 - 72, wherein the gene expression level is determined by quantitative polymerase chain reaction (qPCR).

74. The method according to claim 73, wherein the primers for the qPCR are selected from the group consisting of SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 33, SEQ ID NO: 34, SEQ ID NO: 36, SEQ ID NO: 37, SEQ ID NO: 39, SEQ ID NO: 40, SEQ ID NO: 42, SEQ ID NO: 43, SEQ ID NO: 45, SEQ ID NO: 46, SEQ ID NO: 48, SEQ ID NO: 49, SEQ ID NO: 51, and SEQ ID NO:

52.

75. The method according to any one of claims 68 - 74, wherein the level of the predetermined threshold is selected from the group consisting of - 3.9000 to 1.1000.

76. The method according to any one of claims 68 - 75, wherein the level of the predetermined threshold is - 3.8234.

77. ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ The method according to any one of claims 68 to 75, wherein the level of the predetermined threshold is 1.0000. The method according to claim 1.

78. The method according to any one of claims 68 to 77, wherein the non-responder subject is identified as a candidate for combination therapy. The method according to claim 4.

79. The method according to claim 78, wherein the combination therapy comprises two or more treatments selected from the group consisting of anti-inflammatory therapy, antibiotics, immunomodulators, antidiarrheal agents, analgesics, iron supplementation, and calcium and vitamin D supplementation. The method according to claim 8.

80. The method according to claim 78, wherein the combination therapy comprises administering to the subject one or more agents targeting one or more standard pathways selected from the group consisting of granulocyte adhesion and extravasation, agranulocyte adhesion and extravasation, osteoarthritis pathway , the role of macrophages, fibroblasts and endothelial cells in rheumatoid arthritis, liver fibrosis and activation of hepatic stellate cells, inhibition of matrix metalloproteinases, atherosclerotic signal nal transduction, bladder cancer signal transduction, the role of pattern recognition receptors in the recognition of bacteria and viruses, and HMGB1 signal transduction. The method according to claim 15.

81. The method according to any one of claims 55 to 80, wherein the anti-inflammatory therapy is anti-tumor necrosis factor (TNF) therapy, JAK inhibitor (JAKi) therapy, or anti-interleukin (IL) therapy. The method according to claim 19.

82. The method according to any one of claims 55 to 8 1, wherein the anti-inflammatory therapy is anti-IL-23 or anti-IL-12 / 23 therapy.

83. The method according to claim 82, wherein the anti-IL therapy is ustekinumab.

84. The method according to any one of claims 55 to 81, wherein the anti-inflammatory therapy is the JAK inhibitor therapy. The method according to claim 27.

85. The method according to any one of claims 55 to 81, wherein the anti-inflammatory therapy is the anti-TNF therapy. The method according to claim 30.

86. The method according to claim 85, wherein the anti-TNF therapy is golimumab.

87. The method according to any one of claims 1 to 86, further comprising predicting the response based on one or more other characteristics of the subject.

88. The method according to claim 87, wherein the other characteristics are selected from the group consisting of protein levels of the subject, gut microbiota, histological findings, and clinical characteristics.

89. At 6, 30, or 50 weeks or after 6, 30, or 50 weeks of the treatment, or this The method according to any one of claims 1 to 88, further comprising measuring the response at any point in time between them. The method according to any one of claims 1 to 88. **Claim 90** The method according to any one of claims 1 to 89, wherein the sample is a tissue sample or a blood sample. The method according to any one of claims 1 to 89. **Claim 91** The method according to any one of claims 1 to 90, wherein the IBD is at least one of ulcerative colitis (UC) or Crohn's disease (CD). The method according to any one of claims 1 to 90. **Claim 92** The method according to any one of claims 1 to 91, wherein the subject has previously failed or is intolerant to at least one treatment selected from the group consisting of vedolizumab, corticosteroids, azathioprine (AZA), and 6-mercaptopurine (6MP), or the subject has shown corticosteroid dependence. The method according to any one of claims 1 to 91. **Claim 93** A kit for predicting the response to treatment in a subject diagnosed with inflammatory bowel disease (IBD), comprising a set of isolated probes capable of detecting a panel of biomarkers selected from the group consisting of CKLF-like MARVEL transmembrane domain-containing 2 (CMTM2), complement C5a receptor 1 (C5AR1), fibroblast growth factor 2 (FGF2), glycerol kinase (GK), hepatocyte growth factor (HGF), interleukin 1 receptor antagonist (IL1RN), leukocyte immunoglobulin-like receptor A2 (LILRA2), nicotinamide phosphoribosyltransferase (NAMPT), pappalysin 1 (PAPP A), synuclein alpha (SNCA), superoxide dismutase 2, mitochondrial (SOD), STEAP4 metalloreductase (STEAP4), and zinc finger BED type-containing 3 (ZBE3), wherein the panel comprises at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 biomarkers. **Claim 94** CKLF-like MARVEL transmembrane domain-containing 2 (CMTM2), complement C5a receptor 1 (C5AR1), fibroblast growth factor 2 (FGF2), glycerol kinase (GK), hepatocyte growth factor (HGF), interleukin 1 receptor antagonist (IL1RN), leukocyte immunoglobulin-like receptor A2 (LILRA2), nicotinamide phosphoribosyltransferase (NAMPT), pappalysin 1 (PAPP A), synuclein alpha ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ (SNCA), superoxide dismutase 2, mitochondrial (SOD2), STE AP4 metalloreductase (STEAP4), and zinc finger BED type containing 3 (Z BED3), the kit according to claim 93, comprising an isolated set of probes capable of detecting all biomarkers selected from the group consisting of .

95. The kit according to claim 93 or 94, further comprising a therapeutic agent.

96. The kit according to any one of claims 93 to 95, wherein the IBD is at least one of ulcerative colitis (UC) and Crohn's disease (CD). ​

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