Biomarkers and methods for measuring and monitoring juvenile idiopathic arthritis activity

Abstract

Biomarkers useful for assessing inflammatory disease or flare activity, in particular in juvenile idiopathic arthritis, are provided, along with kits for measuring expression of the biomarkers. The invention also provides predictive models, based on the biomarkers, as well as computer systems, and software embodiments of the models for scoring and optionally classifying samples.

1 . A method for monitoring the presence or absence of juvenile idiopathic arthritis (JIA) disease activity in a subject, or for predicting flare activity in a subject having JIA, the method comprising:
 providing a test sample comprising a sample of bodily fluid taken from the mammal;   determining sample concentrations for three or more biomarkers selected from the group consisting of alpha-2-macroglobulin (A2M); amyloid P component, serum (SAP); angiopoietin 1 (AGP1) antithrombin III (ATIII); ataxia telangiectasia mutated (ATM); B-cell activating factor (BAFF); chemokine (C—C motif) ligand 2 (CCL2); chemokine (C—C motif) ligand 3 (CCL3); chemokine (C—C motif) ligand 11 (CCL11); chemokine (C—C motif) ligand 22 (CCL22); chemokine (C—X—C motif) ligand 9 (CXCL9); chemokine (C—X—C motif) ligand 10 (CXCL10); CD40 ligand (CD40LG); C-reactive protein (CRP); complement C3; complement C4; complement factor H (CFH); epidermal growth factor (EGF); gelsolin (GSN); granzyme (GZM); haptoglobin (HP); heat shock protein 60 (HSP60); interleukin 6 (IL-6); leptin (LEP); MF; matrix metalloproteinase-1 (MMP1); matrix metalloproteinase-3 (MMP3); matrix metalloproteinase-9 (MMP9); resistin (RETN); serum amyloid (SAA); tumor necrosis factor receptor, type 1 (TNF-R1); vascular cell adhesion molecule-1 (VCAM1); vascular endothelial growth factor A (VEGF-A); Calprotectin; intercellular adhesion molecule 1 (ICAM-1); interleukin-1 beta (IL-1B); interleukin-6 receptor (IL-6R); interleukin-8 (IL-8); interleukin-8 (IL-10); interleukin-8 (IL-17); interleukin-8 (IL-18); interleukin-8 (IL-21); L-selectin; MDC; P-selectin; pyridinoline (PYD); S100 A12; S100A14; TIMP metallopeptidase inhibitor 1 (TIMP1); TNF receptor-associated protein 1 (TRAP-1); transthyretin (TTR); tumor protein 53 (TP53); and YKL-40;   determining whether the sample concentration for each said biomarker is statistically significantly greater than minimum diagnostic concentrations of corresponding control biomarkers that are indicative of JIA; and   classifying disease activity of JIA in the subject or predicting flare activity in the subject, based at least in part on the determination of whether the sample concentrations for the biomarkers from the subject are statistically significantly greater than minimum diagnostic concentrations indicative of JIA.   
     
     
         2 . The method of  claim 1  wherein the biomarkers comprise VCAM-1, EGF, VEGF-A, IL-6, TNF-R1, MMP-1, MMP-3, YKL-40, Leptin, Resistin, SAA, and CRP. 
     
     
         3 . The method of  claim 1  wherein the biomarkers comprise IL-6, MMP3, CRP, TNF-R1, Calprotectin, YKL-40, ICAM-1, SAA, VCAM-1 and MMP1. 
     
     
         4 . The method of  claim 1  where the biomarkers comprise IL-6, MMP3, CRP, TNF-R1, YKL-40, ICAM-1, SAA, VCAM-1 and MMP1. 
     
     
         5 . The method of  claim 1  wherein the sample concentrations for the subject are predictive of a clinical assessment. 
     
     
         6 . The method of  claim 5  wherein said clinical assessment is selected from the group consisting of physician global assessment of disease activity (MD global), parent/child global assessment of well-being (PGA), child/parent health assessment questionnaire (CHAQ), active arthritic joint counts, Westergren erythrocyte sedimentation rate (ESR), and juvenile arthritis disease activity score (JADAS). 
     
     
         7 . The method of  claim 1  wherein said JIA is selected from the group consisting of oligoarticular JIA, polyarticular rheumatoid factor (RF) positive JIA, polyarticular RF negative JIA, systemic JIA, psoriatic JIA, enthesitis-related arthritis, and undifferentiated arthritis. 
     
     
         8 . The method of  claim 1  where the subject has received a treatment for JIA, and determining efficacy of the treatment based on a statistically significant difference between the sample concentrations from the subject and the sample concentrations of the control. 
     
     
         9 . The method of  claim 1  wherein a report is prepared in a format that is capable of being disseminated to the subject or a caregiver of the subject that provides information allowing the subject or caregiver to make decisions based disease or flare activity. 
     
     
         10 . A method for monitoring the presence or absence of juvenile idiopathic arthritis (JIA) disease activity in a subject, or for predicting flare activity in a subject having JIA, the method comprising:
 determining a first dataset associated with samples from a population of individuals wherein said population is negative for JIA, wherein said first dataset comprises quantitative data for three or more biomarkers selected from the group consisting of alpha-2-macroglobulin (A2M); amyloid P component, serum (SAP); angiopoietin 1 (AGP1) antithrombin III (ATIII); ataxia telangiectasia mutated (ATM); B-cell activating factor (BAFF); chemokine (C—C motif) ligand 2 (CCL2); chemokine (C—C motif) ligand 3 (CCL3); chemokine (C—C motif) ligand 11 (CCL11); chemokine (C—C motif) ligand 22 (CCL22); chemokine (C—X—C motif) ligand 9 (CXCL9); chemokine (C—X—C motif) ligand 10 (CXCL10); CD40 ligand (CD40LG); C-reactive protein (CRP); complement C3; complement C4; complement factor H (CFH); epidermal growth factor (EGF); gelsolin (GSN); granzyme (GZM); haptoglobin (HP); heat shock protein 60 (HSP60); interleukin 6 (IL-6); leptin (LEP); MF; matrix metalloproteinase-1 (MMP1); matrix metalloproteinase-3 (MMP3); matrix metalloproteinase-9 (MMP9); resistin (RETN); serum amyloid (SAA); tumor necrosis factor receptor, type 1 (TNF-R1); vascular cell adhesion molecule-1 (VCAM1); vascular endothelial growth factor A (VEGF-A); YKL-40; Calprotectin; intercellular adhesion molecule 1 (ICAM-1); interleukin-1 beta (IL-1B); interleukin-6 receptor (IL-6R); interleukin-8 (IL-8); interleukin-8 (IL-10); interleukin-8 (IL-17); interleukin-8 (IL-18); interleukin-8 (IL-21); L-selectin; MDC; P-selectin; pyridinoline (PYD); S100 A12; S100A14; TIMP metallopeptidase inhibitor 1 (TIMP1); TNF receptor-associated protein 1 (TRAP-1); transthyretin (TTR); tumor protein 53 (TP53); and YKL-40; determining a plurality of DAI scores for the individuals in said population based on the first dataset;   deriving an aggregate DAI value for said population;   determining a second dataset associated with a sample from said subject wherein said second dataset comprises the selected biomarkers;   determining a DAI score for said subject;   comparing the aggregate DAI value to the DAI score for the subject; and   determining disease activity of JIA in the subject, or predicting flare activity in the subject, based at least in part on said comparison.   
     
     
         11 . The method of  claim 10  wherein the biomarkers comprise VCAM-1, EGF, VEGF-A, IL-6, TNF-R1, MMP-1, MMP-3, YKL-40, Leptin, Resistin, SAA, and CRP. 
     
     
         12 . The method of  claim 10  wherein the biomarkers comprise IL-6, MMP3, CRP, TNF-R1, Calprotectin, YKL-40, ICAM-1, SAA, VCAM-1 and MMP1. 
     
     
         13 . The method of  claim 10  wherein the biomarkers comprise IL-6, MMP3, CRP, TNF-R1, YKL-40, ICAM-1, SAA, VCAM-1 and MMP1. 
     
     
         14 . The method of  claim 10  wherein said datasets are obtained by a method comprising:
 obtaining said samples from said population and said sample from said subject, wherein said samples comprise a plurality of analytes; 
 contacting said samples with reagents; 
 generating a plurality of complexes between said reagents with said plurality of analytes; and 
 detecting said plurality of complexes to obtain said datasets wherein said datasets comprise quantitative data for said biomarkers. 
 
     
     
         15 . The method of  claim 10  wherein said DAI score for the subject is predictive of a clinical assessment. 
     
     
         16 . The method of  claim 15  wherein said clinical assessment is selected from the group consisting of physician global assessment of disease activity (MD global), parent/child global assessment of well-being (PGA), child/parent health assessment questionnaire (CHAQ), active arthritic joint counts, Westergren erythrocyte sedimentation rate (ESR), and juvenile arthritis disease activity score (JADAS). 
     
     
         17 . The method of  claim 10  wherein said JIA is selected from the group consisting of oligoarticular JIA, polyarticular rheumatoid factor (RF) positive JIA, polyarticular RF negative JIA, systemic JIA, psoriatic JIA, enthesitis-related arthritis, and undifferentiated arthritis. 
     
     
         18 . The method of  claim 10 , further comprising:
 receiving a third dataset associated with a second sample obtained from said subject, wherein said sample obtained from said subject and said second sample are obtained from said subject at different times;   determining a second DAI score for said subject from said third dataset; and   comparing said DAI score and said second DAI score for said subject to determine a change in said DAI scores, wherein said change indicates a change in JIA activity in said subject, the presence of JIA in the subject, or the prediction of flare in a subject having JIA.   
     
     
         19 . The method of  claim 10  wherein a report is prepared in a format that is capable of being disseminated to the subject or a caregiver of the subject that provides information allowing the subject or caregiver to make decisions based on the disease or flare activity. 
     
     
         20 . The method of  claim 10  wherein said subject has received a treatment for JIA, and further comprising the steps of:
 determining a second DAI score for a second subject wherein said second subject is of the same species as said first subject and wherein said second subject has received treatment for JIA; 
 comparing said DAI score of said subject to said second DAI score; and 
 determining a treatment efficacy for said first subject based on said score comparison. 
 
     
     
         21 . A computer-implemented method for generating quantitative data for a subject, said method comprising:
 performing at least one immunoassay on a first sample from the first subject to generate a first dataset comprising the quantitative data, wherein the quantitative data comprises at least three or more biomarkers selected from the group consisting of alpha-2-macroglobulin (A2M); amyloid P component, serum (SAP); angiopoietin 1 (AGP1) antithrombin III (ATIII); ataxia telangiectasia mutated (ATM); B-cell activating factor (BAFF); chemokine (C—C motif) ligand 2 (CCL2); chemokine (C—C motif) ligand 3 (CCL3); chemokine (C—C motif) ligand 11 (CCL11); chemokine (C—C motif) ligand 22 (CCL22); chemokine (C—X—C motif) ligand 9 (CXCL9); chemokine (C—X—C motif) ligand 10 (CXCL10); CD40 ligand (CD40LG); C-reactive protein (CRP); complement C3; complement C4; complement factor H (CFH); epidermal growth factor (EGF); gelsolin (GSN); granzyme (GZM); haptoglobin (HP); heat shock protein 60 (HSP60); interleukin 6 (IL-6); leptin (LEP); MF; matrix metalloproteinase-1 (MMP1); matrix metalloproteinase-3 (MMP3); matrix metalloproteinase-9 (MMP9); resistin (RETN); serum amyloid (SAA); tumor necrosis factor receptor, type 1 (TNF-R1); vascular cell adhesion molecule-1 (VCAM1); vascular endothelial growth factor A (VEGF-A); YKL-40; Calprotectin; intercellular adhesion molecule 1 (ICAM-1); interleukin-1 beta (IL-1B); interleukin-6 receptor (IL-6R); interleukin-8 (IL-8); interleukin-8 (IL-10); interleukin-8 (IL-17); interleukin-8 (IL-18); interleukin-8 (IL-21); L-selectin; MDC; P-selectin; pyridinoline (PYD); S100 A12; S100A14; TIMP metallopeptidase inhibitor 1 (TIMP1); TNF receptor-associated protein 1 (TRAP-1); transthyretin (TTR); tumor protein 53 (TP53); and YKL-40;   comparing the first dataset to a trained dataset representing the at least three or more biomarkers; and   generating quantitative data that is derived from the difference between the first and trained datasets, wherein the first subject has JIA or is suspected of having JIA.   
     
     
         22 . The method of  claim 21  wherein the biomarkers comprise VCAM-1, EGF, VEGF-A, IL-6, TNF-R1, MMP-1, MMP-3, YKL-40, Leptin, Resistin, SAA, and CRP. 
     
     
         23 . The method of  claim 21  wherein the biomarkers comprise IL-6, MMP3, CRP, TNF-R1, Calprotectin, YKL-40, ICAM-1, SAA, VCAM-1 and MMP1. 
     
     
         24 . The method of  claim 21  wherein the biomarkers comprise IL-6, MMP3, CRP, TNF-R1, YKL-40, ICAM-1, SAA, VCAM-1 and MMP1. 
     
     
         25 . The method of  claim 21  wherein said DAI score for the subject is predictive of a clinical assessment. 
     
     
         26 . The method of  claim 25  wherein said clinical assessment is selected from the group consisting of physician global assessment of disease activity (MD global), parent/child global assessment of well-being (PGA), child/parent health assessment questionnaire (CHAQ), active arthritic joint counts, Westergren erythrocyte sedimentation rate (ESR), and juvenile arthritis disease activity score (JADAS). 
     
     
         27 . The method of  claim 21  wherein said JIA is selected from the group consisting of oligoarticular JIA, polyarticular rheumatoid factor (RF) positive JIA, polyarticular RF negative JIA, systemic JIA, psoriatic JIA, enthesitis-related arthritis, and undifferentiated arthritis. 
     
     
         28 . The method of  claim 21  wherein a report is prepared in a format that is capable of being disseminated to the subject or a caregiver of the subject that provides information allowing the subject or caregiver to make decisions based on the disease or flare activity. 
     
     
         29 . A method of treating a subject, the method comprising
 classifying disease activity of JIA in the subject, or predicting flare activity in the subject according to  claim 1 ; and   selecting a JIA therapeutic regimen based on said DAI score.   
     
     
         30 . The method of  claim 29  comprising providing said JIA therapeutic regimen. 
     
     
         31 . The method of  claim 29 , further comprising determining a response to the treatment based on said DAI score. 
     
     
         32 . The method of  claim 29 , further comprising determining a JIA treatment course based on said DAI score.