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US 12,140,592 B2Granted
Biomarkers for assessing risk of transitioning to systemic lupus erythematosus classification and disease pathogenesis
AssigneeOklahoma Medical Research Foundation
InventorsJudith Ann James, Melissa Elizabeth Munroe
Life of this patent
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Abstract
The present invention includes methods, systems, and kits, for identifying and modifying the treatment of a systemic lupus erythematosus (SLE) patient prior to the presence of autoantibodies, comprising: (a) obtaining a dataset representing protein expression level values for cytokines and molecules; (b) assessing the dataset for protein expression levels of at least one innate serum mediator; (c) assessing the dataset for protein expression levels of at least one adaptive serum mediator; and (d) determining the likelihood that the patient will develop SLE prior to the onset of autoantibodies when compared to a control.
Claims15
A method for determining, for a subject who has not reached clinical disease classification of systemic lupus erythematosus (SLE), a score indicative of whether the subject is at an increased risk to transition to clinical disease classification of SLE, comprising:
- (a) assessing a blood, serum, plasma, or urine sample obtained from the subject for an amount of protein expression of innate serum or plasma mediator biomarkers comprising each of:
- interleukin-1α (IL-1α), interleukin-1β (IL-1β), interleukin-1RA (IL-1RA), interleukin-12p70 (IL-12p70), interleukin-6 (IL-6), and interleukin-23p19 (IL-23p19);
- (b) assessing the sample for an amount of protein expression of adaptive serum or plasma mediator biomarkers comprising each of:
- interleukin-2 (IL-2), interferon-gamma (IFN-γ), interleukin-4 (IL-4), interleukin-5 (IL-5), interleukin-1β (IL-1β), interleukin-17A (IL-17A), interleukin-21 (IL-21), and transforming growth factor beta (TGF-β);
- (c) assessing the sample for an amount of protein expression of chemokine biomarkers comprising each of:
- Interleukin-8 (IL-8/CXCL8), interferon gamma-induced protein 10 (IP-10/CXCL10), monokine induced by gamma interferon (MIG/CXCL9), macrophage inflammatory protein-1alpha (MIP-1a/CCL3), and monocyte chemotactic protein-3 (MCP-3/CCL7);
- (d) assessing the sample for an amount of protein expression of soluble tumor necrosis factor (TNF) superfamily biomarkers comprising each of:
- TNFRI, TNFRII, Fas, CD40L/CD154, B Lymphocyte Stimulator (BLyS), and A proliferation-inducing ligand (APRIL);
- (e) assessing the sample for an amount of protein expression of inflammatory mediator biomarkers comprising each of:
- stem cell factor (SCF), plasminogen activator inhibitor 1 (PAL-1), and Resistin;
- (f) assessing the sample for an amount of SLE-associated autoantibody specificity biomarkers comprising each of:
- double-stranded DNA (dsDNA), chromatin, ribosomal P (RiboP), Sjögren's-syndrome-related antigen A (Ro/SSA), Sjögren's syndrome type B antigen (La/SSB), Sm, Sm-ribonucleoprotein (SmRNP), and ribonucleoprotein (RNP);
- (g) determining the score indicative of whether the subject will transition to clinical disease classification of SLE,
- wherein determining the score comprises:
- log transforming assessed expression levels for each of the plurality of innate serum or plasma mediator biomarkers, adaptive serum or plasma mediator biomarkers, chemokine biomarkers, TNF superfamily biomarkers, inflammatory mediator biomarkers, and SLE-associated-autoantibody specificity biomarkers;
- standardizing the assessed expression levels for each of the plurality of innate serum or plasma mediator biomarkers, adaptive serum or plasma mediator biomarkers, chemokine biomarkers, TNF superfamily biomarkers, inflammatory mediator biomarkers, and SLE-associated-autoantibody specificity biomarkers;
- weighting the assessed expression levels for each of the plurality of innate serum or plasma mediator biomarkers, adaptive serum or plasma mediator biomarkers, chemokine biomarkers, TNF superfamily biomarkers, inflammatory mediator biomarkers, and SLE-associated-autoantibody specificity biomarkers by a Spearman r correlation between a total number of positive autoantibody specificities and each of the plurality of innate serum or plasma mediator biomarkers, adaptive serum or plasma mediatory biomarkers, chemokine biomarkers, TNF superfamily biomarkers, inflammatory mediator biomarkers, and SLE-associated-autoantibody specificity biomarkers;
- and
- summing the assessed expression levels for each of the plurality of innate serum or plasma mediator biomarkers, adaptive serum or plasma mediator biomarkers, chemokine biomarkers, TNF-superfamily biomarkers, inflammatory mediator biomarkers, and SLE-associated-autoantibody specificity biomarkers to yield the score, wherein a higher score relative to a healthy control score indicates that the subject is at increased risk to transition to a clinical disease classification of SLE, wherein the healthy control score is based upon samples taken from at least one non-SLE subject who was not later classified as having SLE;
- and
- (h) administering a treatment to the subject who has not reached clinical disease classification after determining that the subject is at an increased risk to transition to a clinical disease classification of SLE, wherein the treatment comprises at least one of:
- hydroxychloroquine (HCQ), belimumab, a nonsteroidal anti-inflammatory drug, a steroid, and a disease-modifying anti-rheumatic drug (DMARD).
19 more elements
A method for assessing a subject who has not reached systemic lupus erythematosus (SLE) clinical disease classification comprising:
- (a) assessing a blood, serum, plasma, or urine sample obtained from the subject for an amount of protein expression of innate serum or plasma mediator biomarkers comprising each of:
- interleukin-1α (IL-1α), interleukin-1β (IL-1β), interleukin-1RA (IL-1RA), interleukin-12p70 (IL-12p70), interleukin-6 (IL-6), and interleukin-23p19 (IL-23p19);
- (b) assessing the sample for an amount of protein expression of adaptive serum or plasma mediator biomarkers comprising each of:
- interleukin-2 (IL-2), interferon-gamma (IFN-γ), interleukin-4 (IL-4), interleukin-5 (IL-5), interleukin-1β (IL-1β), interleukin-17A (IL-17A), interleukin-21 (IL-21), and transforming growth factor beta (TGF-β);
- (c) assessing the sample for an amount of protein expression of chemokine biomarkers comprising each of:
- Interleukin-8 (IL-8/CXCL8), interferon gamma-induced protein 10 (IP-10/CXCL10), monokine induced by gamma interferon (MTG/CXCL9), macrophage inflammatory protein-1alpha (MIP-1a/CCL3), and monocyte chemotactic protein-3 (MCP-3/CCL7);
- (d) assessing the sample for an amount of protein expression of soluble tumor necrosis factor (TNF) superfamily biomarkers comprising each of:
- TNFRI, TNFRII, Fas, CD40L/CD154, B Lymphocyte Stimulator (BLyS), and A proliferation-inducing ligand (APRIL);
- (e) assessing the sample for an amount of protein expression of inflammatory mediator biomarkers comprising each of:
- stem cell factor (SCF), plasminogen activator inhibitor 1 (PAL-1), and Resistin;
- (f) assessing the sample for an amount of SLE-associated autoantibody specificity biomarkers comprising each of:
- double-stranded DNA (dsDNA), chromatin, ribosomal P (RiboP), Sjögren's-syndrome-related antigen A (Ro/SSA), Sjögren's syndrome type B antigen (La/SSB), Sm, Sm-ribonucleoprotein (SmRNP), and ribonucleoprotein (RNP);
- (g) log transforming assessed expression levels for each of the plurality of innate serum or plasma mediator biomarkers, adaptive serum or plasma mediator biomarkers, chemokine biomarkers, TNF superfamily biomarkers, inflammatory mediator biomarkers, and SLE-associated-autoantibody specificity biomarkers;
- (h) standardizing the assessed expression levels for each of the plurality of innate serum or plasma mediator biomarkers, adaptive serum or plasma mediator biomarkers, chemokine biomarkers, TNF superfamily biomarkers, inflammatory mediator biomarkers, and SLE-associated-autoantibody specificity biomarkers;
- (i) weighting the assessed expression levels for each of the plurality of innate serum or plasma mediator biomarkers, adaptive serum or plasma mediator biomarkers, chemokine biomarkers, TNF superfamily biomarkers, inflammatory mediator biomarkers, and SLE-associated-autoantibody specificity biomarkers by a Spearman r correlation between a total number of positive autoantibody specificities and each of the plurality of innate serum or plasma mediator biomarkers, adaptive serum or plasma mediator biomarkers, chemokine biomarkers, TNF superfamily biomarkers, inflammatory mediator biomarkers, and SLE-associated-autoantibody specificity biomarkers;
- (j) summing the assessed expression levels for each of the plurality of innate serum or plasma mediator biomarkers, adaptive serum or plasma mediator biomarkers, chemokine biomarkers, TNF superfamily biomarkers, inflammatory mediator biomarkers, and SLE-associated-autoantibody specificity biomarkers;
- and
- (k) administering a treatment to the subject who has not reached clinical disease classification, wherein the treatment comprises at least one of:
- hydroxychloroquine (HCQ), belimumab, a nonsteroidal anti-inflammatory drug, a steroid, and a disease-modifying anti-rheumatic drug (DMARD).
16 more elements
A method for treating a subject who has not reached clinical disease classification of systemic lupus erythematosus (SLE), comprising:
- (a) obtaining a blood, serum, plasma or urine sample from the subject;
- (b) assessing the sample for an amount of protein expression of innate serum or plasma mediator biomarkers comprising each of:
- interleukin-1α (IL-1α), interleukin-1β (IL-1β), interleukin-1RA (IL-1RA), interleukin-12p70 (IL-12p70), interleukin-6 (IL-6), and interleukin-23p19 (IL-23p19);
- (c) assessing the sample for an amount of protein expression of adaptive serum or plasma mediator biomarkers comprising each of:
- interleukin-2 (IL-2), interferon-gamma (IFN-γ), interleukin-4 (IL-4), interleukin-5 (IL-5), interleukin-1β (IL-1β), interleukin-17A (IL-17A), interleukin-21 (IL-21), and transforming growth factor beta (TGF-β);
- (d) assessing the sample for an amount of protein expression of chemokine biomarkers comprising each of:
- Interleukin-8 (IL-8/CXCL8), interferon gamma-induced protein 10 (IP-10/CXCL10), monokine induced by gamma interferon (MIG/CXCL9), macrophage inflammatory protein-1alpha (MIP-1a/CCL3), and monocyte chemotactic protein-3 (MCP-3/CCL7);
- (e) assessing the sample for an amount of protein expression of soluble tumor necrosis factor (TNF) superfamily biomarkers comprising each of:
- TNFRI, TNFRII, Fas, CD40L/CD154, and B Lymphocyte Stimulator (BLyS), and A proliferation-inducing ligand (APRIL);
- (f) assessing the sample for an amount of protein expression of inflammatory mediator biomarkers comprising each of:
- stem cell factor (SCF), plasminogen activator inhibitor 1 (PAL-1), and Resistin;
- (g) assessing the sample for an amount of SLE-associated autoantibody specificity biomarkers comprising each of:
- double-stranded DNA (dsDNA), chromatin, ribosomal P (RiboP), Sjögren's-syndrome-related antigen A (Ro/SSA), Sjögren's syndrome type B antigen (La/SSB), Sm, Sm-ribonucleoprotein (SmRNP), and ribonucleoprotein (RNP);
- (h) log transforming assessed expression levels for each of the plurality of innate serum or plasma mediator biomarkers, adaptive serum or plasma mediator biomarkers, chemokine biomarkers, TNF superfamily biomarkers, inflammatory mediator biomarkers, and SLE-associated-autoantibody specificity biomarkers;
- (i) standardizing the assessed expression levels for each of the plurality of innate serum or plasma mediator biomarkers, adaptive serum or plasma mediator biomarkers, chemokine biomarkers, TNF superfamily biomarkers, inflammatory mediator biomarkers, and SLE-associated-autoantibody specificity biomarkers;
- (j) weighting the assessed expression levels for each of the plurality of innate serum or plasma mediator biomarkers, adaptive serum or plasma mediator biomarkers, chemokine biomarkers, TNF superfamily biomarkers, inflammatory mediator biomarkers, and SLE-associated-autoantibody specificity biomarkers by a Spearman r correlation between a total number of autoantibody specificities and each of the plurality of innate serum or plasma mediator biomarkers, adaptive serum or plasma mediator biomarkers, chemokine biomarkers, TNF superfamily biomarkers, inflammatory mediator biomarkers, and SLE-associated-autoantibody specificity biomarkers;
- (k) summing the assessed expression levels for each of the plurality of innate serum or plasma mediator biomarkers, adaptive serum or plasma mediator biomarkers, chemokine biomarkers, TNF superfamily biomarkers, inflammatory mediator biomarkers, and SLE-associated-autoantibody specificity biomarkers;
- and
- (l) administering a treatment to the subject prior to the subject reaching clinical disease classification of SLE, wherein the treatment comprises at least one of:
- hydroxychloroquine (HCQ), belimumab, a nonsteroidal anti-inflammatory drug, a steroid, and a disease-modifying anti-rheumatic drug (DMARD),
- wherein the treatment is initiated prior to the subject reaching clinical disease classification of SLE.
18 more elements
A method for treating a subject who has not reached clinical disease classification of systemic lupus erythematosus (SLE) prior to the subject reaching clinical disease classification of SLE, comprising administering a treatment to the subject prior to the subject reaching clinical disease classification of SLE, wherein the treatment comprises at least one of:
- hydroxychloroquine (HCQ), belimumab, a nonsteroidal anti-inflammatory drug, a steroid, and a disease-modifying anti-rheumatic drug (DMARD),
- wherein the clinical disease classification of SLE of the subject is determined by the steps of:
- (a) obtaining a blood, serum, plasma or urine sample from the subject;
- (b) assessing the sample for an amount of protein expression of innate serum or plasma mediator biomarkers comprising each of:
- interleukin-1α (IL-1α), interleukin-1β (IL-1β), interleukin-1RA (IL-1RA), interleukin-12p70 (IL-12p70), interleukin-6 (IL-6), and interleukin-23p19 (IL-23p19);
- (c) assessing the sample for an amount of protein expression of adaptive serum or plasma mediator biomarkers comprising each of:
- interleukin-2 (IL-2), interferon-gamma (IFN-γ), interleukin-4 (IL-4), interleukin-5 (IL-5), interleukin-1β (IL-13), interleukin-17A (IL-17A), interleukin-21 (IL-21), and transforming growth factor beta (TGF-β);
- (d) assessing the sample for an amount of protein expression of chemokine biomarkers comprising each of:
- Interleukin-8/(IL-8/CXCL8), interferon gamma-induced protein 10 (IP-10/CXCL10), monokine induced by gamma interferon (MIG/CXCL9), macrophage inflammatory protein-1alpha (MIP-1a/CCL3), and monocyte chemotactic protein-3 (MCP-3/CCL7);
- (e) assessing the sample for an amount of protein expression of soluble tumor necrosis factor (TNF) superfamily biomarkers comprising each of:
- TNFRI, TNFRII, Fas, CD40L/CD154, and B Lymphocyte Stimulator (BLyS), and A proliferation-inducing ligand (APRIL);
- (f) assessing the sample for an amount of protein expression of inflammatory mediator biomarkers comprising each of:
- stem cell factor (SCF), plasminogen activator inhibitor 1 (PAL-1), and Resistin;
- (g) assessing the sample for an amount of SLE-associated autoantibody specificity biomarkers comprising each of:
- double-stranded DNA (dsDNA), chromatin, ribosomal P (RiboP), Sjögren's-syndrome-related antigen A (Ro/SSA), Sjögren's syndrome type B antigen (La/SSB), Sm, Sm-ribonucleoprotein (SmRNP), and ribonucleoprotein (RNP);
- (h) log transforming assessed expression levels for each of the plurality of innate serum or plasma mediator biomarkers, adaptive serum or plasma mediator biomarkers, chemokine biomarkers, TNF superfamily biomarkers, inflammatory mediator biomarkers, and SLE-associated-autoantibody specificity biomarkers;
- (i) standardizing the assessed expression levels for each of the plurality of innate serum or plasma mediator biomarkers, adaptive serum or plasma mediator biomarkers, chemokine biomarkers, TNF superfamily biomarkers, inflammatory mediator biomarkers, and SLE-associated-autoantibody specificity biomarkers;
- (j) weighting the assessed expression levels for each of the plurality of innate serum or plasma mediator biomarkers, adaptive serum or plasma mediator biomarkers, chemokine biomarkers, TNF superfamily biomarkers, inflammatory mediator biomarkers, and SLE-associated-autoantibody specificity biomarkers by a Spearman r correlation between a total number of autoantibody specificities and each of the plurality of innate serum or plasma mediator biomarkers, adaptive serum or plasma mediator biomarkers, chemokine biomarkers, TNF superfamily biomarkers, inflammatory mediator biomarkers, and SLE-associated-autoantibody specificity biomarkers;
- and
- (k) summing the assessed expression levels for each of the plurality of innate serum or plasma mediator biomarkers, adaptive serum or plasma mediator biomarkers, chemokine biomarkers, TNF superfamily biomarkers, inflammatory mediator biomarkers, and SLE-associated-autoantibody specificity biomarkers.
17 more elements
Dependencies are inferred from the claim text.