Methods for diagnosing and monitoring the status of systemic lupus erythematosus

• US 8,148,067 B2
• Filed: 11/09/2007
• Issued: 04/03/2012
• Est. Priority Date: 11/09/2006
• Status: Active Grant

• Current Assignee: CareDx, Inc.
• Original Assignee: XDx Incorporated
• Inventors: Lal, Preeti G., Williams, Gavin E., Fry, Kirk E., Sun, Jingtao, Dedrick, Russell L.
• Primary Examiner(s): Martinell, James
• Application Number:
  US11/938,227
• Publication Number:
  US 20090298060A1
• Time in Patent Office: 1,607 Days
• Field of Search: None
• US Class Current: 435/6.1
• CPC Class Codes: C12Q 1/6809 Methods for determination or identification of nucleic acids involving differential detection
• CPC Class Codes: C12Q 1/6883 for diseases caused by alterations of genetic material
• CPC Class Codes: C12Q 2600/106 Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
• CPC Class Codes: C12Q 2600/112 Disease subtyping, staging or classification

Abstract

The invention presents a method of diagnosing or monitoring the status of systemic lupus erythematosus (SLE) in a subject or patient comprising detecting the expression of all genes of a diagnostic set in the subject or patient wherein the diagnostic set comprises two or more genes having expression correlated with the classification or status of SLE; and diagnosing or monitoring the status of SLE in the subject or patient by applying at least one statistical method to the expression of the genes of the diagnostic set.

Claims

1. A method of diagnosing a patient as having a longitudinally stable classification of SLE comprising:

detecting the expression of two or more interferon response (INFr) genes in a sample from the patient; and

diagnosing the patient as having type 1 or type 2 SLE based on analyzing the expression of the two or more genes using a statistical method, wherein expression of the two or more interferon response genes correlates with the expression of IFI27 from about 0.5 to about 1.0 and from about −

0.5 to about −

1.0 as calculated using a Pearson correlation.

2. The method of claim 1 wherein at least one of the two or more genes is selected from the group consisting of the genes comprising SEQ ID NOs:

589-802.

3. The method of claim 1 wherein the statistical method comprises a linear algorithm to produce an INFr score.

4. The method of claim 3 wherein the INFr score is determined to be a high INFr score if the score is above an average of INFr scores taken from a plurality of patients, and the INFr score is determined to be a low INFr score if the score is below an average of INFr scores taken from a plurality of patients.

5. The method of claim 4 wherein a high INFr score is correlated with type 1 SLE and a low INFr score is correlated with type 2 SLE.

6. The method of claim 3 wherein the linear algorithm comprises IFI27 +IFI144*(1.1296) +OAS3*(1.8136).

7. The method of claim 1 further comprising assigning the patient to a clinical trial based on the diagnosis of type 1 or type 2 SLE.

8. The method of claim 1 further comprising monitoring the status of the patient based on the diagnosis of type 1 or type 2 SLE.

9. The method of claim 8 wherein the status of the patient is incipient flare or disease activity.

10. The method of claim 8 wherein the status of the patient comprises a response to a therapeutic agent administered to the patient.

11. The method of claim 10 wherein the therapeutic agent is selected from the group consisting of ACE inhibitors, aspirin, azathioprine, B7RP-1-fc,β

-blockers, brequinar sodium, campath-1H, celecoxib, chloroquine, corticosteroids, warfarin, cyclophosphamide, cyclosporin A, dehydroepiandrosterone, deoxyspergualin, dexamethasone, diclofenac, diflunisal, etodolac, everolimus, FK778, piroxicam, fenoprofen, flurbiprofen, heparin, hydralazine, hydroxychloroquine, CTLA-4 or LFA3 immunoglobulin, ibuprofen, indomethacin, ISAtx-247, ketoprofen, ketorolac, leflunomide, meclophenamate, mefenamic acid, mepacrine, 6-mercaptopurine, meloxicam, methotrexate, mizoribine, mycophenolate mofetil, naproxen, oxaprozin, hydroxychloroquine, NOX-100, prednisone, methylprednisolone, rapamycin (sirolimus), sulindac, tacrolimus anti-thymocyte globulin, tolmetin, tresperimus, U0126, and antibodies including but not limited to alpha lymphocyte antibodies, adalimumab, anti-CD3, anti-CD25, anti-CD52, anti-IL2R, and anti-TAC antibodies, basiliximab, daclizumab, etanercept, hu5C8, infliximab, OKT4, and natalizumab.

12. The method of claim 8 wherein the status of the patient comprises a response to an immunosuppressant administered to the patient.

13. The method of claim 12 wherein the immunosuppressant is selected from the group consisting of aspirin, azathioprine, chloroquine, corticosteroids, cyclophosphamide, cyclosporin A, dehydroepiandrosterone, deoxyspergualin, dexamethasone, everolimus, fenoprofen, hydralazine, hydroxychloroquine, immunoglobulin, ibuprofen, indomethacin, leflunomide, ketoprofen, meclophenamate, mepacrine, 6-mercaptopurine, methotrexate, mizoribine, mycophenolate mofetil, naproxen, prednisone, methylprednisolone, rapamycin (sirolimus), methylprednisolone sodium succinate, tacrolimus, anti-thymocyte globulin, tolmetin, tresperimus, and triamcinolone.

14. A method for predicting flare in a patient diagnosed with SLE comprising:

analyzing expression in a sample from the patient to produce a gene expression profile

wherein a first portion of the analysis comprises using the expression of at least one gene selected from each of at least two of the clusters 1 through 15 of Table 1 and at least one statistical method to produce a patient gene expression profile, and

a second portion of the analysis comprises using expression of at least two interferon response genes and a linear algorithm to classify the patient as having type 1 SLE or type 2 SLE, wherein expression of the two or more interferon response genes correlates with the expression of IFI27 from about 0.5 to about 1.0 and from about −

0.5 to about −

1.0 as calculated using a Pearson correlation; and

predicting flare by comparing the patient gene expression profile to at least one reference profile.

15. The method of claim 14 wherein the at least two INFr genes are selected from the group consisting of the genes comprising SEQ ID NOs:

589-802.

16. The method of claim 14 wherein the at least one reference profile is selected from the group consisting of at least one normal subject, at least one patient classified as having type 1 SLE with quiescent status, at least one patient classified as having type 1 SLE in flare, at least one patient classified as having type 2 SLE with quiescent status, and at least one patient classified as having type 2 SLE in flare.