Detection and diagnosis of inflammatory disorders

• US 7,989,173 B2
• Filed: 08/25/2008
• Issued: 08/02/2011
• Est. Priority Date: 12/27/2006
• Status: Expired due to Fees

• Current Assignee: Johns Hopkins University
• Original Assignee: Johns Hopkins University
• Inventors: Chen, Lieping
• Primary Examiner(s): OUSPENSKI, ILIA I
• Application Number:
  US12/198,014
• Publication Number:
  US 20090011444A1
• Time in Patent Office: 1,072 Days
• Field of Search: None
• US Class Current: 435/7.1
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 27/16 Otologicals
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 7/06 Antianaemics
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: G01N 2800/10 Musculoskeletal or connective tissue disorders
• CPC Class Codes: G01N 33/6875 Nucleoproteins

Abstract

Soluble H4 (sH4) levels have been discovered to correlate with the stage or severity of inflammatory disorders including autoimmune disorders. In particular, circulating levels of sH4 can be used as a diagnostic for determining the severity of an inflammatory disorder or the propensity for developing an inflammatory disorder. The severity of an inflammatory disorder can be determined by assaying the levels of sH4 in a subject and comparing the levels of sH4 to reference sH4 concentrations that correlate to specific stages of an inflammatory disorder. The therapeutic efficacy of treatments for inflammatory disorders can also be determined by comparing levels of sH4 before and during treatment. Methods and devices for measuring sH4 are also provided.

Claims

1. A method for determining the severity of an inflammatory disorder in a subject having or suspected of having an inflammatory disorder comprising

(a) determining the level of soluble B7-H4 in a biological sample from a subject;

and

(b) comparing the level of soluble B7-H4 in the biological sample to reference levels of soluble B7-H4 that correlate with disease severity of an inflammatory disorder to determine the severity of the inflammatory disorder of the subject.

2. The method of claim 1 wherein the inflammatory disorder is selected from the group consisting of rheumatoid arthritis, systemic lupus erythematosus, alopecia areata, anklosing spondylitis, antiphospholipid syndrome, autoimmune Addison'"'"'s disease, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune inner ear disease, autoimmune lymphoproliferative syndrome (alps), autoimmune thrombocytopenic purpura (ATP), Behcet'"'"'s disease, bullous pemphigoid, cardiomyopathy, celiac sprue-dermatitis, chronic fatigue syndrome immune deficiency, syndrome (CFIDS), chronic inflammatory demyelinating polyneuropathy, cicatricial pemphigoid, cold agglutinin disease, Crest syndrome, Crohn'"'"'s disease, Dego'"'"'s disease, dermatomyositis, dermatomyositis—

juvenile, discoid lupus, essential mixed cryoglobulinemia, fibromyalgia—

fibromyositis, grave'"'"'s disease, guillain-barre, hashimoto'"'"'s thyroiditis, idiopathic pulmonary fibrosis, idiopathic thrombocytopenia purpura (ITP), Iga nephropathy, insulin dependent diabetes (Type I), juvenile arthritis, Meniere'"'"'s disease, mixed connective tissue disease, multiple sclerosis, myasthenia gravis, pemphigus vulgaris, pernicious anemia, polyarteritis nodosa, polychondritis, polyglancular syndromes, polymyalgia rheumatica, polymyositis and dermatomyositis, primary agammaglobulinemia, primary biliary cirrhosis, psoriasis, Raynaud'"'"'s phenomenon, Reiter'"'"'s syndrome, rheumatic fever, sarcoidosis, scleroderma, Sjogren'"'"'s syndrome, stiff-man syndrome, Takayasu arteritis, temporal arteritis/giant cell arteritis, ulcerative colitis, uveitis, vasculitis, vitiligo, and Wegener'"'"'s granulomatosis.

3. The method of claim 1 wherein the soluble B7-H4 levels are determined from a fluid sample obtained from the subject.

4. The method of claim 3 wherein the fluid sample is selected from the group consisting of blood, plasma, saliva, lymph, cerebrospinal fluid, synovial fluid, urine, and sputum.

5. The method of claim 1 wherein levels of soluble B7-H4 are determined using mass spectroscopy, immunohistological methods, immunoprecipitation, an enzyme immunoassay, and a radioimmunoassay.

19. The method of claim 3 wherein the fluid is serum and the inflammatory disorder is rheumatoid arthritis or systemic lupus erythematosus.

20. The method of claim 19 wherein the inflammatory disease is rheumatoid arthritis and wherein a serum reference level of less than about 100 ng/ml is indicative of less than 4 active joints and a reference level of greater than about 100 ng/ml is indicative of 5 or more active joints.

6. A method for assisting in the diagnosis of an inflammatory disorder or assessing the propensity for developing an inflammatory disorder in a subject comprising

determining the level of soluble B7-H4 in a biological sample from a subject, wherein an elevated level of soluble B7-H4 in the biological sample relative to the level of soluble B7-H4 in a control is indicative of an inflammatory disorder or an increased propensity for developing an inflammatory disorder.

7. The method of claim 6 wherein the biological sample is selected from the group consisting of blood, plasma, saliva, lymph, cerebrospinal fluid, synovial fluid, urine, and sputum.

8. The method of claim 6 wherein levels of soluble B7-H4 are determined using mass spectroscopy, immunohistological methods, immunoprecipitation, an enzyme immunoassay, and a radioimmunoassay.

10. The method of claim 6 wherein the biological sample is selected from the group consisting of blood, plasma, saliva, lymph, cerebrospinal fluid, synovial fluid, urine, and sputum.

11. The method of claim 6 wherein levels of soluble B7-H4 are determined using mass spectroscopy, immunohistological methods, immunoprecipitation, an enzyme immunoassay, and a radioimmunoassay.

21. The method of claim 6 wherein the control is the level of soluble B7-H4 in a biological sample from a subject without an inflammatory disorder.

22. The method of claim 21 wherein the control is pooled or averaged from more than one subject without an inflammatory disorder.

23. The method of claim 6 wherein the biological sample is serum and the inflammatory disorder is rheumatoid arthritis or systemic lupus erythematosus.

9. A method for determining the efficacy of a treatment for an inflammatory disorder in a subject comprising

determining the level of soluble B7-H4 from one or more biological samples obtained from the subject before or during the course of the treatment, wherein a decrease in the level of soluble B7-H4 in samples obtained from the subject over time is indicative that the treatment is efficacious.

24. The method of claim 9 wherein the biological sample is serum and the inflammatory disorder is rheumatoid arthritis or systemic lupus erythematosus.

12. A method for determining neutrophil levels of a subject comprising

(a) determining the level of soluble B7-H4 in a biological sample obtained from the subject;

(b) comparing the level of soluble B7-H4 in the biological sample to reference levels of soluble B7-H4 wherein the reference levels correlate with levels of neutrophils; and

(c) selecting the level of neutrophils that matches the level of soluble B7-H4 in the biological sample.

13. The method of claim 12 wherein elevated levels of soluble B7-H4 relative to a control are indicative of elevated levels of neutrophils relative to a control.

25. The method of claim 13 wherein the control is the level of soluble B7-H4 in a biological sample from a subject without an inflammatory disorder.

26. The method of claim 25 wherein the control is pooled or averaged from more than one subject without an inflammatory disorder.

14. A method for selecting a subject for treatment of an inflammatory disorder comprising

(a) determining the level of soluble B7-H4 in a biological sample obtained from the subject;

(b) comparing the level of soluble B7-H4 in the biological sample to the level of soluble B7-H4 in a control;

and

(c) selecting the subject for treatment when the level of soluble B7-H4 in the biological sample is higher than the level of soluble B7-H4 in the control.

15. The method of claim 14 wherein the inflammatory disorder is selected from the group consisting of rheumatoid arthritis, systemic lupus erythematosus, alopecia areata, anklosing spondylitis, antiphospholipid syndrome, autoimmune Addison'"'"'s disease, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune inner ear disease, autoimmune lymphoproliferative syndrome (alps), autoimmune thrombocytopenic purpura (ATP), Behcet'"'"'s disease, bullous pemphigoid, cardiomyopathy, celiac sprue-dermatitis, chronic fatigue syndrome immune deficiency, syndrome (CFIDS), chronic inflammatory demyelinating polyneuropathy, cicatricial pemphigoid, cold agglutinin disease, Crest syndrome, Crohn'"'"'s disease, Dego'"'"'s disease, dermatomyositis, dermatomyositis—

juvenile, discoid lupus, essential mixed cryoglobulinemia, fibromyalgia—

fibromyositis, grave'"'"'s disease, guillain-barre, hashimoto'"'"'s thyroiditis, idiopathic pulmonary fibrosis, idiopathic thrombocytopenia purpura (ITP), Iga nephropathy, insulin dependent diabetes (Type I), juvenile arthritis, Meniere'"'"'s disease, mixed connective tissue disease, multiple sclerosis, myasthenia gravis, pemphigus vulgaris, pernicious anemia, polyarteritis nodosa, polychondritis, polyglancular syndromes, polymyalgia rheumatica, polymyositis and dermatomyositis, primary agammaglobulinemia, primary biliary cirrhosis, psoriasis, Raynaud'"'"'s phenomenon, Reiter'"'"'s syndrome, rheumatic fever, sarcoidosis, scleroderma, Sjogren'"'"'s syndrome, stiff-man syndrome, Takayasu arteritis, temporal arteritis/giant cell arteritis, ulcerative colitis, uveitis, vasculitis, vitiligo, and Wegener'"'"'s granulomatosis.

16. The method of claim 14 wherein the biological sample is a fluid sample.

17. The method of claim 16 wherein the fluid sample is selected from the group consisting of blood, plasma, saliva, lymph, cerebrospinal fluid, synovial fluid, urine, and sputum.

18. The method of claim 14 wherein the level of soluble B7-H4 in the biological sample is determined using a method selected from the group consisting of mass spectroscopy, immunohistological methods, immunoprecipitation, enzyme immunoassays, or a radioimmunoassay.

27. The method of claim 14 wherein the control is level of soluble B7-H4 in a biological sample from a subject without an inflammatory disorder.

28. The method of claim 27 wherein the control is pooled or averaged from more than one subject without an inflammatory disorder.

29. The method of claim 16 wherein the fluid is serum and the inflammatory disease is rheumatoid arthritis or systemic lupus erythematosus.

30. A method for determining the efficacy of a treatment for an inflammatory disorder in a subject comprising

determining the levels of soluble B7-H4 in a first biological sample and a second biological sample taken after the first sample,

wherein the samples are obtained from the subject over the course of the treatment, and

wherein a decrease in the level of soluble B7-H4 in the second sample compared to the first sample is indicative that the treatment is efficacious.

31. The method of claim 30 wherein the biological samples are selected from the group consisting of blood, plasma, saliva, lymph, cerebrospinal fluid, synovial fluid, urine, and sputum.

32. The method of claim 30 wherein levels of soluble B7-H4 are determined using mass spectroscopy, immunohistological methods, immunoprecipitation, an enzyme immunoassay, and a radioimmunoassay.

33. The method of claim 30 wherein the biological samples are serum and the inflammatory disorder is rheumatoid arthritis or systemic lupus erythematosus.

34. A method for assisting in the diagnosis of an inflammatory disorder or assessing the propensity for developing an inflammatory disorder in a subject comprising determining the levels of soluble B7-H4 in a first biological sample and a second biological sample taken after the first sample, wherein an increase in the level of soluble B7-H4 in the second sample compared to the first sample is indicative of development or worsening of an autoimmune disease.

35. A method for selecting a subject for treatment of an inflammatory disorder comprising determining the levels of soluble B7-H4 in a first biological sample and a second biological sample taken after the first sample, and selecting the subject for treatment when the level of soluble B7-H4 in the second biological sample is higher than the level of soluble B7-H4 in the first sample.

36. The method of claim 35 wherein the treatment comprises administering to the subject an effective amount of an antagonist of soluble B7-H4 or an agonist of B7-H4.