Method for Evaluating Risk in Multiple Sclerosis

Abstract

The invention relates to methods and reagents for diagnosing and assessing the prognosis of multiple sclerosis. The present invention is based, in part, upon the discovery that anti-glycan antibodies are useful in evaluating the risk of whether clinically isolated syndrome (CIS) patients suggestive of Multiple sclerosis (MS) will have a clinical relapse within, e.g., 24 months. The invention is also based upon the discovery that anti-glycan antibodies are useful for evaluating the risk of CIS patients suggestive of MS to have a rapid disease progression and accumulate disabilities, e.g., permanent disability, within a certain time frame, e.g., 5 years.

1 . A method of identifying a subject with a clinically isolated syndrome (CIS) who will progress to clinically definitive multiple sclerosis (CDMS) within twenty-four months, the method comprising:
 providing a test sample from said subject;   detecting in said test sample an anti-Glc (α 1,2) Glc (α) antibody, an anti-Glc (α 1,3) Glc (α) antibody, an anti-Glc (α 1,4) Glc (α) antibody, and an anti-Glc (α 1,6) Glc (α) antibody; and   comparing the levels of said antibodies in said test sample to a reference level of said antibodies, wherein a higher level of at least one of said antibodies compared to the reference level of said antibodies indicates that said subject is likely to progress to CDMS within twenty-four months.   
   
   
       2 . The method of  claim 1 , wherein a higher level of one of said antibodies in said test sample compared to the reference level of said antibodies indicates said subject is at risk of having a second neurological attack within thirty-six months. 
   
   
       3 . The method of  claim 1 , wherein a higher level of one of said antibodies in said test sample compared to the reference level of said antibodies indicates said subject is at risk of having a second neurological attack within forty-eight months. 
   
   
       4 . The method of  claim 1 , wherein said test sample is a biological fluid is whole blood, serum, or plasma. 
   
   
       5 . The method of  claim 1 , wherein said antibodies are IgM isotype antibodies. 
   
   
       6 . A method of identifying a subject with CIS who is likely to experience rapid progression of MS disease severity within twenty years, the method comprising:
 providing a test sample from a subject at the time of a CIS;   detecting in said test sample an anti-Glc(α1,2)Glc(α) (GAGA2) antibody, an anti-Glc(α1,3)Glc(α) (GAGA3) antibody, an anti-Glc(α1,4)Glc(α) (GAGA4) antibody, or an anti-Glc(α1,6)Glc(α) (GAGA6) antibody;   comparing the sample level of each antibody in said test sample to a reference level of said antibody; and   wherein a higher level of at least one of said antibodies compared to said reference level indicates that said subject is likely to progress greater than one unit in EDSS score within twenty years, said EDSS score being indicative of disease severity.   
   
   
       7 . The method of  claim 6 , wherein a higher level of at least one of said antibodies indicates that said subject is likely to progress at least two units in EDSS score within twenty years. 
   
   
       8 . The method of  claim 6 , wherein a higher level of at least one of said antibodies indicates that said subject is likely to progress at least three units in EDSS score within twenty years. 
   
   
       9 . The method of  claim 6 , wherein a higher level of at least one of said antibodies indicates that said subject is likely to progress greater than three units in EDSS score within twenty years. 
   
   
       10 . The method of  claim 6 , wherein a higher level of at least one of said antibodies indicates that said subject is likely to progress greater than six units in EDSS score within twenty years. 
   
   
       11 . The method of  claim 6 , wherein a higher level of at least one of said antibodies indicates that said subject is likely to progress greater than one unit in EDSS score within ten years 
   
   
       12 . The method of  claim 6 , wherein a higher level of at least one of said antibodies indicates that said subject is likely to progress greater than one unit in EDSS score within seven years. 
   
   
       13 . The method of  claim 6 , wherein a higher level of at least one of said antibodies indicates that said subject is likely to progress greater than one unit in EDSS score within five years. 
   
   
       14 . The method of  claim 6 , wherein a higher level of at least one of said antibodies indicates that said subject is likely to progress greater than one unit in EDSS score within four years. 
   
   
       15 . The method of  claim 6 , wherein said test sample is a biological fluid is whole blood, serum, or plasma. 
   
   
       16 . The method of  claim 6 , wherein said antibodies are IgM isotype antibodies. 
   
   
       17 . A method of identifying a subject with CIS who is likely to experience a slow progression of MS disease severity, the method comprising:
 providing a test sample from a subject at the time of a CIS;   detecting in said test sample an anti-Glc(α1,2)Glc(α) (GAGA2) antibody, an anti-Glc(α1,3)Glc(α) (GAGA3) antibody, an anti-Glc(α1,4)Glc(α) (GAGA4) antibody, and an anti-Glc(α1,6)Glc(α) (GAGA6) antibody;   comparing the sample level of each antibody in said test sample to a reference level of said antibody; and   wherein a equal or lower level of each of said antibodies indicates that said subject is likely to progress slowly in EDSS score within twenty years, said EDSS score being indicative of disease severity.   
   
   
       18 . The method of  claim 17 , wherein an equal or lower level of each of said antibodies indicates that said subject is likely to not progress greater than one unit in EDSS score within five years. 
   
   
       19 . The method of  claim 17 , wherein said test sample is a biological fluid is whole blood, serum, or plasma. 
   
   
       20 . The method of  claim 17 , wherein said antibodies are IgM isotype antibodies. 
   
   
       21 . A method of identifying a subject who will develop breakthrough MS, the method comprising:
 providing a test sample from said subject;   detecting in said test sample an anti-Glc (α 1,2) Glc (α) antibody, an anti-Glc (α 1,3) Glc (α) antibody, an anti-Glc (α 1,4) Glc (α) antibody, and an anti-Glc (α 1,6) Glc (α) antibody; and   comparing the levels of said antibodies in said test sample to a reference level of said antibodies, wherein a higher level of at least one of said antibodies compared to the reference level of said antibodies indicates that said subject is likely to develop breakthrough MS.   
   
   
       22 . The method of  claim 21 , wherein a higher level of at least one of said antibodies indicates that said subject is likely to develop breakthrough MS within five years. 
   
   
       23 . The method of  claim 21 , wherein said test sample is a biological fluid is whole blood, serum, or plasma. 
   
   
       24 . The method of  claim 21 , wherein said antibodies are IgM isotype antibodies. 
   
   
       25 . A computer-readable medium having computer-executable instructions for performing a method comprising:
 storing at least one first variable associated with the level of at least one antibody in a test sample of a CIS patient;   storing at least one second variable associated with at least one reference level;   calculating the patient's risk factor for conversion to clinically definite multiple sclerosis (CDMS) as a function of at least the first and second variables; and   outputting the risk factor.   
   
   
       26 . The computer-readable medium of  claim 25 , wherein the at least one first variable corresponds to levels of an anti-Glc (α 1,2) Glc (α) antibody, an anti-Glc (α 1,3) Glc (α) antibody, an anti-Glc (α 1,4) Glc (α) antibody, and an anti-Glc (α 1,6) Glc (α) antibody in the test sample. 
   
   
       27 . The computer-readable medium of  claim 25 , wherein the at least one first variable corresponds to at least one level of antibody in the test sample selected from the group consisting of: an anti-Glc(α1,2)Glc(α) (GAGA2) IgM isotype antibody, an anti-Glc(α1,3)Glc(α) (GAGA3) IgM isotype antibody, an anti-Glc(α1,4)Glc(α) (GAGA4) IgM isotype antibody, and an anti-Glc(α1,6)Glc(α) (GAGA6) IgM isotype antibody. 
   
   
       28 . A computer-readable medium having computer-executable instructions for performing a method comprising:
 storing at least one first variable associated with the level of at least one antibody in a test sample of a CIS patient;   storing at least one second variable associated with at least one reference level;   calculating the patient's risk factor for progressing in EDSS score as a function of at least the first and second variables; and   outputting the risk factor.   
   
   
       29 . The computer-readable medium of  claim 28 , wherein the at least one first variable corresponds to levels of an anti-Glc (α 1,2) Glc (α) antibody, an anti-Glc (α 1,3) Glc (α) antibody, an anti-Glc (α 1,4) Glc (α) antibody, and an anti-Glc (α 1,6) Glc (α) antibody in the test sample. 
   
   
       30 . The computer-readable medium of  claim 28 , wherein the at least one first variable corresponds to at least one level of antibody in the test sample selected from the group consisting of an anti-Glc(α1,2)Glc(α) (GAGA2) IgM isotype antibody, an anti-Glc(α1,3)Glc(α) (GAGA3) IgM isotype antibody, an anti-Glc(α1,4)Glc(α) (GAGA4) IgM isotype antibody, and an anti-Glc(α1,6)Glc(α) (GAGA6) IgM isotype antibody. 
   
   
       31 . A computer-readable medium having computer-executable instructions for performing a method comprising:
 storing at least one first variable associated with the level of at least one antibody in a test sample of a patient;   storing at least one second variable associated with at least one reference level;   calculating the patient's risk factor for developing breakthrough MS as a function of at least the first and second variables; and   outputting the risk factor.   
   
   
       32 . The computer-readable medium of  claim 31 , wherein the at least one first variable corresponds to levels of an anti-Glc (α 1,2) Glc (α) antibody, an anti-Glc (α 1,3) Glc (α) antibody, an anti-Glc (α 1,4) Glc (α) antibody, and an anti-Glc (α 1,6) Glc (α) antibody in the test sample. 
   
   
       33 . The computer-readable medium of  claim 31 , wherein the at least one first variable corresponds to at least one level of antibody in the test sample selected from the group consisting of: an anti-Glc(α1,2)Glc(α) (GAGA2) IgM isotype antibody, an anti-Glc(α1,3)Glc(α) (GAGA3) IgM isotype antibody, an anti-Glc(α1,4)Glc(α) (GAGA4) IgM isotype antibody, and an anti-Glc(α1,6)Glc(α) (GAGA6) IgM isotype antibody.