DETERMINING RESPONSIVENESS OF AUTOIMMUNE PATIENTS TO DMARD TREATMENT
The invention is directed to a method of screening patients suffering from an autoimmune disease for responsiveness to treatment with a disease modifying anti-rheumatic drug, or DMARD. In some embodiments the method of the invention comprises the steps of (a) measuring an IgH clonotype profile from B-cells in a sample of tissue affected by the autoimmune disease, the IgH clonotype profile including IgH clonotypes, IgG clonotypes, and IgD clonotypes; and (b) classifying a patient as being more likely to respond to DMARD treatment, whenever the patient has, with respect to reference levels characteristic of normal tissue, elevated IgH concentration, elevated IgG fraction, and reduced IgD fraction.
1 . A method of screening patients suffering from an autoimmune disease for responsiveness to treatment with a disease modifying anti-rheumatic drug (DMARD), the method comprising the steps of:
determining an IgH clonotype profile from B-cells in a sample of tissue affected by the autoimmune disease, the IgH clonotype profile including IgH clonotypes, IgG clonotypes, and IgD clonotypes; and
classifying a patient as being more likely to respond to DMARD treatment, whenever the patient has, with respect to reference levels characteristic of normal tissue, elevated IgH concentration, elevated IgG fraction, and reduced IgD fraction.
2 . The method of claim 1 wherein said elevated level of IgH concentration is at least twice said reference level.
3 . The method of claim 1 wherein said elevated IgG fraction is at least twice said reference level.
4 . The method of claim 1 wherein said reduced IgD fraction is at least 10-fold less than said reference level.
5 . The method of claim 1 wherein said IgH clonotype profile further includes IgM clonotypes and wherein said step of classifying further includes classifying said patient as being more likely to respond to DMARD treatment, whenever said patient further has, with respect to said reference levels characteristic of normal tissue, an elevated IgM somatic mutation rate.
6 . The method of claim 5 wherein said elevated IgM somatic mutation rate is at least twice said reference level.
7 . The method of claim 1 wherein said step of classifying further includes classifying said patient as being more likely to respond to DMARD treatment, whenever said patient further has, with respect to said reference levels characteristic of normal tissue, a reduced IgD diversity and a reduced IgM diversity.
8 . The method of claim 7 wherein a measure of said IgD diversity is a number of different IgD clonotypes in a highest ten percent of frequencies of IgD clonotypes.
9 . The method of claim 8 wherein said reduced IgD diversity is less than twenty-five percent of said reference level.
10 . The method of claim 7 wherein a measure of said IgM diversity is a number of different IgM clonotypes in a highest twenty-five percent of frequencies of IgM clonotypes.
11 . The method of claim 10 wherein said reduced IgM diversity is less than ten percent of said reference level.
12 . The method of claims 1 through 11 wherein said normal tissue is peripheral blood mononuclear cells.
13 . The method of claim 12 wherein said autoimmune disease is psoriatic arthritis and wherein said tissue affected by said autoimmune disease is synovial fluid.
14 . The method of 1 wherein said autoimmune disease is systemic lupus erythematosis.
15 . A method of determining responsiveness of a patient having psoriatic arthritis to treatment with a disease modifying anti-rheumatic drug (DMARD), the method comprising the steps of:
determining an IgH clonotype profile from B-cells in a sample of synovial fluid, the IgH clonotype profile including IgH clonotypes, IgG clonotypes, and IgD clonotypes; and
classifying a patient as being more likely to respond to DMARD treatment, whenever the patient has, with respect to reference levels characteristic of normal tissue, elevated IgH concentration, elevated IgG fraction, and reduced IgD fraction.
16 . The method of claim 15 wherein said elevated level of IgH concentration is at least twice said reference level.
17 . The method of claim 15 wherein said elevated IgG fraction is at least twice said reference level.
18 . The method of claim 15 wherein said reduced IgD fraction is at least 10-fold less than said reference level.
19 . The method of claim 15 wherein said IgH clonotype profile further includes IgM clonotypes and wherein said step of classifying further includes classifying said patient as being more likely to respond to DMARD treatment, whenever said patient further has, with respect to said reference levels characteristic of normal tissue, an elevated IgM somatic mutation rate.
20 . The method of claim 19 wherein said elevated IgM somatic mutation rate is at least twice said reference level.
21 . The method of claim 15 wherein said step of classifying further includes classifying said patient as being more likely to respond to DMARD treatment, whenever said patient further has, with respect to said reference levels characteristic of normal tissue, a reduced IgD diversity and a reduced IgM diversity.
22 . The method of claim 21 wherein a measure of said IgD diversity is a number of different IgD clonotypes in a highest ten percent of frequencies of IgD clonotypes.
23 . The method of claim 22 wherein said reduced IgD diversity is less than twenty-five percent of said reference level.
24 . The method of claim 21 wherein a measure of said IgM diversity is a number of different IgM clonotypes in a highest twenty-five percent of frequencies of IgM clonotypes.
25 . The method of claim 24 wherein said reduced IgM diversity is less than ten percent of said reference level.
26 . The method of claims 15 through 25 wherein said normal tissue is peripheral blood mononuclear cells.
27 . The method of claim 15 wherein said IgH clonotype profile indicates at least two of the following conditions hold for said patient: with respect to reference levels characteristic of peripheral blood mononuclear cells, (a) elevated IgH concentration, (b) elevated IgG fraction, (c) reduced IgD fraction, (d) reduced IgD diversity, (e) reduced IgM diversity, and (f) elevated IgM somatic mutation rate.
28 . The method of claim 15 wherein said IgH clonotype profile indicates at least three of the following conditions hold for said patient: with respect to reference levels characteristic of peripheral blood mononuclear cells, (a) elevated IgH concentration, (b) elevated IgG fraction, (c) reduced IgD fraction, (d) reduced IgD diversity, (e) reduced IgM diversity, and (f) elevated IgM somatic mutation rate.