IP Library › Granted Patent US 12,449,427
Granted Patent B2
US 12,449,427 · App. 17/993,502 · Granted Oct 21, 2025

Methods for treating and diagnosing systemic lupus erythematosus

Inventors: Thierry Dervieux (San Diego, CA); Derren Barken (San Diego, CA)
Assignee: Exagen Inc.
G01N33/6893A61K40/36G01N33/564G01N33/6854G01N2333/705G01N2800/104G01N2800/24G01N2800/50G01N2800/52G01N2800/56G01N2800/60
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Quick Facts
Patent No.
US 12,449,427
App. No.
17/993,502
Granted
Oct 21, 2025
Kind
B2
Abstract

Methods and reagents for diagnosing, prognosing, and treating systemic lupus erythematosus (SLE) are disclosed, involving calculating an SLE risk score for a subject based on a level of each of an erythrocyte C4d (EC4d) marker, a B-cell C4d (BC4d) marker, anti-nuclear antibodies (ANA), and optional rule-out markers.

Claims (40)

1. A method of treating systemic lupus erythematosus in a human subject in need thereof, the method comprising:

(a) receiving a systemic lupus erythematosus risk score for the human subject, wherein the systemic lupus erythematosus risk score is produced by a method comprising the steps of:

(i) log normalizing a level of erythrocyte-bound C4d (EC4d) marker to produce a log normalized level of EC4d marker and multiplying the log normalized level of EC4d marker by a predetermined weighting coefficient to produce a weighted score for EC4d marker, wherein the level of EC4d marker is detected in a blood sample obtained from the human patient;

(ii) log normalizing a level of B-lymphocyte-bound C4d (BC4d) marker to produce a log normalized level of BC4d marker and multiplying the log normalized level of BC4d marker by a predetermined weighting coefficient to produce a weighted score for BC4d marker, wherein the level of BC4d marker is detected in a blood sample obtained from the human patient;

(iii) multiplying a level of anti-nuclear antibody (ANA) by a predetermined weighting coefficient to produce a weighted score for ANA, wherein the level of ANA is detected in a blood sample obtained from the human patient;

(iv) adjusting the level of anti-Sjögren's syndrome type B antigen antibody, the level of anti-Scl-70 antibody, the level of anti-Jo-1 antibody, and the level of anti-centromere protein B antibody to produce a weighted score for anti-Sjögren's syndrome type B antigen antibody, a weighted score for anti-Scl-70 antibody, a weighted score for anti-Jo-1 antibody, and a weighted score for anti-centromere protein B antibody; wherein the level of anti-Sjögren's syndrome type B antigen antibody, the level of anti-Scl-70 antibody, the level of anti-Jo-1 antibody, and the level of anti-centromere protein B antibody are detected in a blood sample obtained from the human patient;

(v) combining the weighted score for anti-Sjögren's syndrome type B antigen antibody, the weighted score for anti-Scl-70 antibody, the weighted score for anti-Jo-1 antibody, and the weighted score for anti-centromere protein B antibody to produce an antibody specificity component score;

(vi) combining the weighted score for EC4d marker, the weighted score for BC4d marker, the weighted score for ANA, and the antibody specificity component score to produce the systemic lupus erythematosus risk score; wherein the systemic lupus erythematosus risk score does not include a score for a level of double-stranded DNA antibody;

(b) diagnosing the human subject with systemic lupus erythematosus based on the systemic lupus erythematosus risk score, prognosing the human subject with systemic lupus erythematosus based on the systemic lupus erythematosus risk score, determining a level of systemic lupus erythematosus disease activity in the human subject based on the systemic lupus erythematosus risk score, or monitoring systemic lupus erythematosus disease activity in the human subject based on the systemic lupus erythematosus risk score; and

(c) treating the human subject from step (b) with an effective amount of cyclophosphamide, a corticosteroid, mycophenolate, methotrexate, azathioprine, leflunomide, belimumab, or hydroxychloroquine.

2. The method of claim 1 , further comprising comparing the systemic lupus erythematosus risk score to a standard.

3. The method of claim 1 , wherein receiving the systemic lupus erythematosus risk score comprises receiving a comparison of the systemic lupus erythematosus risk score to a standard.

4. The method of claim 1 , wherein step (b) comprises diagnosing the human subject with systemic lupus erythematosus based on the systemic lupus erythematosus risk score.

5. The method of claim 1 , wherein step (b) comprises prognosing the human subject with systemic lupus erythematosus based on the systemic lupus erythematosus risk score.

6. The method of claim 1 , wherein step (b) comprises determining the level of systemic lupus erythematosus disease activity in the human subject based on the systemic lupus erythematosus risk score.

7. The method of claim 1 , wherein step (b) comprises monitoring systemic lupus erythematosus disease activity in the human subject based on the systemic lupus erythematosus risk score.

8. A method of treating systemic lupus erythematosus in a human subject in need thereof, the method comprising:

(a) selecting the human subject having a diagnosis of systemic lupus erythematosus based on a systemic lupus erythematosus risk score, wherein the systemic lupus erythematosus risk score is produced by a method comprising the steps of:

(i) log normalizing a level of erythrocyte-bound C4d (EC4d) marker to produce a log normalized level of EC4d marker and multiplying the log normalized level of EC4d marker by a predetermined weighting coefficient to produce a weighted score for EC4d marker, wherein the level of EC4d marker is detected in a blood sample obtained from the human patient;

(ii) log normalizing a level of B-lymphocyte-bound C4d (BC4d) marker to produce a log normalized level of BC4d marker and multiplying the log normalized level of BC4d marker by a predetermined weighting coefficient to produce a weighted score for BC4d marker, wherein the level of BC4d marker is detected in a blood sample obtained from the human patient;

(iii) multiplying a level of anti-nuclear antibody (ANA) by a predetermined weighting coefficient to produce a weighted score for ANA, wherein the level of ANA is detected in a blood sample obtained from the human patient;

(iv) adjusting the level of anti-Sjögren's syndrome type B antigen antibody, the level of anti-Scl-70 antibody, the level of anti-Jo-1 antibody, and the level of anti-centromere protein B antibody to produce a weighted score for anti-Sjögren's syndrome type B antigen antibody, a weighted score for anti-Scl-70 antibody, a weighted score for anti-Jo-1 antibody, and a weighted score for anti-centromere protein B antibody; wherein the level of anti-Sjögren's syndrome type B antigen antibody, the level of anti-Scl-70 antibody, the level of anti-Jo-1 antibody, and the level of anti-centromere protein B antibody are detected in a blood sample obtained from the human patient

(v) combining the weighted score for anti-Sjögren's syndrome type B antigen antibody, the weighted score for anti-Scl-70 antibody, the weighted score for anti-Jo-1 antibody, and the weighted score for anti-centromere protein B antibody to produce an antibody specificity component score;

(vi) combining the weighted score for EC4d marker, the weighted score for BC4d marker, the weighted score for ANA, and the antibody specificity component score to produce the systemic lupus erythematosus risk score; wherein the systemic lupus erythematosus risk score does not include a score for a level of double-stranded DNA antibody; and

(b) treating the human subject having the diagnosis of systemic lupus erythematosus based on the systemic lupus erythematosus risk score from (a) with an effective amount of cyclophosphamide, a corticosteroid, mycophenolate, methotrexate, azathioprine, leflunomide, belimumab, or hydroxychloroquine.

9. A method of treating systemic lupus erythematosus in a human subject in need thereof, the method comprising:

(a) detecting a level of erythrocyte-bound C4d (EC4d) marker, a level of B-lymphocyte-bound C4d (BC4d) marker, a level of anti-nuclear antibody (ANA), a level of anti-Sjögren's syndrome type B antigen antibody, a level of anti-Scl-70 antibody, a level of anti-Jo-1 antibody, and a level of anti-centromere protein B antibody in a blood sample obtained from the human patient;

(b) log normalizing the level of EC4d marker to produce a log normalized level of EC4d marker and multiplying the log normalized level of EC4d marker by a predetermined weighting coefficient to produce a weighted score for EC4d marker;

(c) log normalizing the level of BC4d marker to produce a log normalized level of BC4d marker and multiplying the log normalized level of BC4d marker by a predetermined weighting coefficient to produce a weighted score for BC4d marker;

(d) multiplying the level of ANA by a predetermined weighting coefficient to produce a weighted score for ANA;

(e) adjusting the level of anti-Sjögren's syndrome type B antigen antibody, the level of anti-Scl-70 antibody, the level of anti-Jo-1 antibody, and the level of anti-centromere protein B antibody to produce a weighted score for anti-Sjögren's syndrome type B antigen antibody, a weighted score for anti-Scl-70 antibody, a weighted score for anti-Jo-1 antibody, and a weighted score for anti-centromere protein B antibody;

(f) combining the weighted score for anti-Sjögren's syndrome type B antigen antibody, the weighted score for anti-Scl-70 antibody, the weighted score for anti-Jo-1 antibody, and the weighted score for anti-centromere protein B antibody to produce an antibody specificity component score;

(g) combining the weighted score for EC4d marker, the weighted score for BC4d marker, the weighted score for ANA, and the antibody specificity component score to produce the systemic lupus erythematosus risk score; wherein the systemic lupus erythematosus risk score does not include a score for a level of double-stranded DNA antibody;

(h) diagnosing the human subject with systemic lupus erythematosus based on the systemic lupus erythematosus risk score, prognosing the human subject with systemic lupus erythematosus based on the systemic lupus erythematosus risk score, determining a level of systemic lupus erythematosus disease activity in the human subject based on the systemic lupus erythematosus risk score, or monitoring systemic lupus erythematosus disease activity in the human subject based on the systemic lupus erythematosus risk score; and

(i) treating the human subject from step (h) with an effective amount of cyclophosphamide, a corticosteroid, mycophenolate, methotrexate, azathioprine, leflunomide, belimumab, or hydroxychloroquine.

10. The method of claim 9 , further comprising comparing the systemic lupus erythematosus risk score to a standard.

11. The method of claim 9 , wherein step (h) comprises diagnosing the human subject with systemic lupus erythematosus based on the systemic lupus erythematosus risk score.

12. The method of claim 9 , wherein step (h) comprises prognosing the human subject with systemic lupus erythematosus based on the systemic lupus erythematosus risk score.

13. The method of claim 9 , wherein step (h) comprises determining a level of systemic lupus erythematosus disease activity in the human subject based on the systemic lupus erythematosus risk score.

14. The method of claim 9 , wherein step (h) comprises monitoring systemic lupus erythematosus disease activity in the human subject based on the systemic lupus erythematosus risk score.

Assignments (3)
SECURITY INTEREST Recorded Apr 25, 2025
From: EXAGEN INC.
To: PERCEPTIVE CREDIT HOLDINGS IV, LP
Reel/Frame 070952/0802 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Apr 24, 2024
From: DERVIEUX, THIERRY; BARKEN, DERREN
To: EXAGEN DIAGNOSTICS, INC.
Reel/Frame 067214/0775 →
CHANGE OF NAME Recorded Apr 24, 2024
From: EXAGEN DIAGNOSTICS, INC.
To: EXAGEN INC.
Reel/Frame 067217/0739 →
Continuity (3)
Continuation 14767461
Provisional Application 61792284 · Mar 15, 2013
Related Publication 20230194553A1 · Jun 22, 2023
References Cited (74)
US 7361517B2 · Ahearn et al. · 2008 [cited by applicant]
US 7390631B2 · Ahearn et al. · 2008 [cited by applicant]
US 7585640B2 · Ahearn et al. · 2009 [cited by applicant]
US 7588905B2 · Ahearn et al. · 2009 [cited by applicant]
US 8080382B2 · Ahearn et al. · 2011 [cited by applicant]
US 8126654B2 · Ahearn et al. · 2012 [cited by applicant]
US 9804156B2 · Ramachandran et al. · 2017 [cited by applicant]
US 10132813B2 · Dervieux et al. · 2018 [cited by applicant]
US 11360099B2 · Dervieux et al. · 2022 [cited by applicant]
US 11531033B2 · Dervieux et al. · 2022 [cited by applicant]
US 11761965B2 · Dervieux et al. · 2023 [cited by applicant]
US 11885812B2 · Dervieux et al. · 2024 [cited by applicant]
US 20060071797A1 · Rosenfeld et al. · 2006 [cited by applicant]
US 20060105419A1 · Blankenberg et al. · 2006 [cited by applicant]
US 20070148704A1 · Klause et al. · 2007 [cited by applicant]
US 20100233752A1 · Ahearn et al. · 2010 [cited by applicant]
US 20110177531A1 · Dervieux et al. · 2011 [cited by applicant]
US 20220276259A1 · Dervieux et al. · 2022 [cited by applicant]
US 20230228768A1 · Dervieux et al. · 2023 [cited by applicant]
US 20240288441A1 · Dervieux et al. · 2024 [cited by applicant]
EP 2336769A1 · 2011 [cited by applicant]
WO WO2007039280A1 · 2007 [cited by applicant]
WO WO2007117141A1 · 2007 [cited by applicant]
WO WO2010045611A2 · 2010 [cited by applicant]
WO WO2010045611A3 · 2010 [cited by applicant]
WO WO2011047337A2 · 2011 [cited by applicant]
WO WO2011047337A3 · 2011 [cited by applicant]
WO WO2011101487A1 · 2011 [cited by applicant]
WO WO2012109592A1 · 2012 [cited by applicant]
Hanly et al., Measurement of autoantibodies using multiplex methodology in patients with systemic lupus erythematosus; 2010, Journal of Immunological Methods, 352: 147-152. (Year: 2010). [cited by examiner]
Eriksson, C. et al. (Feb. 22, 2011). “Autoantibodies predate the onset of systemic lupus erythematosus in northern Sweden,” Arthritis Research & Therapy 13(1):R30. [cited by applicant]
Reichlin et al, One-Hour Rule-out and Rule-in of Acute Myocardial Infarction Using High-Sensitivity Cardiac Troponin T, Arch Intern Med, 172(16):1211-1218 (2012). [cited by applicant]
Aarden, L.A. et al. (1975). “Immunology of DNA. III. [cited by applicant]
Amissah-Arthur, M.B. et al. (Jul. 2010). “Contemporary treatment of systemic lupus erythematosus: an update for clinicians,” [cited by applicant]
Bang, H. et al. (Aug. 2007). “Mutation and citrullination modifies vimentin to a novel autoantigen for rheumatoid arthritis,” [cited by applicant]
Bastian, H.M. et al. (2002). “Systemic lupus erythematosus n three ethnic groups. XII. Risk factors for lupus nephritis after diagnosis,” [cited by applicant]
Batal, I, et al. (Jan. 2012, e-published Sep. 29, 2011). “Prospective assessment of C4d deposits on circulating cells and renal tissues in lupus nephritis: a pilot study,” [cited by applicant]
Clough, J.D. et al. (Feb. 1984). “Weighted criteria for the diagnosis of systemic lupus erythematosus,” [cited by applicant]
Corvetta, A. et al., (Jul. 1991) “Low No. of complement C3b/C4b receptors (CR1) on erythrocytes from patients with essential mixed cryoglobulinemia, systemic lupus erythematosus and rheumatoid arthritis: relationship wi… [cited by applicant]
Costenbader, K.H. et al. (Dec. 2002). “Defining lupus cases for clinical studies: the Boston weighted criteria for the classification of systemic lupus erythematosus,” [cited by applicant]
Durcan, L. et al. (Nov. 2015, e-published Oct. 1, 2015). “Hydroxychloroquine Blood Levels in Systemic Lupus Erythematosus: Clarifying Dosing Controversies and Improving Adherence,” [cited by applicant]
Egner, W. (Jun. 2000). “The use of laboratory tests in the diagnosis of SLE,” [cited by applicant]
Helmick, C.G. et al. (Jan. 2008). “Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part I,” [cited by applicant]
Hosmer, D.W. et al. (Apr. 2013). [cited by applicant]
Hullo, D. et al. (2009), “Citrullinated antibodies in systemic lupus erythematosus and primary Sjogren's syndrome,” [cited by applicant]
Ilda, K. et al. (May 1982). “Complement receptor (CR1) deficiency in erythrocytes from patients with systemic lupus mythematosus,” [cited by applicant]
International Search Report mailed on Jul. 25, 2012, for PCT Application No. PCT/US2012/024729, filed Feb. 10, 2012, 4 pages. [cited by applicant]
International Search Report mailed on Aug. 1, 2014, for PCT Application No. PCT/US2014/025264, filed Mar. 13, 2014, 5 pages. [cited by applicant]
Kalunian, et al. (2011) “The contribution of cell bound complement activation products to the diagnosis of Systemic Lupus Erythematosus,” [cited by applicant]
Kalunian, K.C. et al., (Dec. 2012). “Measurement of cell-bound complement activation products enhances diagnostic performance in systemic lupus erythematosus,” [cited by applicant]
Kao A.H et al. (Mar. 2010). “Erythrocyte C3d and C4d for monitoring lisease activity in systemic lupus erythematosus,” [cited by applicant]
Liu, C-C. et al., (2009), “Lymphocyte-bound complement activation products as biomarkers for diagnosis of systemic lupus erythematosus,” Clinical and Translational Science, 2(4):300-308. [cited by applicant]
Manderson, A.P. et al. (2004). “The role of complement in the development of systemic lupus erythematosus,” [cited by applicant]
Manzi, S. et al., (2004) “New insights into complement: a mediator of injury and marker of disease activity in systemic lupus erythematosus,” [cited by applicant]
Manzi, S. et al., (Nov. 2004). “Measurement of erythorycte C4d and complement receptor 1 in systemic lupus erythemastosus,” [cited by applicant]
Mok, C.C. et al. (Sep. 2016, e-published Jul. 27, 2016). “Hydroxychloroquine Serum Concentrations and Flares of Systemic Lupus Erythematosus: A Longitudinal Cohort Analysis,” Arthritis Care Res 68(9):1295-1302. [cited by applicant]
Navratil, J.S. et al. (Feb. 2006). “Platelet C4d is highly specific for systemic lupus erythematosus,” [cited by applicant]
Park, H.A. (Apr. 2013). An introduction to logistic regression: from basic concepts to interpretation with particular attention to nursing domain, [cited by applicant]
Petri, M. et al. (2004). “Classification criteria for systemic lupus erythematosus: a review,” [cited by applicant]
Petri, M.A. et al. (Mar. 30, 2019). “Platelet-bound C4d, low C3 and lupus anticoagulant associate with thrombosis in SLE,” [cited by applicant]
Poulsom, H. et al. (2008). “Antibodies to Citrullinated Vimentin are a Specific and Sensitive Marker for the Diagnosis of Rheumatoid Arthritis,” [cited by applicant]
Putterman, C. et al., (Oct. 2013). “An Assay Panel Combining Cell Bound Complement Activation Products With Autoantibodies to Extractable Nuclear Antigens and Mutated Citrullinated Vimentin Helps with the Differential D… [cited by applicant]
Putterman, C. et al., (Dec. 3, 2013). “Multicenter study in the An Assay Panel Combining Cell Bound Complement Activation Products with Autoantibodies to Extractable Nuclear Antigens and Mutated Citrullinated Vimentin H… [cited by applicant]
Putterman, C. et al. (Oct. 1, 2014). “Cell-bound complement activation products in systemic lupus erythematosus: comparison with anti-double-stranded DNA and standard complement measurements,” [cited by applicant]
Rahman, A. et al. (Feb. 28, 2008). “Systemic lupus erythematosus,” [cited by applicant]
Ross, G.D. et al. (1985) “Disease-associated loss of erythrocyte complement receptors CR1, C3b receptors) in patients with systemic lupus erythematosus and other diseases involving autoantibodies and/or complement activ… [cited by applicant]
Singh, V. et al. (Oct. 2008, e-published Aug. 15, 2008). “Erythrocyte C4d and complement receptor 1 in systemic lupus erythematosus,” [cited by applicant]
Smith, E.L. et al. (1999). “The American College of Rheumatology criteria for the classification of systemic lupus erythematosus: strengths, weaknesses, and opportunities for improvement,” [cited by applicant]
Sperandei, S. et al. (2014). “Undersanding Logistic Regression Analysis,” Biochemia Medica 24(1):12-18. [cited by applicant]
Tan, E.M. et al. (Nov. 1982). “The 1982 revised criteria for the classification pf systemic lupus erythematosus,” [cited by applicant]
Written Opinion mailed on Aug. 1, 2014, for PCT Application No. PCT/US2014/025264, filed Mar. 13, 2014, 6 pages. [cited by applicant]
Yang, D.H. et al. (Sep. 2009, e-published Jun. 24, 2009). “Usefulness of erythrocyte- bound C4d as a biomarker to predict lisease activity in patients with systemic lupus erythematosus,” [cited by applicant]
Amezcua-Guerra, L.M. et al. (2006). “Presence of antibodies against cyclic citrullinated peptides in patients with ‘rhupus’: a cross-sectional study,” [cited by applicant]
Bernknopf, A. et al. (May 2011). “A Review of Systemic Lupus Erythematosus and Current Treatment Options,” [cited by applicant]