# US 2026/0074073 A1 · Biomarker for Seronegative Rheumatoid Arthritis

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- Number: US 2026/0074073 A1
- Document ID: US20260074073A1
- Status: Published application
- Kind: A1
- Application number: 19/320,153
- Filed: 2025-09-05
- Published: 2026-03-12
- Earliest claimed: 2024-09-06
- Assignees: Mayo Foundation for Medical Education and Research
- Applicants: Mayo Foundation for Medical Education and Research
- Inventors: Jaeyun Sung; John M. Davis, III; Benjamin Hur
- Web page: https://patentgrep.com/patent/US20260074073A1

## CPC

- G16H 50/20: for computer-aided diagnosis, e.g. based on medical expert systems
- G16B 40/20: Supervised data analysis
- G16H: HEALTHCARE INFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR THE HANDLING OR PROCESSING OF MEDICAL OR HEALTHCARE DATA
- G16B: BIOINFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR GENETIC OR PROTEIN-RELATED DATA PROCESSING IN COMPUTATIONAL MOLECULAR BIOLOGY

## Abstract

The disclosure generally relates to methods of selecting a biomarker associated with a disorder or disease, and computer program products and systems for performing such methods. The disclosure further relates to biomarkers for rheumatoid arthritis and methods of use such biomarkers.

## Claims

### Claim 1

A method of treating a subject afflicted with rheumatoid arthritis (RA), said method comprising the steps of diagnosing the subject with rheumatoid arthritis (RA), comprising:
(a) obtaining a blood sample from the subject; and
(b) determining the amount of a plurality of biomolecules comprising plasma proteins, plasma metabolites and plasma autoantibodies in the blood sample; wherein
(i) the amount of at least 25 plasma proteins from Table A, and/or at least 25 plasma metabolites from Table B, and/or at least 25 plasma autoantibodies from Table C, or a combination of at least 50 biomolecules from Tables A, B and C, is higher in the blood sample relative to an amount of the biomolecules in a control sample from a subject without RA and indicates the subject has seronegative RA (ACPA− RA); or
(ii) the amount of at least 25 plasma proteins from Table D, and/or at least 25 plasma metabolites from Table E, and/or at least 25 plasma autoantibodies from Table F, or a combination of at least 50 biomolecules from Tables D, E and F, is higher in the blood sample relative to an amount of the biomolecules in a control sample from a subject without RA indicates the subject has seropositive RA (ACPA+ RA); and
(c) administering at least one therapy to the subject.

### Claim 2

(canceled)

### Claim 3

(canceled)

### Claim 4 (depends on 1)

The method according to claim 1, wherein the determining the amount of biomolecules in step (b) produces a multi-omic data set, wherein the multi-omic data set is processed through a trained machine learning model, and wherein the processed multi-omic data set provides a RA phenotype classification.

### Claim 5

A method of diagnosing a subject with rheumatoid arthritis (RA), said method comprising the steps of preparing a RA phenotype classification network comprising:
(a) receiving multi-omic data from a blood sample from a subject, wherein the multi-omic data includes proteomic, metabolomic, and autoantibody profiles;
(b) processing the received multi-omic data through a trained machine learning model;
(c) classifying the subject's RA phenotype based on the processed multi-omic data; and
(d) outputting the classification result; and wherein:
(i) the classification is ACPA− RA when the amount of at least 25 plasma proteins from Table A, and/or at least 25 plasma metabolites from Table B, and/or at least 25 plasma autoantibodies from Table C, or a combination of at least 50 biomolecules from Tables A, B and C is detected; or
(ii) the classification is ACPA+ RA when the amount of at least 25 plasma proteins from Table D, and/or at least 25 plasma metabolites from Table E, and/or at least 25 plasma autoantibodies from Table F, or a combination of at least 50 biomolecules from Tables D, E and F is detected.

### Claim 6 (depends on 5)

The method of claim 5, wherein the trained machine learning model is trained by
(a) selecting a cohort of subjects comprising subgroups of ACPA− RA patients, ACPA+ RA patients, and control individuals without RA;
(b) collecting blood samples from the selected cohort;
(c) performing deep multi-omic profiling on the collected blood samples, wherein the deep multi-omic profiling includes proteomic profiling, metabolomic profiling, and autoantibody profiling;
(d) analyzing the multi-omic data to identify biomolecular features associated with each RA subgroup through statistical analyses, set comparisons, and network inference techniques;
(e) constructing a global multi-omic network based on the identified biomolecular features and their associations with clinical attributes, including RA phenotypes;
(f) applying a network diffusion technique to prioritize features closely linked to the RA phenotypes;
thereby training the machine learning model using the prioritized features to distinguish between ACPA− RA subjects, ACPA+ RA subjects, and control subjects.

### Claim 7

A method of treating a subject with rheumatoid arthritis (RA), said method comprising the steps of:
(I) diagnosing a subject with rheumatoid arthritis (RA), said method comprising the steps of preparing a RA phenotype classification network comprising:
(a) receiving multi-omic data from a blood sample from a subject, wherein the multi-omic data includes proteomic, metabolomic, and autoantibody profiles;
(b) processing the received multi-omic data through a trained machine learning model;
(c) classifying the subject's RA phenotype based on the processed multi-omic data; and
(d) outputting the classification result; and wherein:
(i) the classification is ACPA− RA when the amount of at least 25 plasma proteins from Table A, and/or at least 25 plasma metabolites from Table B, and/or at least 25 plasma autoantibodies from Table C, or a combination of at least 50 biomolecules from Tables A, B and C is detected; or
(ii) the classification is ACPA+ RA when the amount of at least 25 plasma proteins from Table D, and/or at least 25 plasma metabolites from Table E, and/or at least 25 plasma autoantibodies from Table F, or a combination of at least 50 biomolecules from Tables D, E and F is detected; and
(II) administering at least one therapy to the subject

### Claim 8 (depends on 1)

The method according to claim 1, wherein the subject is a mammal.

### Claim 9 (depends on 8)

The method of claim 8 wherein the mammal is a human.

### Claim 10 (depends on 1)

The method of claim 1, wherein the determining the amount of plasma proteins comprises an aptamer-based assay technique.

### Claim 11 (depends on 10)

The method of claim 10, wherein the determining the amount of plasma proteins comprises an aptamer-based assay that measures binding of target proteins to aptamers in relative fluorescent units (RFUs).

### Claim 12 (depends on 1)

The method according to claim 1, wherein the determining the amount of plasma metabolites comprises a mass spectrometry technique.

### Claim 13 (depends on 12)

The method of claim 12, wherein the determining the amount of plasma proteins comprises ultra-high-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS).

### Claim 14 (depends on 1)

The method of according to claim 1, wherein the determining the amount of plasma autoantibodies comprises a microarray-based assay technique.

### Claim 15 (depends on 1)

The method according claim 1, wherein the therapy comprises administering one or more of a small molecule agent, immunotherapy, disease-modifying antirheumatic drugs (DMARDs), nonsteroidal anti-inflammatory drugs (NSAIDs), steroids, a biologic agent, and surgery.

### Claim 16 (depends on 15)

The method of claim 15, wherein the therapy comprises ibuprofen and/or naproxen sodium.

### Claim 17 (depends on 15)

The method of claim 15, wherein the therapy comprises a corticosteroid comprising one or more of cortisone, prednisolone, methylprednisolone, dexamethasone, betamethasone, and hydrocortisone.

### Claim 18 (depends on 15)

The method of claim 15, wherein the therapy comprises at least one DMARD comprising methotrexate, leflunomide, hydroxychloroquine, and sulfasalazine.

### Claim 19 (depends on 15)

The method of claim 15, wherein the therapy comprises at least one of abatacept, adalimumab, anakinra, certolizumab, etanercept, golimumab, infliximab, rituximab, sarilumab, tocilizumab, baricitinib, tofacitinib, and upadacitinib.

### Claim 20 (depends on 16)

The method of claim 16, wherein the therapy comprises snynovectomy, tendon repair, joint fusion, and joint replacement.

### Claim 21 (depends on 15)

The method according to claim 15, wherein 1, 2, 3, 4 or more therapies are administered.