Differential biomarkers for Anti-interleukin-6 and Anti-tumor necrosis factor-Α treatment response in rheumatoid arthritis

Abstract

Provided herein are technologies (e.g., methods, compositions, kits, and systems, etc.) involving biomarkers that are useful for monitoring or determining whether a subject with rheumatoid arthritis shows early responsiveness to a rheumatoid arthritis therapy. Methods of treating rheumatoid arthritis are also provided herein.

Description

Attorney Docket No. 768830: SA9-910PCDIFFERENTIAL BIOMARKERS FOR ANTI-INTERLEUKIN-6 AND ANTI-TUMOR NECROSIS FACTOR-A TREATMENT RESPONSE IN RHEUMATOID ARTHRITISCROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims priority to EP Application No. 24306423.5 filed August 30, 2024, and claims the benefit of U.S. Provisional Patent Application No. 63 / 688,956, filed August 30, 2024, which are each incorporated by reference herein in their entirety.SEQUENCE LISTING

[0002] The content of the electronically submitted Sequence Listing in XML format (Name: 768830_SA9-910PC_ST26.xml; Size: 244,600 bytes; and Date of Creation: August 26, 2025) is incorporated herein by reference in its entirety.BACKGROUND

[0003] Rheumatoid arthritis (RA) is a chronic autoimmune disease that primarily affects the synovial joints. The progressive destruction of cartilage and bone during the disease course may lead to an irreversible disability. The advent of biologic disease modifying antirheumatic drugs (bDMARDs) revolutionized the treatment of RA. However, not all subjects treated with bDMARDs respond adequately. A subject who is not responsive to one class of drug could respond to another class of drug that targets the active pathway of RA. However, determining a proper treatment for each individual subject is largely a “trial-and-error” approach, which is likely to cause irreversible joint damage and increase the health and economic burden.SUMMARY

[0004] The present disclosure, among other things, provides insights and technologies for achieving more effective RA treatment. In some embodiments, provided technologies may be or include one or more compositions (e.g., systems, combinations, kits, etc.), and / or methods (e.g., of treating, using, assessing, etc.), as will be clear to one skilled in the art reading the disclosure provided herein.-1-Attorney Docket No. 768830: SA9-910PC

[0005] In some embodiments, the present disclosure, among other things, identified biomarkers that are useful for achieving early detection or assessment of likelihood of responsiveness of a subject to a rheumatoid arthritis treatment (e.g., an IL-6 inhibitor therapy or a TNF-a inhibitor therapy). Such biomarkers are particularly useful for identifying RA subjects who are or who are not likely benefiting from the current RA treatment (e.g., an IL-6 inhibitor therapy or a TNF-a inhibitor therapy) and providing proper guidance or adjustment at early stage of the treatment accordingly.

[0006] In one aspect, the present disclosure provides a method of assessing or monitoring early responsiveness of a subject having rheumatoid arthritis to an interleukin-6 inhibitor therapy, the method comprising: determining, in a sample from a subject having rheumatoid arthritis and receiving an IL-6 inhibitor therapy, a change in expression level from a reference level of at least one biomarker comprising azurocidin (AZU1), matrix metalloproteinase-9 (MMP-9), matrix metalloproteinase- 1 (MMP-1), oncostatin-M (OSM), tumor necrosis factor receptor superfamily 14 (TNFRSF14), epithelial cell adhesion molecule (Ep-CAM), C-C motif chemokine 4 (CCL4), low-density lipoprotein receptors (LDL-receptor), fms-related tyrosine kinase 3 ligand (Flt3L), or any combinations thereof; wherein the change in expression level from the reference level of the at least one biomarker is an indication of the likelihood of early responsiveness to the IL-6 inhibitor therapy.

[0007] In certain exemplary embodiments, the IL-6 inhibitor therapy comprises an IL-6 receptor (IL-6R) inhibitor. In certain exemplary embodiments, the IL-6R inhibitor comprises an anti-IL-6R antibody agent. In certain exemplary embodiments, the anti-IL-6R antibody agent comprises sarilumab. In certain exemplary embodiments, the subject is receiving sarilumab at a dose of about 200 mg every two weeks.

[0008] In certain exemplary embodiments, in a second sample from the subject who is determined to continue to receive the IL-6 inhibitor therapy, a second change in expression level from a second reference level of at least one biomarker comprising AZU1, MMP9, MMP1, OSM, TNFSF1414, Ep-CAM, CCL4, LDL-receptor, Flt3L, or combinations thereof, wherein the second change in expression level is measured after the subject is determined to continue to receive the IL-6 inhibitor therapy.-2-Attorney Docket No. 768830: SA9-910PC

[0009] In certain exemplary embodiments, the at least one biomarker used for determining the second change in expression level is the same as the at least one biomarker used for determining a first change in expression level.

[0010] In certain exemplary embodiments, the at least one biomarker used for determining the second change in expression level is different from the at least one biomarker used for determining a first change in expression level.

[0011] In certain exemplary embodiments, the reference level or a first reference level is expression level of the at least one biomarker in a sample from the subject prior to receiving the IL-6 inhibitor therapy. In certain exemplary embodiments, the second reference level is the same as the first reference level. In certain exemplary embodiments, the second reference level is different from a first reference level.

[0012] In certain exemplary embodiments, the sample comprises a serum or blood sample. In certain exemplary embodiments, the sample is from the subject after receiving the therapy for about two weeks to about twelve weeks.

[0013] In certain exemplary embodiments, the change in expression level is an mRNA expression level. In certain exemplary embodiments, the change in expression level is a protein expression level.

[0014] In certain exemplary embodiments, the subject was previously administered at least one disease modifying antirheumatic drug (DMARD) other than the IL-6 inhibitor therapy or the TNF- a inhibitor therapy, which is being received by the subject. In certain exemplary embodiments, the subject had an inadequate response to or did not tolerate the at least one DMARD.

[0015] In certain exemplary embodiments, the at least one DMARD comprises methotrexate (MTX).

[0016] In one aspect, the present disclosure provides a method of treating rheumatoid arthritis, the method comprising: determining, in a sample of a subject having rheumatoid arthritis and receiving an IL-6 inhibitor therapy, a change in expression level from a reference level, of at least one biomarker comprising Ep-CAM, CCL4, LDL-receptor, Flt3L, or any combinations thereof; and continuing the IL-6 inhibitor therapy if the expression level of the at least one biomarker is increased relative to the reference level; or-3-Attorney Docket No. 768830: SA9-910PC stopping the IL-6 inhibitor therapy and optionally selecting a different rheumatoid arthritis therapy if the expression level of the at least one biomarker is reduced or is not substantially changed, relative to the reference level.

[0017] In certain exemplary embodiments, the IL-6 inhibitor therapy comprises an IL-6 receptor (IL-6R) inhibitor. In certain exemplary embodiments, the IL-6R inhibitor comprises an anti-IL-6R antibody agent. In certain exemplary embodiments, the anti-IL-6R antibody agent comprises sarilumab. In certain exemplary embodiments, the subject is receiving sarilumab at a dose of about 200 mg every two weeks.

[0018] In certain exemplary embodiments, in a second sample from the subject who is determined to continue to receive the IL-6 inhibitor therapy, a second change in expression level from a second reference level of at least one biomarker comprising AZU1, MMP9, MMP1, OSM, TNFSF1414, Ep-CAM, CCL4, LDL-receptor, Flt3L, or combinations thereof, wherein the second change in expression level is measured after the subject is determined to continue to receive the IL-6 inhibitor therapy.

[0019] In certain exemplary embodiments, the at least one biomarker used for determining the second change in expression level is the same as the at least one biomarker used for determining a first change in expression level.

[0020] In certain exemplary embodiments, the at least one biomarker used for determining the second change in expression level is different from the at least one biomarker used for determining a first change in expression level.

[0021] In certain exemplary embodiments, the reference level or a first reference level is expression level of the at least one biomarker in a sample from the subject prior to receiving the IL-6 inhibitor therapy. In certain exemplary embodiments, the second reference level is the same as the first reference level. In certain exemplary embodiments, the second reference level is different from a first reference level.

[0022] In certain exemplary embodiments, the sample comprises a serum or blood sample. In certain exemplary embodiments, the sample is from the subject after receiving the therapy for about two weeks to about twelve weeks.

[0023] In certain exemplary embodiments, the change in expression level is an mRNA expression level. In certain exemplary embodiments, the change in expression level is a protein expression level.-4-Attorney Docket No. 768830: SA9-910PC

[0024] In certain exemplary embodiments, the subject was previously administered at least one disease modifying antirheumatic drug (DMARD) other than the IL-6 inhibitor therapy or the TNF- a inhibitor therapy, which is being received by the subject. In certain exemplary embodiments, the subject had an inadequate response to or did not tolerate the at least one DMARD.

[0025] In certain exemplary embodiments, the at least one DMARD comprises methotrexate (MTX).

[0026] In one aspect, the present disclosure provides a method of treating rheumatoid arthritis, the method comprising: determining, in a sample of a subject having rheumatoid arthritis and receiving an IL-6 inhibitor therapy, a change in expression level from a reference level, of at least one biomarker comprising AZU1, MMP9, MMP1, OSM, TNFSF1414, or any combinations thereof; and continuing the IL-6 inhibitor therapy if the expression level of the at least one biomarker is reduced relative to the reference level; or stopping the IL-6 inhibitor therapy and optionally selecting a different rheumatoid arthritis therapy if the expression level of the at least one biomarker is increased or is not substantially changed relative to the reference level.

[0027] In certain exemplary embodiments, the IL-6 inhibitor therapy comprises an IL-6 receptor (IL-6R) inhibitor. In certain exemplary embodiments, the IL-6R inhibitor comprises an anti-IL-6R antibody agent. In certain exemplary embodiments, the anti-IL-6R antibody agent comprises sarilumab. In certain exemplary embodiments, the subject is receiving sarilumab at a dose of about 200 mg every two weeks.

[0028] In certain exemplary embodiments, in a second sample from the subject who is determined to continue to receive the IL-6 inhibitor therapy, a second change in expression level from a second reference level of at least one biomarker comprising AZU1, MMP9, MMP1, OSM, TNFSF1414, Ep-CAM, CCL4, LDL-receptor, Flt3L, or combinations thereof, wherein the second change in expression level is measured after the subject is determined to continue to receive the IL-6 inhibitor therapy.

[0029] In certain exemplary embodiments, the at least one biomarker used for determining the second change in expression level is the same as the at least one biomarker used for determining a first change in expression level.-5-Attorney Docket No. 768830: SA9-910PC

[0030] In certain exemplary embodiments, the at least one biomarker used for determining the second change in expression level is different from the at least one biomarker used for determining a first change in expression level.

[0031] In certain exemplary embodiments, the reference level or a first reference level is expression level of the at least one biomarker in a sample from the subject prior to receiving the IL-6 inhibitor therapy. In certain exemplary embodiments, the second reference level is the same as the first reference level. In certain exemplary embodiments, the second reference level is different from a first reference level.

[0032] In certain exemplary embodiments, the sample comprises a serum or blood sample. In certain exemplary embodiments, the sample is from the subject after receiving the therapy for about two weeks to about twelve weeks.

[0033] In certain exemplary embodiments, the change in expression level is an mRNA expression level. In certain exemplary embodiments, the change in expression level is a protein expression level.

[0034] In certain exemplary embodiments, the subject was previously administered at least one disease modifying antirheumatic drug (DMARD) other than the IL-6 inhibitor therapy or the TNF- a inhibitor therapy, which is being received by the subject. In certain exemplary embodiments, the subject had an inadequate response to or did not tolerate the at least one DMARD.

[0035] In certain exemplary embodiments, the at least one DMARD comprises methotrexate (MTX).

[0036] In one aspect, the present disclosure provides a method of treating rheumatoid arthritis, the method comprising: selecting a subject who is having rheumatoid arthritis and receiving an IL-6 inhibitor therapy and who is determined to show a change in expression level from a reference level, of at least one biomarker comprising Ep-CAM, CCL4, LDL-receptor, Flt3L, or any combinations thereof; and continuing the IL-6 inhibitor therapy if the expression level of the at least one biomarker is increased relative to the reference level; or stopping the IL-6 inhibitor therapy and optionally selecting a different rheumatoid arthritis therapy if the expression level of the at least one biomarker is reduced or is not substantially changed, relative to the reference level.-6-Attorney Docket No. 768830: SA9-910PC

[0037] In certain exemplary embodiments, the IL-6 inhibitor therapy comprises an IL-6 receptor (IL-6R) inhibitor. In certain exemplary embodiments, the IL-6R inhibitor comprises an anti-IL-6R antibody agent. In certain exemplary embodiments, the anti-IL-6R antibody agent comprises sarilumab. In certain exemplary embodiments, the subject is receiving sarilumab at a dose of about 200 mg every two weeks.

[0038] In certain exemplary embodiments, in a second sample from the subject who is determined to continue to receive the IL-6 inhibitor therapy, a second change in expression level from a second reference level of at least one biomarker comprising AZU1, MMP9, MMP1, OSM, TNFSF1414, Ep-CAM, CCL4, LDL-receptor, Flt3L, or combinations thereof, wherein the second change in expression level is measured after the subject is determined to continue to receive the IL-6 inhibitor therapy.

[0039] In certain exemplary embodiments, the at least one biomarker used for determining the second change in expression level is the same as the at least one biomarker used for determining a first change in expression level.

[0040] In certain exemplary embodiments, the at least one biomarker used for determining the second change in expression level is different from the at least one biomarker used for determining a first change in expression level.

[0041] In certain exemplary embodiments, the reference level or a first reference level is expression level of the at least one biomarker in a sample from the subject prior to receiving the IL-6 inhibitor therapy. In certain exemplary embodiments, the second reference level is the same as the first reference level. In certain exemplary embodiments, the second reference level is different from a first reference level.

[0042] In certain exemplary embodiments, the sample comprises a serum or blood sample. In certain exemplary embodiments, the sample is from the subject after receiving the therapy for about two weeks to about twelve weeks.

[0043] In certain exemplary embodiments, the change in expression level is an mRNA expression level. In certain exemplary embodiments, the change in expression level is a protein expression level.

[0044] In certain exemplary embodiments, the subject was previously administered at least one disease modifying antirheumatic drug (DMARD) other than the IL-6 inhibitor therapy or the TNF--7-Attorney Docket No. 768830: SA9-910PC a inhibitor therapy, which is being received by the subject. In certain exemplary embodiments, the subject had an inadequate response to or did not tolerate the at least one DMARD.

[0045] In certain exemplary embodiments, the at least one DMARD comprises methotrexate (MTX).

[0046] In one aspect, the present disclosure provides a method of treating rheumatoid arthritis, the method comprising: selecting a subject who is having rheumatoid arthritis and receiving an IL-6 inhibitor therapy and who is determined to show a change in expression level from a reference level, of at least one biomarker comprising AZU1, MMP9, MMP1, OSM, TNFSF1414, or any combinations thereof; and continuing the IL-6 inhibitor therapy if the expression level of the at least one biomarker is reduced relative to the reference level; or stopping the IL-6 inhibitor therapy and optionally selecting a different rheumatoid arthritis therapy if the expression level of the at least one biomarker is increased or is not substantially changed relative to the reference level.

[0047] In certain exemplary embodiments, the IL-6 inhibitor therapy comprises an IL-6 receptor (IL-6R) inhibitor. In certain exemplary embodiments, the IL-6R inhibitor comprises an anti-IL-6R antibody agent. In certain exemplary embodiments, the anti-IL-6R antibody agent comprises sarilumab. In certain exemplary embodiments, the subject is receiving sarilumab at a dose of about 200 mg every two weeks.

[0048] In certain exemplary embodiments, in a second sample from the subject who is determined to continue to receive the IL-6 inhibitor therapy, a second change in expression level from a second reference level of at least one biomarker comprising AZU1, MMP9, MMP1, OSM, TNFSF1414, Ep-CAM, CCL4, LDL-receptor, Flt3L, or combinations thereof, wherein the second change in expression level is measured after the subject is determined to continue to receive the IL-6 inhibitor therapy.

[0049] In certain exemplary embodiments, the at least one biomarker used for determining the second change in expression level is the same as the at least one biomarker used for determining a first change in expression level.-8-Attorney Docket No. 768830: SA9-910PC

[0050] In certain exemplary embodiments, the at least one biomarker used for determining the second change in expression level is different from the at least one biomarker used for determining a first change in expression level.

[0051] In certain exemplary embodiments, the reference level or a first reference level is expression level of the at least one biomarker in a sample from the subject prior to receiving the IL-6 inhibitor therapy. In certain exemplary embodiments, the second reference level is the same as the first reference level. In certain exemplary embodiments, the second reference level is different from a first reference level.

[0052] In certain exemplary embodiments, the sample comprises a serum or blood sample. In certain exemplary embodiments, the sample is from the subject after receiving the therapy for about two weeks to about twelve weeks.

[0053] In certain exemplary embodiments, the change in expression level is an mRNA expression level. In certain exemplary embodiments, the change in expression level is a protein expression level.

[0054] In certain exemplary embodiments, the subject was previously administered at least one disease modifying antirheumatic drug (DMARD) other than the IL-6 inhibitor therapy or the TNF- a inhibitor therapy, which is being received by the subject. In certain exemplary embodiments, the subject had an inadequate response to or did not tolerate the at least one DMARD.

[0055] In certain exemplary embodiments, the at least one DMARD comprises methotrexate (MTX).

[0056] In one aspect, the present disclosure provides a method of treating rheumatoid arthritis, the method comprising: determining, in a sample of a subject having rheumatoid arthritis and receiving an IL-6 inhibitor therapy, a change in expression level from a reference level, of at least one biomarker comprising AZU1, MMP9, MMP1, OSM, TNFSF1414, Ep-CAM, CCL4, LDL-receptor, Flt3L, or any combinations thereof; and continuing the IL-6 inhibitor therapy if:(a) the expression level of at least one biomarker comprising Ep-CAM, CCL4, LDL- receptor, Flt3L, or any combinations thereof is increased relative to its respective reference level; or-9-Attorney Docket No. 768830: SA9-910PC(b) the expression level of at least one biomarker comprising AZU1, MMP9, MMP1, OSM, TNFSF1414, or any combinations thereof is reduced relative to its respective reference level; or(c) both (a) and (b); or stopping the IL-6 inhibitor therapy and optionally selecting a different rheumatoid arthritis therapy if:(d) the expression level of at least one biomarker Ep-CAM, CCL4, LDL-receptor, Flt3L, or any combinations thereof is reduced or is not substantially changed, relative to its respective reference level; or(e) the expression level of at least one biomarker comprising AZU1, MMP9, MMP1, OSM, TNFSF1414, or any combinations thereof is increased or is not substantially changed, relative to its respective reference level; or(f) both (d) and (e).

[0057] In certain exemplary embodiments, the IL-6 inhibitor therapy comprises an IL-6 receptor (IL-6R) inhibitor. In certain exemplary embodiments, the IL-6R inhibitor comprises an anti-IL-6R antibody agent. In certain exemplary embodiments, the anti-IL-6R antibody agent comprises sarilumab. In certain exemplary embodiments, the subject is receiving sarilumab at a dose of about 200 mg every two weeks.

[0058] In certain exemplary embodiments, in a second sample from the subject who is determined to continue to receive the IL-6 inhibitor therapy, a second change in expression level from a second reference level of at least one biomarker comprising AZU1, MMP9, MMP1, OSM, TNFSF1414, Ep-CAM, CCL4, LDL-receptor, Flt3L, or combinations thereof, wherein the second change in expression level is measured after the subject is determined to continue to receive the IL-6 inhibitor therapy.

[0059] In certain exemplary embodiments, the at least one biomarker used for determining the second change in expression level is the same as the at least one biomarker used for determining a first change in expression level.

[0060] In certain exemplary embodiments, the at least one biomarker used for determining the second change in expression level is different from the at least one biomarker used for determining a first change in expression level.-10-Attorney Docket No. 768830: SA9-910PC

[0061] In certain exemplary embodiments, the reference level or a first reference level is expression level of the at least one biomarker in a sample from the subject prior to receiving the IL-6 inhibitor therapy. In certain exemplary embodiments, the second reference level is the same as the first reference level. In certain exemplary embodiments, the second reference level is different from a first reference level.

[0062] In certain exemplary embodiments, the sample comprises a serum or blood sample. In certain exemplary embodiments, the sample is from the subject after receiving the therapy for about two weeks to about twelve weeks.

[0063] In certain exemplary embodiments, the change in expression level is an mRNA expression level. In certain exemplary embodiments, the change in expression level is a protein expression level.

[0064] In certain exemplary embodiments, the subject was previously administered at least one disease modifying antirheumatic drug (DMARD) other than the IL-6 inhibitor therapy or the TNF- a inhibitor therapy, which is being received by the subject. In certain exemplary embodiments, the subject had an inadequate response to or did not tolerate the at least one DMARD.

[0065] In certain exemplary embodiments, the at least one DMARD comprises methotrexate (MTX).

[0066] In one aspect, the present disclosure provides a method of treating rheumatoid arthritis, the method comprising: modifying or continuing a rheumatoid arthritis treatment for a subject having rheumatoid arthritis and receiving an IL-6 inhibitor therapy, at least in part on the basis of a change in expression level from a reference level in a sample from the subject, of at least one biomarker comprising Ep-CAM, CCL4, LDL-receptor, Flt3L, or any combinations thereof, wherein:- if the expression level of the at least one biomarker is increased relative to the reference level, administration of the IL-6 inhibitor therapy to the subject is continued; or- if the expression level of the at least one biomarker is reduced or is not substantially changed relative to the reference level, administration of the IL-6 inhibitor therapy to the subject is stopped and optionally a different rheumatoid arthritis therapy is selected for the subject.

[0067] In certain exemplary embodiments, the IL-6 inhibitor therapy comprises an IL-6 receptor (IL-6R) inhibitor. In certain exemplary embodiments, the IL-6R inhibitor comprises an anti-IL-6R antibody agent. In certain exemplary embodiments, the anti-IL-6R antibody agent comprises-11-Attorney Docket No. 768830: SA9-910PC sarilumab. In certain exemplary embodiments, the subject is receiving sarilumab at a dose of about 200 mg every two weeks.

[0068] In certain exemplary embodiments, in a second sample from the subject who is determined to continue to receive the IL-6 inhibitor therapy, a second change in expression level from a second reference level of at least one biomarker comprising AZU1, MMP9, MMP1, OSM, TNFSF1414, Ep-CAM, CCL4, LDL-receptor, Flt3L, or combinations thereof, wherein the second change in expression level is measured after the subject is determined to continue to receive the IL-6 inhibitor therapy.

[0069] In certain exemplary embodiments, the at least one biomarker used for determining the second change in expression level is the same as the at least one biomarker used for determining a first change in expression level.

[0070] In certain exemplary embodiments, the at least one biomarker used for determining the second change in expression level is different from the at least one biomarker used for determining a first change in expression level.

[0071] In certain exemplary embodiments, the reference level or a first reference level is expression level of the at least one biomarker in a sample from the subject prior to receiving the IL-6 inhibitor therapy. In certain exemplary embodiments, the second reference level is the same as the first reference level. In certain exemplary embodiments, the second reference level is different from a first reference level.

[0072] In certain exemplary embodiments, the sample comprises a serum or blood sample. In certain exemplary embodiments, the sample is from the subject after receiving the therapy for about two weeks to about twelve weeks.

[0073] In certain exemplary embodiments, the change in expression level is an mRNA expression level. In certain exemplary embodiments, the change in expression level is a protein expression level.

[0074] In certain exemplary embodiments, the subject was previously administered at least one disease modifying antirheumatic drug (DMARD) other than the IL-6 inhibitor therapy or the TNF- a inhibitor therapy, which is being received by the subject. In certain exemplary embodiments, the subject had an inadequate response to or did not tolerate the at least one DMARD.-12-Attorney Docket No. 768830: SA9-910PC

[0075] In certain exemplary embodiments, the at least one DMARD comprises methotrexate (MTX).

[0076] In one aspect, the present disclosure provides a method of treating rheumatoid arthritis, the method comprising: modifying or continuing a rheumatoid arthritis treatment for a subject having rheumatoid arthritis and receiving an IL-6 inhibitor therapy, at least in part on the basis of a change in expression level from a reference level in a sample from the subject, of at least one biomarker comprising AZU1, MMP9, MMP1, OSM, TNFSF1414, or any combinations thereof, wherein:- if the expression level of the at least one biomarker is decreased relative to the reference level, administration of the IL-6 inhibitor therapy to the subject is continued; or- if the expression level of the at least one biomarker is increased or is not substantially changed relative to the reference level, administration of the IL-6 inhibitor therapy to the subject is stopped and optionally a different rheumatoid arthritis therapy is selected for the subject.

[0077] In certain exemplary embodiments, the IL-6 inhibitor therapy comprises an IL-6 receptor (IL-6R) inhibitor. In certain exemplary embodiments, the IL-6R inhibitor comprises an anti-IL-6R antibody agent. In certain exemplary embodiments, the anti-IL-6R antibody agent comprises sarilumab. In certain exemplary embodiments, the subject is receiving sarilumab at a dose of about 200 mg every two weeks.

[0078] In certain exemplary embodiments, in a second sample from the subject who is determined to continue to receive the IL-6 inhibitor therapy, a second change in expression level from a second reference level of at least one biomarker comprising AZU1, MMP9, MMP1, OSM, TNFSF1414, Ep-CAM, CCL4, LDL-receptor, Flt3L, or combinations thereof, wherein the second change in expression level is measured after the subject is determined to continue to receive the IL-6 inhibitor therapy.

[0079] In certain exemplary embodiments, the at least one biomarker used for determining the second change in expression level is the same as the at least one biomarker used for determining a first change in expression level.

[0080] In certain exemplary embodiments, the at least one biomarker used for determining the second change in expression level is different from the at least one biomarker used for determining a first change in expression level.-13-Attorney Docket No. 768830: SA9-910PC

[0081] In certain exemplary embodiments, the reference level or a first reference level is expression level of the at least one biomarker in a sample from the subject prior to receiving the IL-6 inhibitor therapy. In certain exemplary embodiments, the second reference level is the same as the first reference level. In certain exemplary embodiments, the second reference level is different from a first reference level.

[0082] In certain exemplary embodiments, the sample comprises a serum or blood sample. In certain exemplary embodiments, the sample is from the subject after receiving the therapy for about two weeks to about twelve weeks.

[0083] In certain exemplary embodiments, the change in expression level is an mRNA expression level. In certain exemplary embodiments, the change in expression level is a protein expression level.

[0084] In certain exemplary embodiments, the subject was previously administered at least one disease modifying antirheumatic drug (DMARD) other than the IL-6 inhibitor therapy or the TNF- a inhibitor therapy, which is being received by the subject. In certain exemplary embodiments, the subject had an inadequate response to or did not tolerate the at least one DMARD.

[0085] In certain exemplary embodiments, the at least one DMARD comprises methotrexate (MTX).

[0086] In one aspect, the present disclosure provides a method of treating rheumatoid arthritis, the method comprising: if a sample of a subject, who has rheumatoid arthritis and is receiving an IL-6 inhibitor therapy, is determined to have an increased expression level of at least one biomarker comprising Ep-CAM, CCL4, LDL-receptor, Flt3L, or any combinations thereof, as compared to a reference level, continuing administration of the IL-6 inhibitor therapy to the subject; or if a sample of a subject, who has rheumatoid arthritis and is receiving an IL-6 inhibitor therapy, is determined to have a reduced or substantially the same expression level of at least one biomarker comprising Ep-CAM, CCL4, LDL-receptor, Flt3L, or any combinations thereof as compared to a reference level, stopping administration of the IL-6 inhibitor therapy to the subject and optionally selecting a different rheumatoid arthritis therapy.

[0087] In certain exemplary embodiments, the IL-6 inhibitor therapy comprises an IL-6 receptor (IL-6R) inhibitor. In certain exemplary embodiments, the IL-6R inhibitor comprises an anti-IL-6R antibody agent. In certain exemplary embodiments, the anti-IL-6R antibody agent comprises-14-Attorney Docket No. 768830: SA9-910PC sarilumab. In certain exemplary embodiments, the subject is receiving sarilumab at a dose of about 200 mg every two weeks.

[0088] In certain exemplary embodiments, in a second sample from the subject who is determined to continue to receive the IL-6 inhibitor therapy, a second change in expression level from a second reference level of at least one biomarker comprising AZU1, MMP9, MMP1, OSM, TNFSF1414, Ep-CAM, CCL4, LDL-receptor, Flt3L, or combinations thereof, wherein the second change in expression level is measured after the subject is determined to continue to receive the IL-6 inhibitor therapy.

[0089] In certain exemplary embodiments, the at least one biomarker used for determining the second change in expression level is the same as the at least one biomarker used for determining a first change in expression level.

[0090] In certain exemplary embodiments, the at least one biomarker used for determining the second change in expression level is different from the at least one biomarker used for determining a first change in expression level.

[0091] In certain exemplary embodiments, the reference level or a first reference level is expression level of the at least one biomarker in a sample from the subject prior to receiving the IL-6 inhibitor therapy. In certain exemplary embodiments, the second reference level is the same as the first reference level. In certain exemplary embodiments, the second reference level is different from a first reference level.

[0092] In certain exemplary embodiments, the sample comprises a serum or blood sample. In certain exemplary embodiments, the sample is from the subject after receiving the therapy for about two weeks to about twelve weeks.

[0093] In certain exemplary embodiments, the change in expression level is an mRNA expression level. In certain exemplary embodiments, the change in expression level is a protein expression level.

[0094] In certain exemplary embodiments, the subject was previously administered at least one disease modifying antirheumatic drug (DMARD) other than the IL-6 inhibitor therapy or the TNF- a inhibitor therapy, which is being received by the subject. In certain exemplary embodiments, the subject had an inadequate response to or did not tolerate the at least one DMARD.

[0095] In certain exemplary embodiments, the at least one DMARD comprises methotrexate (MTX).-15-Attorney Docket No. 768830: SA9-910PC

[0096] In one aspect, the present disclosure provides a method of treating rheumatoid arthritis, the method comprising: if a sample of a subject, who has rheumatoid arthritis and is receiving an IL-6 inhibitor therapy, is determined to have a reduced expression level of at least one biomarker comprising AZU1, MMP9, MMP1, OSM, TNFSF1414, or any combinations thereof, as compared to a reference level, continuing administration of the IL-6 inhibitor therapy to the subject; or if a sample of a subject, who has rheumatoid arthritis and is receiving an IL-6 inhibitor therapy, is determined to have an increased or substantially the same expression level of at least one biomarker comprising AZU1, MMP9, MMP1, OSM, TNFSF1414, or any combinations thereof, as compared to a reference level, stopping administration of the IL-6 inhibitor therapy to the subject and optionally selecting a different rheumatoid arthritis therapy.

[0097] In certain exemplary embodiments, the IL-6 inhibitor therapy comprises an IL-6 receptor (IL-6R) inhibitor. In certain exemplary embodiments, the IL-6R inhibitor comprises an anti-IL-6R antibody agent. In certain exemplary embodiments, the anti-IL-6R antibody agent comprises sarilumab. In certain exemplary embodiments, the subject is receiving sarilumab at a dose of about 200 mg every two weeks.

[0098] In certain exemplary embodiments, in a second sample from the subject who is determined to continue to receive the IL-6 inhibitor therapy, a second change in expression level from a second reference level of at least one biomarker comprising AZU1, MMP9, MMP1, OSM, TNFSF1414, Ep-CAM, CCL4, LDL-receptor, Flt3L, or combinations thereof, wherein the second change in expression level is measured after the subject is determined to continue to receive the IL-6 inhibitor therapy.

[0099] In certain exemplary embodiments, the at least one biomarker used for determining the second change in expression level is the same as the at least one biomarker used for determining a first change in expression level.

[0100] In certain exemplary embodiments, the at least one biomarker used for determining the second change in expression level is different from the at least one biomarker used for determining a first change in expression level.

[0101] In certain exemplary embodiments, the reference level or a first reference level is expression level of the at least one biomarker in a sample from the subject prior to receiving the IL-6 inhibitor therapy. In certain exemplary embodiments, the second reference level is the same-16-Attorney Docket No. 768830: SA9-910PC as the first reference level. In certain exemplary embodiments, the second reference level is different from a first reference level.

[0102] In certain exemplary embodiments, the sample comprises a serum or blood sample. In certain exemplary embodiments, the sample is from the subject after receiving the therapy for about two weeks to about twelve weeks.

[0103] In certain exemplary embodiments, the change in expression level is an mRNA expression level. In certain exemplary embodiments, the change in expression level is a protein expression level.

[0104] In certain exemplary embodiments, the subject was previously administered at least one disease modifying antirheumatic drug (DMARD) other than the IL-6 inhibitor therapy or the TNF- a inhibitor therapy, which is being received by the subject. In certain exemplary embodiments, the subject had an inadequate response to or did not tolerate the at least one DMARD.

[0105] In certain exemplary embodiments, the at least one DMARD comprises methotrexate (MTX).

[0106] In one aspect, the present disclosure provides a method of assessing or monitoring early responsiveness of a subject having rheumatoid arthritis to a tumor necrosis factor-(TNF-a) inhibitor therapy, the method comprising: determining, in a sample from a subject having rheumatoid arthritis and receiving a TNF- a inhibitor therapy, a change in expression level from a reference level of at least one biomarker comprising C-C motif chemokine 20 (CCL20), C-C motif chemokine 4 (CCL4), C-X-C motif chemokine 10 (CXCL10), C-X-C motif chemokine 9 (CXCL9), protein S100-A12 (ENRAGE), oncostatin-M (OSM), interleukin- 10 (IL-10), or any combinations thereof, wherein the change in expression level from the reference level of the at least one biomarker is an indication of the likelihood of early responsiveness to the TNF-a inhibitor therapy.

[0107] In certain exemplary embodiments, the at least one biomarker further comprises a biomarker IFN-y.

[0108] In certain exemplary embodiments, the TNF-a inhibitor therapy comprises an anti-TNF- a antibody agent.-17-Attorney Docket No. 768830: SA9-910PC

[0109] In certain exemplary embodiments, the anti-TNF-a antibody agent comprises adalimumab. In certain exemplary embodiments, the subject is receiving adalimumab at a dose of about 40 mg every two weeks.

[0110] In certain exemplary embodiments, the TNF- a inhibitor therapy comprises a small molecule TNF- a inhibitor.

[0111] In certain exemplary embodiments, the TNF -a inhibitor therapy comprises a TNFR1 signaling inhibitor.

[0112] In certain exemplary embodiments, in a second sample from the subject who is determined to continue to receive the TNF- a inhibitor therapy, a second change in expression level from a second reference level of at least one biomarker comprising CCL20, CCL4, CXCL10, CXCL9, EN-RAGE, OSM IL-10, or any combinations thereof, wherein the second change in expression level is measured after the subject is determined to continue to receive the TNF- a inhibitor therapy.

[0113] In certain exemplary embodiments, the at least one biomarker used for determining the second change in expression level is the same as the at least one biomarker used for determining a first change in expression level.

[0114] In certain exemplary embodiments, the at least one biomarker used for determining the second change in expression level is different from the at least one biomarker used for determining a first change in expression level.

[0115] In certain exemplary embodiments, the reference level or a first reference level is expression level of the at least one biomarker in a sample from the subject prior to receiving the TNF- a inhibitor therapy. In certain exemplary embodiments, the second reference level is the same as the first reference level. In certain exemplary embodiments, the second reference level is different from a first reference level.

[0116] In certain exemplary embodiments, the determining comprises measuring the expression level of the at least one biomarker and comparing the measured expression level with the respective reference level.

[0117] In certain exemplary embodiments, the sample comprises a serum or blood sample. In certain exemplary embodiments, the sample is from the subject after receiving the therapy for about two weeks to about twelve weeks.-18-Attorney Docket No. 768830: SA9-910PC

[0118] In certain exemplary embodiments, the change in expression level is an mRNA expression level. In certain exemplary embodiments, the change in expression level is a protein expression level.

[0119] In certain exemplary embodiments, the subject was previously administered at least one disease modifying antirheumatic drug (DMARD) other than the IL-6 inhibitor therapy or the TNF- a inhibitor therapy, which is being received by the subject. In certain exemplary embodiments, the subject had an inadequate response to or did not tolerate the at least one DMARD.

[0120] In certain exemplary embodiments, the at least one DMARD comprises methotrexate (MTX).

[0121] In one aspect, the present disclosure provides a method of treating rheumatoid arthritis, the method comprising: determining, in a sample of a subject having rheumatoid arthritis and receiving a TNF-a inhibitor therapy, a change in expression level from a reference level, of at least one biomarker comprising CCL20, CCL4, CXCL10, CXCL9, EN-RAGE, OSM, or any combinations thereof; and continuing the TNF-a inhibitor therapy if the expression level of the at least one biomarker is reduced relative to the reference level; or stopping the TNF-a inhibitor therapy and optionally selecting a different rheumatoid arthritis therapy if the expression level of the at least one biomarker is increased or is not substantially changed relative to the reference level.

[0122] In certain exemplary embodiments, the at least one biomarker further comprises a biomarker IFN-y.

[0123] In certain exemplary embodiments, the TNF-a inhibitor therapy comprises an anti-TNF- a antibody agent.

[0124] In certain exemplary embodiments, the anti-TNF-a antibody agent comprises adalimumab. In certain exemplary embodiments, the subject is receiving adalimumab at a dose of about 40 mg every two weeks.

[0125] In certain exemplary embodiments, the TNF- a inhibitor therapy comprises a small molecule TNF- a inhibitor.

[0126] In certain exemplary embodiments, the TNF-a inhibitor therapy comprises a TNFR1 signaling inhibitor.-19-Attorney Docket No. 768830: SA9-910PC

[0127] In certain exemplary embodiments, in a second sample from the subject who is determined to continue to receive the TNF- a inhibitor therapy, a second change in expression level from a second reference level of at least one biomarker comprising CCL20, CCL4, CXCL10, CXCL9, EN-RAGE, OSM IL-10, or any combinations thereof, wherein the second change in expression level is measured after the subject is determined to continue to receive the TNF- a inhibitor therapy.

[0128] In certain exemplary embodiments, the at least one biomarker used for determining the second change in expression level is the same as the at least one biomarker used for determining a first change in expression level.

[0129] In certain exemplary embodiments, the at least one biomarker used for determining the second change in expression level is different from the at least one biomarker used for determining a first change in expression level.

[0130] In certain exemplary embodiments, the reference level or a first reference level is expression level of the at least one biomarker in a sample from the subject prior to receiving the TNF- a inhibitor therapy. In certain exemplary embodiments, the second reference level is the same as the first reference level. In certain exemplary embodiments, the second reference level is different from a first reference level.

[0131] In certain exemplary embodiments, the determining comprises measuring the expression level of the at least one biomarker and comparing the measured expression level with the respective reference level.

[0132] In certain exemplary embodiments, the sample comprises a serum or blood sample. In certain exemplary embodiments, the sample is from the subject after receiving the therapy for about two weeks to about twelve weeks.

[0133] In certain exemplary embodiments, the change in expression level is an mRNA expression level. In certain exemplary embodiments, the change in expression level is a protein expression level.

[0134] In certain exemplary embodiments, the subject was previously administered at least one disease modifying antirheumatic drug (DMARD) other than the IL-6 inhibitor therapy or the TNF- a inhibitor therapy, which is being received by the subject. In certain exemplary embodiments, the subject had an inadequate response to or did not tolerate the at least one DMARD.In certain exemplary embodiments, the at least one DMARD comprises methotrexate (MTX).-20-Attorney Docket No. 768830: SA9-910PC

[0135] In one aspect, the present disclosure provides a method of treating rheumatoid arthritis, the method comprising: determining, in a sample of a subject having rheumatoid arthritis and receiving a TNF-a inhibitor therapy, a change in expression level from a reference level, of at least one biomarker comprising IL-10; and continuing the TNF-a inhibitor therapy if the expression level of the at least one biomarker is increased; or stopping the TNF-a inhibitor therapy and optionally selecting a different rheumatoid arthritis therapy if the expression level of the at least one biomarker is reduced or is not substantially changed.

[0136] In certain exemplary embodiments, the at least one biomarker further comprises a biomarker IFN-y.

[0137] In certain exemplary embodiments, the TNF-a inhibitor therapy comprises an anti-TNF- a antibody agent.

[0070] In certain exemplary embodiments, the anti-TNF-a antibody agent comprises adalimumab.In certain exemplary embodiments, the subject is receiving adalimumab at a dose of about 40 mg every two weeks.

[0138] In certain exemplary embodiments, the TNF- a inhibitor therapy comprises a small molecule TNF- a inhibitor.

[0139] In certain exemplary embodiments, the TNF-a inhibitor therapy comprises a TNFR1 signaling inhibitor.

[0140] In certain exemplary embodiments, in a second sample from the subject who is determined to continue to receive the TNF- a inhibitor therapy, a second change in expression level from a second reference level of at least one biomarker comprising CCL20, CCL4, CXCL10, CXCL9, EN-RAGE, OSM IL-10, or any combinations thereof, wherein the second change in expression level is measured after the subject is determined to continue to receive the TNF- a inhibitor therapy.

[0141] In certain exemplary embodiments, the at least one biomarker used for determining the second change in expression level is the same as the at least one biomarker used for determining a first change in expression level.-21-Attorney Docket No. 768830: SA9-910PC

[0142] In certain exemplary embodiments, the at least one biomarker used for determining the second change in expression level is different from the at least one biomarker used for determining a first change in expression level.

[0143] In certain exemplary embodiments, the reference level or a first reference level is expression level of the at least one biomarker in a sample from the subject prior to receiving the TNF- a inhibitor therapy. In certain exemplary embodiments, the second reference level is the same as the first reference level. In certain exemplary embodiments, the second reference level is different from a first reference level.

[0144] In certain exemplary embodiments, the determining comprises measuring the expression level of the at least one biomarker and comparing the measured expression level with the respective reference level.

[0145] In certain exemplary embodiments, the sample comprises a serum or blood sample. In certain exemplary embodiments, the sample is from the subject after receiving the therapy for about two weeks to about twelve weeks.

[0146] In certain exemplary embodiments, the change in expression level is an mRNA expression level. In certain exemplary embodiments, the change in expression level is a protein expression level.

[0147] In certain exemplary embodiments, the subject was previously administered at least one disease modifying antirheumatic drug (DMARD) other than the IL-6 inhibitor therapy or the TNF- a inhibitor therapy, which is being received by the subject. In certain exemplary embodiments, the subject had an inadequate response to or did not tolerate the at least one DMARD.

[0148] In certain exemplary embodiments, the at least one DMARD comprises methotrexate (MTX).

[0149] In one aspect, the present disclosure provides a method of treating rheumatoid arthritis, the method comprising: selecting a subject who is having rheumatoid arthritis and receiving a TNF -a inhibitor therapy and who is determined to show a change in expression level from a reference level, of at least one biomarker comprising CCL20, CCL4, CXCL10, CXCL9, EN-RAGE, OSM, or any combinations thereof; and continuing the TNF-a inhibitor therapy if the expression level of the at least one biomarker is reduced relative to the reference level; or-22-Attorney Docket No. 768830: SA9-910PC stopping the TNF-a inhibitor therapy and optionally selecting a different rheumatoid arthritis therapy if the expression level of the at least one biomarker is increased or is not substantially changed relative to the reference level.

[0150] In certain exemplary embodiments, the at least one biomarker further comprises a biomarker ZFN-y.

[0151] In certain exemplary embodiments, the TNF-a inhibitor therapy comprises an anti-TNF- a antibody agent.

[0152] In certain exemplary embodiments, the anti-TNF-a antibody agent comprises adalimumab. In certain exemplary embodiments, the subject is receiving adalimumab at a dose of about 40 mg every two weeks.

[0153] In certain exemplary embodiments, the TNF-a inhibitor therapy comprises a small molecule TNF- a inhibitor.

[0154] In certain exemplary embodiments, the TNF-a inhibitor therapy comprises a TNFR1 signaling inhibitor.

[0155] In certain exemplary embodiments, in a second sample from the subject who is determined to continue to receive the TNF- a inhibitor therapy, a second change in expression level from a second reference level of at least one biomarker comprising CCL20, CCL4, CXCL10, CXCL9, EN-RAGE, OSM IL-10, or any combinations thereof, wherein the second change in expression level is measured after the subject is determined to continue to receive the TNF- a inhibitor therapy.

[0156] In certain exemplary embodiments, the at least one biomarker used for determining the second change in expression level is the same as the at least one biomarker used for determining a first change in expression level.

[0157] In certain exemplary embodiments, the at least one biomarker used for determining the second change in expression level is different from the at least one biomarker used for determining a first change in expression level.

[0158] In certain exemplary embodiments, the reference level or a first reference level is expression level of the at least one biomarker in a sample from the subject prior to receiving the TNF- a inhibitor therapy. In certain exemplary embodiments, the second reference level is the same as the first reference level. In certain exemplary embodiments, the second reference level is different from a first reference level.-23-Attorney Docket No. 768830: SA9-910PC

[0159] In certain exemplary embodiments, the determining comprises measuring the expression level of the at least one biomarker and comparing the measured expression level with the respective reference level.

[0160] In certain exemplary embodiments, the sample comprises a serum or blood sample. In certain exemplary embodiments, the sample is from the subject after receiving the therapy for about two weeks to about twelve weeks.

[0161] In certain exemplary embodiments, the change in expression level is an mRNA expression level. In certain exemplary embodiments, the change in expression level is a protein expression level.

[0162] In certain exemplary embodiments, the subject was previously administered at least one disease modifying antirheumatic drug (DMARD) other than the IL-6 inhibitor therapy or the TNF- a inhibitor therapy, which is being received by the subject. In certain exemplary embodiments, the subject had an inadequate response to or did not tolerate the at least one DMARD.

[0163] In certain exemplary embodiments, the at least one DMARD comprises methotrexate (MTX).

[0164] In one aspect, the present disclosure provides a method of treating rheumatoid arthritis, the method comprising: selecting a subject who is having rheumatoid arthritis and receiving a TNF -a inhibitor therapy and who is determined to show a change in expression level from a reference level, of at least one biomarker comprising IL-10; and continuing the TNF-a inhibitor therapy if the expression level of the at least one biomarker is increased; or stopping the TNF-a inhibitor therapy and optionally selecting a different rheumatoid arthritis therapy if the expression level of the at least one biomarker is reduced or is not substantially changed.

[0165] In certain exemplary embodiments, the at least one biomarker further comprises a biomarker FFN-y.

[0166] In certain exemplary embodiments, the TNF-a inhibitor therapy comprises an anti-TNF- a antibody agent.-24-Attorney Docket No. 768830: SA9-910PC

[0167] In certain exemplary embodiments, the anti-TNF-a antibody agent comprises adalimumab. In certain exemplary embodiments, the subject is receiving adalimumab at a dose of about 40 mg every two weeks.

[0168] In certain exemplary embodiments, the TNF-a inhibitor therapy comprises a small molecule TNF- a inhibitor.

[0169] In certain exemplary embodiments, the TNF-a inhibitor therapy comprises a TNFR1 signaling inhibitor.

[0170] In certain exemplary embodiments, in a second sample from the subject who is determined to continue to receive the TNF- a inhibitor therapy, a second change in expression level from a second reference level of at least one biomarker comprising CCL20, CCL4, CXCL10, CXCL9, EN-RAGE, OSM IL-10, or any combinations thereof, wherein the second change in expression level is measured after the subject is determined to continue to receive the TNF- a inhibitor therapy.

[0171] In certain exemplary embodiments, the at least one biomarker used for determining the second change in expression level is the same as the at least one biomarker used for determining a first change in expression level.

[0172] In certain exemplary embodiments, the at least one biomarker used for determining the second change in expression level is different from the at least one biomarker used for determining a first change in expression level.

[0173] In certain exemplary embodiments, the reference level or a first reference level is expression level of the at least one biomarker in a sample from the subject prior to receiving the TNF- a inhibitor therapy. In certain exemplary embodiments, the second reference level is the same as the first reference level. In certain exemplary embodiments, the second reference level is different from a first reference level.

[0174] In certain exemplary embodiments, the determining comprises measuring the expression level of the at least one biomarker and comparing the measured expression level with the respective reference level.

[0175] In certain exemplary embodiments, the sample comprises a serum or blood sample. In certain exemplary embodiments, the sample is from the subject after receiving the therapy for about two weeks to about twelve weeks.-25-Attorney Docket No. 768830: SA9-910PC

[0176] In certain exemplary embodiments, the change in expression level is an mRNA expression level. In certain exemplary embodiments, the change in expression level is a protein expression level.

[0177] In certain exemplary embodiments, the subject was previously administered at least one disease modifying antirheumatic drug (DMARD) other than the IL-6 inhibitor therapy or the TNF- a inhibitor therapy, which is being received by the subject. In certain exemplary embodiments, the subject had an inadequate response to or did not tolerate the at least one DMARD.

[0178] In certain exemplary embodiments, the at least one DMARD comprises methotrexate (MTX).

[0179] In one aspect, the present disclosure provides a method of treating rheumatoid arthritis, the method comprising: determining, in a sample of a subject having rheumatoid arthritis and receiving a TNF -a inhibitor therapy, a change in expression level from a reference level, of at least one biomarker comprising CCL20, CCL4, CXCL10, CXCL9, EN-RAGE, OSM, IL-10, or any combinations thereof; and continuing the TNF-a inhibitor therapy if:(a) the expression level of at least one biomarker comprising CCL20, CCL4, CXCL10, CXCL9, EN-RAGE, OSM, or any combinations thereof is reduced relative to its respective reference level; or(b) the expression level of at least one biomarker comprising IL-10 is increased relative to its respective reference level; or(c) both (a) and (b); or stopping the TNF-a inhibitor therapy and optionally selecting a different rheumatoid arthritis therapy if:(d) the expression level of at least one biomarker CCL20, CCL4, CXCL10, CXCL9, EN-RAGE, OSM, or any combinations thereof is increased or is not substantially changed, relative to its respective reference level; or(e) the expression level of at least one biomarker comprising IL-10 is reduced or is not substantially changed, relative to its respective reference level; or(f) both (d) and (e).-26-Attorney Docket No. 768830: SA9-910PC

[0180] In certain exemplary embodiments, the at least one biomarker further comprises a biomarker IFN-y.

[0181] In certain exemplary embodiments, the TNF-a inhibitor therapy comprises an anti-TNF- a antibody agent.

[0182] In certain exemplary embodiments, the anti-TNF-a antibody agent comprises adalimumab. In certain exemplary embodiments, the subject is receiving adalimumab at a dose of about 40 mg every two weeks.

[0183] In certain exemplary embodiments, the TNF- a inhibitor therapy comprises a small molecule TNF- a inhibitor.

[0184] In certain exemplary embodiments, the TNF-a inhibitor therapy comprises a TNFR1 signaling inhibitor.

[0185] In certain exemplary embodiments, in a second sample from the subject who is determined to continue to receive the TNF- a inhibitor therapy, a second change in expression level from a second reference level of at least one biomarker comprising CCL20, CCL4, CXCL10, CXCL9, EN-RAGE, OSM IL-10, or any combinations thereof, wherein the second change in expression level is measured after the subject is determined to continue to receive the TNF- a inhibitor therapy.

[0186] In certain exemplary embodiments, the at least one biomarker used for determining the second change in expression level is the same as the at least one biomarker used for determining a first change in expression level.

[0187] In certain exemplary embodiments, the at least one biomarker used for determining the second change in expression level is different from the at least one biomarker used for determining a first change in expression level.

[0188] In certain exemplary embodiments, the reference level or a first reference level is expression level of the at least one biomarker in a sample from the subject prior to receiving the TNF- a inhibitor therapy. In certain exemplary embodiments, the second reference level is the same as the first reference level. In certain exemplary embodiments, the second reference level is different from a first reference level.-27-Attorney Docket No. 768830: SA9-910PC

[0189] In certain exemplary embodiments, the determining comprises measuring the expression level of the at least one biomarker and comparing the measured expression level with the respective reference level.

[0190] In certain exemplary embodiments, the sample comprises a serum or blood sample. In certain exemplary embodiments, the sample is from the subject after receiving the therapy for about two weeks to about twelve weeks.

[0191] In certain exemplary embodiments, the change in expression level is an mRNA expression level. In certain exemplary embodiments, the change in expression level is a protein expression level.

[0192] In certain exemplary embodiments, the subject was previously administered at least one disease modifying antirheumatic drug (DMARD) other than the IL-6 inhibitor therapy or the TNF- a inhibitor therapy, which is being received by the subject. In certain exemplary embodiments, the subject had an inadequate response to or did not tolerate the at least one DMARD.

[0193] In certain exemplary embodiments, the at least one DMARD comprises methotrexate (MTX).

[0194] In one aspect, the present disclosure provides a method of treating rheumatoid arthritis, the method comprising: modifying or continuing a rheumatoid arthritis treatment for a subject having rheumatoid arthritis and receiving a TNF-a inhibitor therapy, at least in part on the basis of a change in expression level from a reference level in a sample from the subject, of at least one biomarker comprising CCL20, CCL4, CXCL10, CXCL9, EN-RAGE, OSM, or any combinations thereof, wherein:- if the expression level of the at least one biomarker is reduced relative to the reference level, administration of the TNF-a inhibitor therapy to the subject is continued; or- if the expression level of the at least one biomarker is increased or is not substantially changed relative to the reference level, administration of the TNF-a inhibitor therapy to the subject is stopped and optionally a different rheumatoid arthritis therapy is selected for the subject.

[0195] In certain exemplary embodiments, the at least one biomarker further comprises a biomarker IFN-y.-28-Attorney Docket No. 768830: SA9-910PC

[0196] In certain exemplary embodiments, the TNF-a inhibitor therapy comprises an anti-TNF- a antibody agent.

[0197] In certain exemplary embodiments, the anti-TNF-a antibody agent comprises adalimumab.In certain exemplary embodiments, the subject is receiving adalimumab at a dose of about 40 mg every two weeks.

[0198] In certain exemplary embodiments, the TNF- a inhibitor therapy comprises a small molecule TNF- a inhibitor.

[0199] In certain exemplary embodiments, the TNF-a inhibitor therapy comprises a TNFR1 signaling inhibitor.

[0200] In certain exemplary embodiments, in a second sample from the subject who is determined to continue to receive the TNF- a inhibitor therapy, a second change in expression level from a second reference level of at least one biomarker comprising CCL20, CCL4, CXCL10, CXCL9, EN-RAGE, OSM IL-10, or any combinations thereof, wherein the second change in expression level is measured after the subject is determined to continue to receive the TNF- a inhibitor therapy.

[0201] In certain exemplary embodiments, the at least one biomarker used for determining the second change in expression level is the same as the at least one biomarker used for determining a first change in expression level.

[0202] In certain exemplary embodiments, the at least one biomarker used for determining the second change in expression level is different from the at least one biomarker used for determining a first change in expression level.

[0203] In certain exemplary embodiments, the reference level or a first reference level is expression level of the at least one biomarker in a sample from the subject prior to receiving the TNF- a inhibitor therapy. In certain exemplary embodiments, the second reference level is the same as the first reference level. In certain exemplary embodiments, the second reference level is different from a first reference level.

[0204] In certain exemplary embodiments, the determining comprises measuring the expression level of the at least one biomarker and comparing the measured expression level with the respective reference level.-29-Attorney Docket No. 768830: SA9-910PC

[0205] In certain exemplary embodiments, the sample comprises a serum or blood sample. In certain exemplary embodiments, the sample is from the subject after receiving the therapy for about two weeks to about twelve weeks.

[0206] In certain exemplary embodiments, the change in expression level is an mRNA expression level. In certain exemplary embodiments, the change in expression level is a protein expression level.

[0207] In certain exemplary embodiments, the subject was previously administered at least one disease modifying antirheumatic drug (DMARD) other than the IL-6 inhibitor therapy or the TNF- a inhibitor therapy, which is being received by the subject. In certain exemplary embodiments, the subject had an inadequate response to or did not tolerate the at least one DMARD.

[0208] In certain exemplary embodiments, the at least one DMARD comprises methotrexate (MTX).

[0209] In one aspect, the present disclosure provides a method of treating rheumatoid arthritis, the method comprising: modifying or continuing a rheumatoid arthritis treatment for a subject having rheumatoid arthritis and receiving a TNF-a inhibitor therapy, at least in part on the basis of a change in expression level from a reference level in a sample from the subject, of at least one biomarker comprising IL- 10, wherein:- if the expression level of the at least one biomarker is increased relative to the reference level, administration of the TNF-a inhibitor therapy to the subject is continued; or- if the expression level of the at least one biomarker is reduced or is not substantially changed relative to the reference level, administration of the TNF-a inhibitor therapy to the subject is stopped and optionally a different rheumatoid arthritis therapy is selected for the subject.

[0210] In certain exemplary embodiments, the at least one biomarker further comprises a biomarker IFN-y.

[0211] In certain exemplary embodiments, the TNF-a inhibitor therapy comprises an anti-TNF- a antibody agent.

[0212] In certain exemplary embodiments, the anti-TNF-a antibody agent comprises adalimumab.-30-Attorney Docket No. 768830: SA9-910PCIn certain exemplary embodiments, the subject is receiving adalimumab at a dose of about 40 mg every two weeks.

[0213] In certain exemplary embodiments, the TNF- a inhibitor therapy comprises a small molecule TNF- a inhibitor.

[0214] In certain exemplary embodiments, the TNF -a inhibitor therapy comprises a TNFR1 signaling inhibitor.

[0215] In certain exemplary embodiments, in a second sample from the subject who is determined to continue to receive the TNF- a inhibitor therapy, a second change in expression level from a second reference level of at least one biomarker comprising CCL20, CCL4, CXCL10, CXCL9, EN-RAGE, OSM IL-10, or any combinations thereof, wherein the second change in expression level is measured after the subject is determined to continue to receive the TNF- a inhibitor therapy.

[0216] In certain exemplary embodiments, the at least one biomarker used for determining the second change in expression level is the same as the at least one biomarker used for determining a first change in expression level.

[0217] In certain exemplary embodiments, the at least one biomarker used for determining the second change in expression level is different from the at least one biomarker used for determining a first change in expression level.

[0218] In certain exemplary embodiments, the reference level or a first reference level is expression level of the at least one biomarker in a sample from the subject prior to receiving the TNF- a inhibitor therapy. In certain exemplary embodiments, the second reference level is the same as the first reference level. In certain exemplary embodiments, the second reference level is different from a first reference level.

[0219] In certain exemplary embodiments, the determining comprises measuring the expression level of the at least one biomarker and comparing the measured expression level with the respective reference level.

[0220] In certain exemplary embodiments, the sample comprises a serum or blood sample. In certain exemplary embodiments, the sample is from the subject after receiving the therapy for about two weeks to about twelve weeks.-31-Attorney Docket No. 768830: SA9-910PC

[0221] In certain exemplary embodiments, the change in expression level is an mRNA expression level. In certain exemplary embodiments, the change in expression level is a protein expression level.

[0222] In certain exemplary embodiments, the subject was previously administered at least one disease modifying antirheumatic drug (DMARD) other than the IL-6 inhibitor therapy or the TNF- a inhibitor therapy, which is being received by the subject. In certain exemplary embodiments, the subject had an inadequate response to or did not tolerate the at least one DMARD.

[0223] In certain exemplary embodiments, the at least one DMARD comprises methotrexate (MTX).

[0224] In one aspect, the present disclosure provides a method of treating rheumatoid arthritis, the method comprising: if a sample of a subject, who has rheumatoid arthritis and is receiving a TNF-a inhibitor therapy, is determined to have a reduced expression level of at least one biomarker comprising CCL20, CCL4, CXCL10, CXCL9, EN-RAGE, OSM, or any combinations thereof, as compared to a reference level, continuing administration of the IL-6 inhibitor therapy to the subject; or if a sample of a subject, who has rheumatoid arthritis and is receiving an TNF-a inhibitor therapy, is determined to have an increased or substantially the same expression level of at least one biomarker comprising CCL20, CCL4, CXCL10, CXCL9, EN-RAGE, OSM, or any combinations thereof, as compared to a reference level, stopping administration of the TNF-a inhibitor therapy to the subject and optionally selecting a different rheumatoid arthritis therapy.

[0225] In certain exemplary embodiments, the at least one biomarker further comprises a biomarker IFN-y.

[0226] In certain exemplary embodiments, the TNF-a inhibitor therapy comprises an anti-TNF- a antibody agent.

[0227] In certain exemplary embodiments, the anti-TNF-a antibody agent comprises adalimumab.In certain exemplary embodiments, the subject is receiving adalimumab at a dose of about 40 mg every two weeks.

[0228] In certain exemplary embodiments, the TNF- a inhibitor therapy comprises a small molecule TNF- a inhibitor.-32-Attorney Docket No. 768830: SA9-910PC

[0229] In certain exemplary embodiments, the TNF -a inhibitor therapy comprises a TNFR1 signaling inhibitor.

[0230] In certain exemplary embodiments, in a second sample from the subject who is determined to continue to receive the TNF- a inhibitor therapy, a second change in expression level from a second reference level of at least one biomarker comprising CCL20, CCL4, CXCL10, CXCL9, EN-RAGE, OSM IL-10, or any combinations thereof, wherein the second change in expression level is measured after the subject is determined to continue to receive the TNF- a inhibitor therapy.

[0231] In certain exemplary embodiments, the at least one biomarker used for determining the second change in expression level is the same as the at least one biomarker used for determining a first change in expression level.

[0232] In certain exemplary embodiments, the at least one biomarker used for determining the second change in expression level is different from the at least one biomarker used for determining a first change in expression level.

[0233] In certain exemplary embodiments, the reference level or a first reference level is expression level of the at least one biomarker in a sample from the subject prior to receiving the TNF- a inhibitor therapy. In certain exemplary embodiments, the second reference level is the same as the first reference level. In certain exemplary embodiments, the second reference level is different from a first reference level.

[0234] In certain exemplary embodiments, the determining comprises measuring the expression level of the at least one biomarker and comparing the measured expression level with the respective reference level.

[0235] In certain exemplary embodiments, the sample comprises a serum or blood sample. In certain exemplary embodiments, the sample is from the subject after receiving the therapy for about two weeks to about twelve weeks.

[0236] In certain exemplary embodiments, the change in expression level is an mRNA expression level. In certain exemplary embodiments, the change in expression level is a protein expression level.

[0237] In certain exemplary embodiments, the subject was previously administered at least one disease modifying antirheumatic drug (DMARD) other than the IL-6 inhibitor therapy or the TNF- a inhibitor therapy, which is being received by the subject. In certain exemplary-33-Attorney Docket No. 768830: SA9-910PC embodiments, the subject had an inadequate response to or did not tolerate the at least one DMARD.

[0238] In certain exemplary embodiments, the at least one DMARD comprises methotrexate (MTX).

[0239] In one aspect, the present disclosure provides a method of treating rheumatoid arthritis, the method comprising: if a sample of a subject, who has rheumatoid arthritis and is receiving a TNF-a inhibitor therapy, is determined to have an increased expression level of at least one biomarker comprising IL-10, as compared to a reference level, continuing administration of the TNF-a inhibitor therapy to the subject; or if a sample of a subject, who has rheumatoid arthritis and is receiving an TNF-a inhibitor therapy, is determined to have a reduced or substantially the same expression level of at least one biomarker comprising IL-10, as compared to a reference level, stopping administration of the TNF- a inhibitor therapy to the subject and optionally selecting a different rheumatoid arthritis therapy.

[0240] In certain exemplary embodiments, the at least one biomarker further comprises a biomarker FFN-y.

[0241] In certain exemplary embodiments, the TNF-a inhibitor therapy comprises an anti-TNF- a antibody agent.

[0242] In certain exemplary embodiments, the anti-TNF-a antibody agent comprises adalimumab.

[0243] In certain exemplary embodiments, the subject is receiving adalimumab at a dose of about 40 mg every two weeks.

[0244] In certain exemplary embodiments, the TNF- a inhibitor therapy comprises a small molecule TNF- a inhibitor.

[0245] In certain exemplary embodiments, the TNF-a inhibitor therapy comprises a TNFR1 signaling inhibitor.

[0246] In certain exemplary embodiments, in a second sample from the subject who is determined to continue to receive the TNF- a inhibitor therapy, a second change in expression level from a second reference level of at least one biomarker comprising CCL20, CCL4, CXCL10, CXCL9, EN-RAGE, OSM IL-10, or any combinations thereof, wherein the second-34-Attorney Docket No. 768830: SA9-910PC change in expression level is measured after the subject is determined to continue to receive the TNF- a inhibitor therapy.

[0247] In certain exemplary embodiments, the at least one biomarker used for determining the second change in expression level is the same as the at least one biomarker used for determining a first change in expression level.

[0248] In certain exemplary embodiments, the at least one biomarker used for determining the second change in expression level is different from the at least one biomarker used for determining a first change in expression level.

[0249] In certain exemplary embodiments, the reference level or a first reference level is expression level of the at least one biomarker in a sample from the subject prior to receiving the TNF- a inhibitor therapy. In certain exemplary embodiments, the second reference level is the same as the first reference level. In certain exemplary embodiments, the second reference level is different from a first reference level.

[0250] In certain exemplary embodiments, the determining comprises measuring the expression level of the at least one biomarker and comparing the measured expression level with the respective reference level.

[0251] In certain exemplary embodiments, the sample comprises a serum or blood sample. In certain exemplary embodiments, the sample is from the subject after receiving the therapy for about two weeks to about twelve weeks.

[0252] In certain exemplary embodiments, the change in expression level is an mRNA expression level. In certain exemplary embodiments, the change in expression level is a protein expression level.

[0253] In certain exemplary embodiments, the subject was previously administered at least one disease modifying antirheumatic drug (DMARD) other than the IL-6 inhibitor therapy or the TNF- a inhibitor therapy, which is being received by the subject. In certain exemplary embodiments, the subject had an inadequate response to or did not tolerate the at least one DMARD.

[0254] In certain exemplary embodiments, the at least one DMARD comprises methotrexate (MTX).

[0255] In one aspect is a kit for assessing or monitoring early responsiveness to or determining continuation of an IL-6 inhibitor therapy in a subject having rheumatoid arthritis, the kit-35-Attorney Docket No. 768830: SA9-910PC comprising at least one agent for detecting in a biological sample from a subject having rheumatoid arthritis and receiving an IL-6 inhibitor therapy expression level of at least one biomarker comprising AZU1, MMP9, MMP1, OSM, TNFSF1414, Ep-CAM, CCL4, LDL- receptor, Ftl3L, or any combinations thereof.

[0256] In certain exemplary embodiments, the kit further comprises an instruction providing that a decrease in expression level from a reference level of at least one biomarker comprising AZU1, MMP9, MMP1, OSM, TNFSF1414, or any combinations thereof indicates (i) an increased likelihood of responsiveness to the IL-6 inhibitor therapy, (ii) a recommended continuation of the IL-6 inhibitor therapy, or (iii) both (i) and (ii).

[0257] In certain exemplary embodiments, the kit, further comprises an instruction providing that an increase in expression level from a reference level of at least one biomarker comprising Ep-CAM, CCL4, LDL-receptor, Ftl3L, or any combinations thereof indicates (i) an increased likelihood of responsiveness to the IL-6 inhibitor therapy, (ii) a recommended continuation of the IL-6 inhibitor therapy, or (iii) both (i) and (ii).

[0258] In certain exemplary embodiments, the reference level is expression level of the at least one biomarker in a biological sample from the subject prior to receiving the IL-6 inhibitor therapy.

[0259] In certain exemplary embodiments, the biological sample comprises a serum or blood sample.

[0260] In certain exemplary embodiments, the biological sample is from the subject after receiving the therapy for about two weeks to about twelve weeks.

[0261] In certain exemplary embodiments, the expression level is an mRNA expression level. In certain exemplary embodiments, the expression level is a protein expression level.

[0262] In one aspect is a kit for assessing or monitoring early responsiveness to or determining continuation of an TNF-a inhibitor therapy in a subject having rheumatoid arthritis, the kit comprising at least one agent for detecting in a biological sample from a subject having rheumatoid arthritis and receiving an TNF-a inhibitor therapy expression level of at least one biomarker comprising CCL20, CCL4, CXCL10, CXCL9, EN-RAGE, OSM, IL-10, or any combinations thereof.

[0263] In certain exemplary embodiments, the kit further comprises an instruction providing that an increase in expression level from a reference level of at least one biomarker comprising IL--36-Attorney Docket No. 768830: SA9-910PC10 indicates (i) an increased likelihood of responsiveness to the TNF-a inhibitor therapy, (ii) a recommended continuation of the TNF-a inhibitor therapy, or (iii) both (i) and (ii).

[0264] In certain exemplary embodiments, the kit further comprises an instruction providing that a decrease in expression level from a reference level of at least one biomarker comprising CCL20, CCL4, CXCL10, CXCL9, EN-RAGE, OSM, or any combinations thereof indicates (i) an increased likelihood of responsiveness to the TNF-a inhibitor therapy, (ii) a recommended continuation of the TNF-a inhibitor therapy, or (iii) both (i) and (ii).

[0265] In certain exemplary embodiments, the kit further comprises at least one agent for detecting in a biological sample from a subject having rheumatoid arthritis and receiving an TNF-a inhibitor therapy expression level of a biomarker IFN-y.

[0266] In certain exemplary embodiments, the kit further comprises an instruction providing that an increase in expression level from a reference level of the biomarker IFN-y indicates (i) an increased likelihood of responsiveness to the TNF-a inhibitor therapy, (ii) a recommended continuation of the TNF-a inhibitor therapy, or (iii) both (i) and (ii).

[0267] In certain exemplary embodiments, the kit comprises a reference level in which the expression level is expression level of the at least one biomarker in a biological sample from the subject prior to receiving the TNF-a inhibitor therapy.

[0268] In certain exemplary embodiments, the biological sample comprises a serum or blood sample.

[0269] In certain exemplary embodiments, the biological sample is from the subject after receiving the therapy for about two weeks to about twelve weeks.

[0270] In certain exemplary embodiments, the expression level is an mRNA expression level. In certain exemplary embodiments, the expression level is a protein expression level.

[0271] In one aspect, is a system for assessing or monitoring early responsiveness to or determining continuation of an IL-6 inhibitor therapy in a subject having rheumatoid arthritis and receiving the IL-6 inhibitor therapy, the system comprising: at least one database that receives and stores expression levels of at least one biomarker comprising AZU1, MMP9, MMP1, OSM, TNFSF1414, Ep-CAM, CCL4, LDL-receptor, Ftl3L, or any combinations thereof, the expression levels determined from a biological sample from a subject having rheumatoid arthritis and receiving an IL-6 inhibitor therapy; and-37-Attorney Docket No. 768830: SA9-910PC a computing device comprising at least memory and a processor, wherein the memory is for storing program instructions and the processor is configured to execute the program instructions that when executed perform operations comprising: determining a change in expression level of the at least one biomarker compared to a reference level, and generating instructions:(i) to continue the IL-6 inhibitor therapy if:(a) expression level of at least one biomarker comprising Ep-CAM, CCL4, LDL-receptor, or Flt3L is increased relative to its respective reference level; or(b) expression level of at least one biomarker comprising AZU1, MMP9, MMP1, OSM, TNFSF14, or any combinations thereof is reduced relative to its respective reference level; or(c) both (a) and (b); or(ii) to stop the IL-6 inhibitor therapy and optionally to select or identify a different rheumatoid arthritis therapy if:(d) expression level of at least one biomarker Ep-CAM, CCL4, LDL- receptor, Flt3L, or any combinations thereof is reduced or is not substantially changed, relative to its respective reference level; or(e) expression level of at least one biomarker comprising AZU1, MMP9, MMP1, OSM, TNFSF1414, or any combinations thereof is increased or is not substantially changed, relative to its respective reference level; or(f) both (d) and (e).

[0272] In certain exemplary embodiments, the reference level is expression level of the at least one biomarker in a biological sample from the subject prior to receiving the IL-6 inhibitor therapy.

[0273] In certain exemplary embodiments, the biological sample comprises a serum or blood sample.

[0274] In certain exemplary embodiments, the biological sample is from the subject after receiving the therapy for about two weeks to about twelve weeks.-38-Attorney Docket No. 768830: SA9-910PC

[0275] In certain exemplary embodiments, the expression level is an mRNA expression level.

[0276] In certain exemplary embodiments, the expression level is a protein expression level.

[0277] In another aspect is a system for assessing or monitoring early responsiveness to or determining continuation of a TNF-a inhibitor therapy in a subject having rheumatoid arthritis and receiving the TNF-a inhibitor therapy, the system comprising: at least one database that receives and stores expression levels of at least one biomarker comprising CCL20, CCL4, CXCL10, CXCL9, EN-RAGE, OSM, IL-10, or any combinations thereof; the expression levels determined from a biological sample from a subject having rheumatoid arthritis and receiving a TNF-a inhibitor therapy; and a computing device comprising at least memory and a processor, wherein the memory is for storing program instructions and the processor is configured to execute the program instructions that when executed perform operations comprising: determining a change in expression level of the at least one biomarker compared to a reference level, and generating instructions:(i) to continue the TNF-a inhibitor therapy if:(a) expression level of at least one biomarker comprising CCL20, CCL4, CXCL10, CXCL9, EN-RAGE, OSM, or any combinations thereof is reduced relative to its respective reference level; or(b) expression level of at least one biomarker comprising IL- 10 is increased relative to its respective reference level; or(c) both (a) and (b); or(ii) to stop the TNF-a inhibitor therapy and optionally to select or identify a different rheumatoid arthritis therapy if:(d) expression level of at least one biomarker CCL20, CCL4, CXCL10, CXCL9, EN-RAGE, OSM, or any combinations thereof is increased or is not substantially changed, relative to its respective reference level; or(e) expression level of at least one biomarker comprising IL-10 is reduced or is not substantially changed, relative to its respective reference level; or(f) both (d) and (e).-39-Attorney Docket No. 768830: SA9-910PC

[0278] In certain exemplary embodiments, the reference level is expression level of the at least one biomarker in a biological sample from the subject prior to receiving the TNF-a inhibitor therapy.

[0279] In certain exemplary embodiments, the at least one database further receives and stores expression level of a biomarker IFN-y.

[0280] In certain exemplary embodiments, the at least one database further receives and stores respective reference level(s) of the at least one biomarker.

[0281] In certain exemplary embodiments, the biological sample comprises a serum or blood sample.

[0282] In certain exemplary embodiments, the biological sample is from the subject after receiving the therapy for about two weeks to about twelve weeks.

[0283] In certain exemplary embodiments, the expression level is an mRNA expression level.

[0284] In certain exemplary embodiments, the expression level is a protein expression level.BRIEF DESCRIPTION OF THE FIGURES

[0285] The foregoing and other features and advantages of the present disclosure will be more fully understood from the following detailed description of illustrative embodiments taken in conjunction with the accompanying drawings. The file of this patent application contains at least one drawing / photograph executed in color. Copies of this patent with color drawing(s) / photograph(s) will be provided by the Office upon request and payment of the necessary fee.

[0286] FIG. 1 (A-C) graphically represent baseline biomarkers for anti-IL-6R and anti-TNF-a treatment response in subjects with RA. (A) Top 30 baseline biomarkers predicting clinical disease activity index (CD Al) response at week 24 after anti-IL-6R treatment in subjects with RA. (B) Top 30 baseline biomarkers predicting CD Al response at week 24 after anti-TNF-a treatment in subjects with RA. (C) Overlap of top 30 baseline predictive biomarkers for anti- IL-6R and anti-TNF-a treatments demonstrate only 8 overlapping biomarkers between them.

[0287] FIG. 2 (A-D) graphically represent biomarkers identified at week 2 after treatment initiation for anti-IL-6R and anti-TNF-a treatment response in subjects with RA. (A) Top 30 early predictive biomarkers predicting CD Al response at week 24 after anti-IL-6R treatment in subjects with RA. (B) Top 30 early biomarkers predicting CD Al response at week 24 after anti-TNF-a treatment in subjects with RA. (C) Overlap of top 30 early predictive biomarkers-40-Attorney Docket No. 768830: SA9-910PC between anti-IL-6R and anti-TNF-a treatment groups demonstrating six overlapping biomarkers between them. (D) Heatmap for the top 30 early predictive biomarkers demonstrating deregulation of biomarkers at week 2 after anti-IL-6R and anti-TNF-a treatments. Biomarkers were selected from change in week 24 CD Al versus change in week 2 Olink analysis in at least one treatment arm. Shown are the normalized protein expression (NPX) values of each biomarker are presented across treatment arms and visits. The NPX values are Olink’ s relative protein quantification unit on a log2 scale.

[0288] FIG. 3 (A-D) graphically represents biomarkers identified at week 24 after treatment initiation for anti-IL-6R and anti-TNF-a treatment response in subjects with RA. (A) Top 30 late biomarkers predicting CD Al response at week 24 after anti-IL-6R treatment in subjects with RA. (B) Top 30 late biomarkers predicting CD Al response at week 24 after anti-TNF-a treatment in subjects with RA. (C) Overlap of top 30 late predictive biomarkers between anti- IL-6R and anti-TNF-a treatment groups demonstrating six overlapping biomarkers between them. (D) Heatmap for leading 30 late predictive biomarkers demonstrating deregulation of biomarkers observed at week 24 after anti-IL-6R and anti-TNF-a treatments were selected from change in week 24 CDAI versus change in week 24 Olink analysis in at least one treatment arm. Shown are the normalized protein expression (NPX) values of each biomarker are presented across treatment arms and visits. The NPX values are Olink’ s relative protein quantification unit on a log2 scale.

[0289] FIG. 4 (A-B) graphically represents an overlap of biomarkers identified at baseline, week 2, and week 24 predicting CDAI response at week 24 after anti-IL-6R and anti-TNF-a treatment. (A) Overlap of top 30 biomarkers predicting anti-IL-6R treatment response at baseline, week 2, and week 24 demonstrating limited overlap. (B) Overlap of top 30 biomarkers predicting anti-TNF-a treatment response at baseline, week 2, and week 24 demonstrating limited overlap.

[0290] FIG. 5 (A-C) graphically represents pharmacodynamic biomarkers for anti-IL-6R and anti-TNF-a treatment response that were selected based on, e.g., False Discovery Rate (FDR) <0.05 and Fold Change (FC) >1.2 or FC < 1 / 1.2 in at least one treatment arm at Week 2 (A and B) or Week 24 (A and C). (A) Heatmaps for pharmacodynamic biomarkers demonstrating deregulation of biomarkers at week 2 and week 24 after anti-IL-6R and anti-TNF-a treatments. (B) Pharmacodynamic biomarkers identifying the degree and variability of deregulation of-41-Attorney Docket No. 768830: SA9-910PC pharmacodynamic biomarkers at week 2 after anti-IL-6R and anti-TNF-a treatments. (C) Pharmacodynamic biomarkers identifying the degree and variability of deregulation of pharmacodynamic biomarkers at week 24 after anti-IL-6R and anti-TNF-a treatments.

[0291] FIG. 6 (A-G) shows RNA sequencing analysis at baseline and week 2 after anti-IL-6R and anti-TNF-a treatment initiation. (A) Venn diagrams of deregulated genes identified at week 2 in anti-IL-6R and anti-TNF-a treatment arms demonstrating limited overlap of genes between both treatment arms. (B) RA pathway with dysregulation of genes by anti-IL-6R treatment. (C) RA pathway with dysregulation of genes by anti-TNF-a treatment. (D) Graphical summary of biological themes regulated by anti-IL-6R treatment. (E) Graphical summary of biological themes regulated by anti-TNF-a treatments. (F) Canonical pathway analysis identifying signaling pathways that were significantly activated or inhibited by anti- IL-6R treatment. (G) Canonical pathway analysis identifying signaling pathways that were significantly activated or inhibited by anti-TNF-a treatment.

[0292] FIG. 7. Deregulation of predictive and pharmacodynamic biomarkers after anti-IL-6R and anti-TNF-a treatments at week 2 and week 24. Biomarkers were selected from change in week 24 CD Al versus change in week 2 or week 24 Olink analysis in at least one treatment arm; the normalized F values of each biomarker are presented across treatment arms and visits.

[0293] FIG. 8. Graphically shows the quantitative change in predictive and pharmacodynamic biomarkers (in alphabetical order) from baseline to week 2 and week 24 after anti-IL-6R and anti-TNF-a treatment. The lighter gray bars correspond to anti-TNF-a treatment while the darker gray bars correspond to anti-IL-6R treatment.

[0294] FIG. 9 (A-B) shows the comparison of RNA sequencing analysis and Olink proteomics analysis for anti-IL-6R and anti-TNF-a treatment. (A) Pharmacodynamic biomarkers identified by Olink proteomics analysis and genes regulated by anti-IL-6R treatment from baseline to week 2 showing an overlap of 14 pharmacodynamic biomarkers and genes regulated biomarkers. (B) Pharmacodynamic biomarkers identified by Olink proteomics analysis and genes regulated by anti-TNF-a treatment from baseline to week 2 showing an overlap of 20 pharmacodynamic biomarkers and genes regulated biomarkers.

[0295] FIG. 10 depicts a block diagram of an embodiment of a system that is suitable for use in practicing various embodiments of the disclosure.-42-Attorney Docket No. 768830: SA9-910PCDETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

[0296] Before the application is described, it is to be understood that this application is not limited to methods and experimental conditions described, as such methods and conditions may vary. It is also to be understood that the terminology used herein is for the purpose of describing embodiments only, and is not intended to be limiting, because the scope of the present disclosure will be limited only by the appended claims.

[0297] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs.

[0298] Although any methods and materials similar or equivalent to those described herein can be used in the practice of the present disclosure, the typical methods and materials are now described. All publications mentioned herein are incorporated herein by reference in their entirety.Certain Definitions

[0299] The term “about,” or “approximately” when used in reference to a particular recited numerical value, means that a value that is similar to the recited value. In general, those skilled in the art, familiar within the context, will appreciate the relevant degree of variance encompassed by “about” or “approximately” in that context. For example, in some embodiments, the term “approximately” or “about” may encompass a range of values that are within 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less of the recited value.

[0300] As used herein, the term “administering” or “administration” typically refers to the administration of a composition to a subject to achieve delivery of an agent that is, or is included in, a composition to a target site or a site to be treated. Those of ordinary skill in the art will be aware of a variety of routes that may, in appropriate circumstances, be utilized for administration to a subject, for example a human. For example, in some embodiments, administration may be parenteral. In some embodiments, administration is subcutaneous. In some embodiments, administration is intravenous. In some embodiments, administration may involve only a single dose. In some embodiments, administration may involve application of a fixed number of doses. In some embodiments, administration may involve dosing that is intermittent (e.g., a plurality of doses separated in time) and / or periodic (e.g., individual doses-43-Attorney Docket No. 768830: SA9-910PC separated by a common period of time) dosing. In some embodiments, administration may involve continuous dosing (e.g., perfusion) for at least a selected period of time.

[0301] The term “antibody agent” as used herein refers to an agent that specifically binds to a particular antigen. In some embodiments, the term encompasses any polypeptide or polypeptide complex that includes immunoglobulin structural elements sufficient to confer specific binding. Exemplary antibody agent agents include but are not limited to monoclonal antibodies or polyclonal antibodies. In some embodiments, an antibody agent may include one or more constant region sequences that are characteristic of mouse, rabbit, primate, or human antibodies. In some embodiments, an antibody agent may include one or more sequence elements are humanized, primatized, chimeric, etc., as is known in the art. In many embodiments, the term “antibody agent” is used to refer to one or more of the art-known or developed constructs or formats for utilizing antibody agent structural and functional features in alternative presentation. For example, in some embodiments, an antibody agent utilized in accordance with the present disclosure is in a format selected from, but not limited to, intact IgA, IgG, IgE or IgM antibodies; bi- or multi-specific antibodies (e.g., ZYBODIES®, etc.); antibody agent fragments such as Fab fragments, Fab' fragments, F(ab')2 fragments, Fd' fragments, Fd fragments, and isolated complementarity determining regions (CDRs) or sets thereof; single chain Fvs; polypeptide-Fc fusions; single domain antibodies (e.g., shark single domain antibodies such as IgNAR or fragments thereof); cameloid antibodies; masked antibodies (e.g., PROBODIES®); Small Modular ImmunoPharmaceuticals (“SMIPs™”); single chain or Tandem diabodies (TANDAB®); VHHs; Anticalins®; Nanobodies® immunoglobulin single variable domains; BiTE®s; ankyrin repeat proteins or DARPINs®;AVIMERS®; DARTs; TCR-like antibodies; ADNECTINS®; AFFILINS®; Trans-Bodies®; Affibodies®; TRIMERX®; MicroProteins; FYNOMERS®, CENTYRINS®; and KALBITOR®s. In many embodiments, an antibody agent is or comprises a polypeptide whose amino acid sequence includes one or more structural elements recognized by those skilled in the art as a complementarity determining region (CDR); in some embodiments an antibody agent is or comprises a polypeptide whose amino acid sequence includes at least one CDR (e.g., at least one heavy chain CDR and / or at least one light chain CDR) that is substantially identical to one found in a reference antibody agent. In some embodiments an included CDR is substantially identical to a reference CDR in that it is either identical in sequence or contains-44-Attorney Docket No. 768830: SA9-910PC between 1-5 amino acid substitutions as compared with the reference CDR. In some embodiments an included CDR is substantially identical to a reference CDR in that it shows at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the reference CDR. In some embodiments, an included CDR is substantially identical to a reference CDR in that it shows at least 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the reference CDR In some embodiments an included CDR is substantially identical to a reference CDR in that at least one amino acid within the included CDR is deleted, added, or substituted as compared with the reference CDR but the included CDR has an amino acid sequence that is otherwise identical with that of the reference CDR. In some embodiments an included CDR is substantially identical to a reference CDR in that 1-5 amino acids within the included CDR are deleted, added, or substituted as compared with the reference CDR but the included CDR has an amino acid sequence that is otherwise identical to the reference CDR. In some embodiments, an included CDR is substantially identical to a reference CDR in that at least one amino acid within the included CDR is substituted as compared with the reference CDR but the included CDR has an amino acid sequence that is otherwise identical with that of the reference CDR. In some embodiments, an included CDR is substantially identical to a reference CDR in that 1 -5 amino acids within the included CDR are deleted, added, or substituted as compared with the reference CDR but the included CDR has an amino acid sequence that is otherwise identical to the reference CDR. In some embodiments, an antibody agent is or comprises a polypeptide whose amino acid sequence includes structural elements recognized by those skilled in the art as an immunoglobulin variable domain. In some embodiments, an antibody agent is a polypeptide protein having a binding domain which is homologous or largely homologous to an immunoglobulin-binding domain.

[0302] The term” baseline” refers to a level, value or score corresponding to status of a given condition of a subject prior to being administered with a rheumatoid arthritis therapy. For example, the term “baseline” when used in reference to an expression level, refers to a level, value, or score corresponding to expression level of an analyte (e.g., a biomarker as described herein) as measured from a sample of a subject that was obtained prior to being administered with a rheumatoid arthritis therapy.-45-Attorney Docket No. 768830: SA9-910PC

[0303] The term “biomarker” refers to a biological molecule, or a fragment of a biological molecule, the change in the level (e.g., expression level) or the detection of the presence, and / or form or both of which can be used to correlate with a particular condition, event, or state of interest. The terms “marker” and “biomarker” are used interchangeably throughout the disclosure. The biological molecules can be nucleic acids, amino acids, including a gene (and nucleotide sequences of such genes) or mRNA (nucleotide sequences of such mRNA), protein (amino acid sequences of such proteins), carbohydrates or lipids, the expression of which in a sample can be detected by known methods or methods as described herein. In some embodiments, a biomarker described herein is substantially identical to the biomarker as referenced by its Uniprot identification as shown in Table 5. In some embodiments, such a biomarker has an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% (up to 100%) identical to the corresponding sequence as shown in Table 5. In some embodiments, a biomarker described herein has an amino acid sequence is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or higher, identical to the corresponding sequence as shown in Table 5.

[0304] The term “decreased expression” or “decrease in expression” or “reduced expression” or “reduction in expression” or equivalent terms refers to a downward deviation in levels of expression in a sample as compared to a reference level.

[0305] The term “early responsiveness” refers to a change in expression level of a recited biomarker from a reference level that precedes an observable or detectable improvement in at least one symptom of rheumatoid arthritis. In some embodiments, an “early responsiveness” refers to a change in expression level of a recited biomarker from a reference level that precedes a detectable change in any clinical disease activity score for rheumatoid arthritis.

[0306] The term “expression level” or “level of expression” are used interchangeably and refers to the amount of a polynucleotide or an amino acid product or protein in a biological sample. “Expression” refers to the process by which gene encoded information is converted into the structures present and operating in the cell. Therefore, the “expression” of a gene may refer to transcription into a polynucleotide, translation into a protein or even posttranslational modification of the protein. Fragments of the transcribed polynucleotide, the translated protein or the postranslationally modified protein shall also be regarded as expressed whether they originate from a transcript generated by alternative splicing, a degraded transcript, or from a-46-Attorney Docket No. 768830: SA9-910PC posttranslational processing of the protein, e.g., by proteolysis. “Expressed genes” include those that are transcribed into a polynucleotide as mRNA and then translated into a protein; and include expressed genes that are transcribed into RNA but not translated into a protein (for example, transfer and ribosomal RNAs).

[0307] The term “increased expression” or “increase in expression” or equivalent terms thereof refers to an upward deviation in levels of expression in a sample as compared to a reference level.

[0308] The term “IL-6 inhibitor therapy” refers to a therapy comprising an IL-6 inhibitor.

[0309] The term “isolated antibody agent,” refers to an antibody agent that has been identified and separated and / or recovered from at least one component of its natural environment. For example, an antibody agent that has been separated or removed from at least one component of an organism, or from a tissue or cell in which the antibody agent naturally exists or is naturally produced, is an "isolated antibody agent." In various embodiments, the isolated antibody agent also includes an antibody agent in situ within a recombinant cell. In other embodiments, isolated antibodies are antibodies that have been subjected to at least one purification or isolation step. In various embodiments, an isolated antibody agent may be substantially free of other cellular material and / or chemicals.

[0310] The term “non-responder” as used herein means a subject who does not demonstrate a positive response to rheumatoid arthritis therapy. In some embodiments, a positive response is demonstrated by an improvement to Clinical Disease Activity Index (CD Al) score at week 24 after a rheumatoid arthritis therapy.

[0311] The term “recombinant human antibody agent”, refers to all human antibodies that are prepared, expressed, created or isolated by recombinant means, such as antibodies expressed using a recombinant expression vector transfected into a host cell (described further below), antibodies isolated from a recombinant, combinatorial human antibody agent library (described further below), antibodies isolated from an animal (e.g., a mouse) that is transgenic for human immunoglobulin genes (see e.g., Taylor et al., (1992) Nucl. Acids Res. 20:6287- 6295, incorporated herein by reference in its entirety,) or antibodies prepared, expressed, created, or isolated by any other means that involves splicing of human immunoglobulin gene sequences to other DNA sequences. Such recombinant human antibodies have variable and constant regions derived from human germline immunoglobulin sequences. In certain-47-Attorney Docket No. 768830: SA9-910PC embodiments, however, such recombinant human antibodies are subjected to in vitro mutagenesis (or, when an animal transgenic for human Ig sequences is used, in vivo somatic mutagenesis) and thus the amino acid sequences of the variable heavy chain (VH) regions and variable light chain (VL) regions of the recombinant antibodies are sequences that, while derived from and related to human germline VH and VL sequences, may not naturally exist within the human antibody agent germline repertoire in vivo.

[0312] Human antibodies can exist in two forms that are associated with hinge heterogeneity. In an embodiment, an immunoglobulin molecule comprises a stable four chain construct of approximately 150-160 kDa in which the dimers are held together by an interchain heavy chain disulfide bond. In certain embodiments, the dimers are not linked via inter-chain disulfide bonds and a molecule of about 75-80 kDa is formed composed of a covalently coupled light and heavy chain (half-antibody agent). These embodiments / forms have been extremely difficult to separate, even after affinity purification. The frequency of appearance of the second form in various intact IgG isotypes is due to, but not limited to, structural differences associated with the hinge region isotype of the antibody agent. A single amino acid substitution in the hinge region of the human IgG4 hinge can significantly reduce the appearance of the second form (Angal et al., (1993) Molecular Immunology 30: 105, incorporated by reference in its entirety) to levels typically observed using a human IgGl hinge. The instant disclosure encompasses in various embodiments antibodies having one or more mutations in the hinge, CH2 or CH3 region which may be desirable, for example, in production, to improve the yield of the desired antibody agent form.

[0313] The term “reference” as used herein describes a standard or control relative to which a comparison is performed. For example, in some embodiments, an agent, animal, individual, population, sample, sequence or value of interest is compared with a reference or control agent, animal, individual, population, sample, sequence or value. In some embodiments, a reference or control is tested and / or determined substantially simultaneously with the testing or determination of interest. In some embodiments, a reference or control is a historical reference or control, optionally embodied in a tangible medium. In some embodiments, a reference or control in the context of a reference level of a biomarker refers to a level of a biomarker in a subject or a population of subjects prior to a treatment. Typically, as would be understood by those skilled in the art, a reference or control is determined or characterized under comparable-48-Attorney Docket No. 768830: SA9-910PC conditions or circumstances to those under assessment. Those skilled in the art will appreciate when sufficient similarities are present to justify reliance on and / or comparison to a particular possible reference or control.

[0314] The term “responder” as used herein means a subject who demonstrates a positive response to rheumatoid arthritis therapy. In some embodiments, a positive response is demonstrated by an improvement to Clinical Disease Activity Index (CD Al) score at week 24 after a rheumatoid arthritis therapy.

[0315] The term “sample” refers to a biological sample obtained or derived from a subject. In some embodiments, a sample is a biological sample obtained or derived from a subject’s body fluid or biological tissue. In some embodiments, a sample is a biological sample obtained or derived from a subject’s body fluid. Exemplary body fluids include, but are not limited to, synovial fluid and blood or any blood constituents such as plasma or serum.

[0316] The term “substantially the same” or “not substantially changed” with respect to expression level of a biomarker means that the expression level of a biomarker does not exhibit a meaningful change compared with a reference level. Therefore, the term allows for minor, insignificant change from the reference level.

[0317] The term “small molecule” as used herein means a low molecular weight organic and / or inorganic compound. In general, a “small molecule” is a molecule that is less than about 5 kilodaltons (kD) in size.

[0318] The term “therapeutically effective amount” in some embodiments refers to an amount of an IL-6 inhibitor or a TNF-a inhibitor in a rheumatoid arthritis therapy that results in improvement in one or more subject reported outcomes measures. In some embodiments, a “therapeutically effective amount” also includes an IL-6 inhibitor or a TNF-a inhibitor in a rheumatoid arthritis therapy that inhibits, prevents, lessens, or delays the progression of rheumatoid arthritis in a subject.

[0319] As used herein, the phrase “therapeutically effective amount” means an amount of TNF- a inhibitor therapy that results in improvement in one or more subject reported outcomes measures.

[0320] A “therapeutically effective amount” also includes an amount of TNF-a inhibitor therapy that inhibits, prevents, lessens, or delays the progression of rheumatoid arthritis in a subject

[0321] The term “an TNF-a inhibitor therapy” refers to a therapy comprising a TNF-a inhibitor.-49-Attorney Docket No. 768830: SA9-910PC

[0322] The term “treat,” “treatment,” or “treating” refers to a method used to partially or completely alleviate, ameliorate, relieve, inhibit, prevent, delay onset of, reduce severity of, and / or reduce incidence of one or more symptoms or features of a disease, disorder, and / or condition, e.g., rheumatoid arthritis, either on a temporary or permanent basis.Methods of Monitoring Responsiveness or Activity to a Rheumatoid Arthritis Therapy

[0323] Provided herein are technologies (e.g., methods, systems, and kits, etc.) for assessing or monitoring responsiveness to rheumatoid arthritis therapy of a subject having rheumatoid arthritis. In some embodiments, such technologies are based in part on certain findings of differential expression of at least one specific biomarker in responders vs. non-responders of subjects with rheumatoid arthritis and treated with different rheumatoid arthritis therapies (e.g., an IL-6 inhibitor therapy vs an TNF-a inhibitor therapy).

[0324] Further provided are methods treating a subject with rheumatoid arthritis by determining, in a sample of a subject having rheumatoid arthritis and receiving a rheumatoid arthritis therapy, a change in expression level of at least one specific biomarker from a reference level, and continuing the rheumatoid arthritis therapy if the expression level of at least one biomarker is increased (or decreased); or stopping the rheumatoid arthritis therapy and optionally selecting a different rheumatoid arthritis therapy if the expression level of the at least one biomarker is reduced (or increased) or is not substantially changed.

[0325] In some embodiments the methods relate to determining a change in expression level of at least one biomarker. In some embodiments, the determining step comprises measuring the expression level (e.g., a protein or gene / mRNA expression) of at least one biomarker. In some embodiments, the determining step comprises measuring the expression level (e.g., a protein or gene / mRNA expression) of at least one biomarker and comparing the measured level with a reference level.

[0326] Provided herein are methods for assessing or monitoring responsiveness of a subject having rheumatoid arthritis to a rheumatoid arthritis therapy. In some embodiments, a method for monitoring responsiveness of a subject having rheumatoid arthritis comprises measuring in a sample obtained from the subject at least one biomarker (including, e.g., at least two, at least three, at least four, at least five, at least six, at least seven, at least eight or at least nine biomarkers) shown in Tables 1 or 2 (wherein biomarker(s) is / are selected based on the rheumatoid arthritis therapy being received or having been received by the subject prior to the-50-Attorney Docket No. 768830: SA9-910PC measurement) wherein a change in expression level (e.g., increase or decrease) from the reference level (e.g. a reference level as described herein, such as in one embodiment a respective baseline level in a subject prior to administration of rheumatoid arthritis therapies (e.g., an IL-6 inhibitor therapy or an TNF-a inhibitor therapy)) of the at least one biomarker (including, e.g., at least two, at least three, at least four, at least five, at least six, at least seven, at least eight or at least nine biomarkers) is an indication of the responsiveness to a rheumatoid arthritis therapy. In some embodiments, such a change (e.g., increase or decrease) in expression level of a biomarker is at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or higher, relative to a reference level (e.g. a reference level as described herein, such as in one embodiment a respective baseline level in a subject prior to administration of rheumatoid arthritis therapies (e.g., an IL-6 inhibitor therapy or an TNF-a inhibitor therapy)). In some embodiments, such a change (e.g., increase or decrease) in expression level of a biomarker is from about 15% to 50%, 15%to 99%, 20% to 99%, 25% to 99%, 30% to 99%, 35% to 99%, 40% to 99%, 45% to 99%, 50% to99%, 55% to 99%, 60% to 99%, 65% to 99%, 70% to 99%, 75% to 99%, 80% to 99%, 85% to 99%, 90% to 99%, 95% to 99%, or higher, relative to a reference level (e.g. a reference level as described herein, such as in one embodiment a respective baseline level in a subject prior to administration of rheumatoid arthritis therapies (e.g., an IL-6 inhibitor therapy or an TNF-a inhibitor therapy)). In some embodiments, such a change (e.g., increase or decrease) in expression level of a biomarker is at least 1.1 -fold, at least 1.5-fold, at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 6-fold, at least 7-fold, at least 8-fold, at least 9-fold, or at least 10-f older, relative to a reference level. In some embodiments, such a change (e.g., increase or decrease) in expression level of a biomarker is 1.1 -fold tolO fold, 1.5- fold to 10-fold, 2-foldto 10-fold, 3-fold to 10-fold, 4-fold to 10-fold, 5-fold to 10-fold, 6-fold to 10-fold, 7-fold to 10-fold, 8-fold to 10-fold, 9-fold to 10-fold, relative to a reference level (e.g. a reference level as described herein, such as in one embodiment a respective baseline level in a subject prior to administration of rheumatoid arthritis therapies (e.g., an IL-6 inhibitor therapy or an TNF-a inhibitor therapy)).

[0327] In some embodiments, the methods include measuring the expression level of at least one biomarker in a sample obtained from the subject, where the at least one biomarker (including,-51-Attorney Docket No. 768830: SA9-910PC e.g., at least two, at least three, at least four, at least five, at least six, at least seven, at least eight or at least nine biomarkers) is selected from Table 1 or Table 2 and the samples are then classified or grouped into the subject as a responder or non -responder based on the expression level of at least one biomarker in the sample obtained from the subject, as compared with a reference level.Table 1. Biomarker(s) associated with responsiveness to IL-6 inhibitor therapy.Table 2. Biomarker(s) associated with responsiveness to TNT -a inhibitor therapy.-52-Attorney Docket No. 768830: SA9-910PC

[0328] In some embodiments, the method of assessing or monitoring the responsiveness of a subject having rheumatoid arthritis to a rheumatoid arthritis therapy includes determining, in one or more samples from a subject having rheumatoid arthritis and receiving a rheumatoid arthritis therapy, a change in expression level from one or more reference levels of at least one biomarker selected from Tables 1 or 2 (based on the rheumatoid arthritis therapy being received or having been received by the subject prior to the determination), wherein the change in expression level from the one or more reference levels of the at least one biomarker is an indication of the responsiveness to the rheumatoid arthritis therapy.

[0329] In some embodiments, a biomarker described herein is substantially identical to the biomarker as referenced by its Uni rot identification as shown in Table 1 or 2. For example, in some such embodiments, a biomarker described herein has an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% (up to 100%) identical to the corresponding sequence (identified by the Uniprot ID) as shown in Table 5. In some embodiments, a biomarker described herein has an amino acid sequence is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or higher, identical to the corresponding sequence (identified by the Uniprot ID) as shown in Table 5.

[0330] In some embodiments, one or more samples includes a first and a second sample used to measure the first and second expression levels respectively. In some embodiments, the second sample is obtained after the first sample is obtained from a subject that was first treated with the rheumatoid arthritis therapy (e.g., IL-6 inhibitor therapy or TNF-a inhibitor therapy). In some embodiments, the sample is obtained from a subject after receiving a rheumatoid arthritis therapy for about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 13 weeks, about 14 weeks, about 15 weeks, about 16 weeks, about 17 weeks, about 18 weeks, about 19 weeks, about 20 weeks, about 21 weeks, about 22 weeks, about 23 weeks, or-53-Attorney Docket No. 768830: SA9-910PC about 24 weeks. In some embodiments, the sample is obtained from a subject after receiving a rheumatoid arthritis therapy for about 2 weeks to about 12 weeks and periodically thereafter (e.g., every two to twelve weeks thereafter for at least 24 weeks or longer, e.g., at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 12 months or longer). In some embodiments, more than one sample is obtained from the same subject but at different times after a rheumatoid arthritis therapy (e.g., an IL-6 inhibitor therapy or an TNF-a inhibitor therapy). In some such embodiments, a first sample can be taken at a first time point after a rheumatoid arthritis therapy (e.g., an IL-6 inhibitor therapy or an TNF- a inhibitor therapy), and a second sample can be taken at a second time point later after it is determined that the subject continues the same treatment. In some embodiments, a first sample can be taken at a first time point after a first rheumatoid arthritis therapy (e.g., an IL-6 inhibitor therapy or an TNF-a inhibitor therapy), and a second sample can be taken at a second time point later after the subject has switched to a different rheumatoid arthritis treatment (e.g., a TNF-a inhibitor therapy or an IL-6 inhibitor therapy). For example, the first sample can be obtained after the first treatment; the second sample can then be obtained after the second treatment and so on and so forth. In some embodiments, the first sample is obtained after a subject is treated for a period of time (e.g., about 2 weeks to about 12 weeks), the second sample is obtained after the first sample and from the subject who has continued the same treatment for a period of time (e.g., about 2 weeks to about 12 weeks) since the first sample was taken. In some embodiments, the first sample is obtained after a subject has received a first rheumatoid arthritis therapy (e.g., an IL-6 inhibitor therapy or an TNF-a inhibitor therapy), and the second sample is obtained after the first sample and from the subject who has switched to a second rheumatoid arthritis therapy that is different from the first rheumatoid arthritis (e.g., a TNF-a inhibitor therapy or an IL-6 inhibitor therapy) for a period of time (e.g., about 2 weeks to about 12 weeks) since the first sample was taken. In some embodiments, the first sample is taken before any rheumatoid arthritis therapy is given.

[0331] In some embodiments, the second sample is used to measure a second change in expression level of at least one biomarker. In some embodiments, the at least one biomarker used for determining the second change in expression level is the same as the biomarkers used to determine the first change in expression level. In some embodiments, the at least one-54-Attorney Docket No. 768830: SA9-910PC biomarker used for determining the second change in expression level is a different biomarker used to determine the first change in expression level.

[0332] In some embodiments where a rheumatoid arthritis therapy comprises an IL-6 inhibitor therapy and a TNF-a inhibitor therapy (a “combined IL-6 / TNF- a inhibitor therapy”; e.g., in some embodiments where an antibody agent is a bispecific antibody agent that targets IL-6 and TNF-a, or in some embodiments where a subject is receiving an IL-6 inhibitor and a TNF- a inhibitor as individual compositions concurrently or sequentially), methods as described herein that involve one or more biomarkers associated with responsiveness to an IL-6 inhibitor therapy can be combined with methods as described herein that involve one or more biomarkers associated with responsiveness to a TNF-a inhibitor therapy. For example, in some embodiments, at least one biomarker (including, e.g., at least two, at least three, at least four, at least five, at least six, at least seven, at least eight or at least nine biomarkers) from Table 1 and at least one biomarker (including, e.g., at least two, at least three, at least four, at least five, at least six, at least seven, at least eight or at least nine biomarkers) from Table 2 can be used to assess or monitor responsiveness (e.g., early responsiveness) to each individual arm of a combined IL-6 / TNF- a inhibitor therapy. In some embodiments, at least one biomarker selected from: AZU1, TNFSF14, OSM, and MMP-9 can be used to assess or monitor responsiveness (e.g., early responsiveness) to the IL-6 inhibition aspect of a combined IL- 6 / TNF- a inhibitor therapy, while at least one biomarker selected from: CXCL9, EN-RAGE, CCL4, CXCL10, and CCL20 can be used to assess or monitor responsiveness (e.g., early responsiveness) to the TNF- a inhibition aspect of the combined IL-6 / TNF- a inhibitor therapy. In some embodiments, at least one biomarker selected from: AZU1, TNFSF14, OSM, and MMP-9 can be used to assess or monitor responsiveness (e.g., early responsiveness) to the IL- 6 inhibition aspect of a combined IL-6 / TNF- a inhibitor therapy, while at least one biomarker selected from IL-10 or IL-10 and IFN-y can be used to assess or monitor responsiveness (e.g., early responsiveness) to the TNF-a inhibition aspect of the combined IL-6 / TNF- a inhibitor therapy. In some embodiments, at least one biomarker selected from: Ep-CAM, LDL-receptor, and Flt3Lcan be used to assess or monitor responsiveness (e.g., early responsiveness) to the IL-6 inhibition aspect of a combined IL-6 / TNF- a inhibitor therapy, while at least one biomarker selected from: CXCL9, EN-RAGE, CCL4, CXCL10, and CCL20 can be used to assess or monitor responsiveness (e.g., early responsiveness) to the TNF- a inhibition aspect-55-Attorney Docket No. 768830: SA9-910PC of the combined IL-6 / TNF- a inhibitor therapy. In some embodiments, at least one biomarker selected from: Ep-CAM, LDL-receptor, and Flt3Lcan be used to assess or monitor responsiveness (e.g., early responsiveness) to the IL-6 inhibition aspect of a combined IL- 6 / TNF- a inhibitor therapy, while at least one biomarker selected from: IL- 10 or IL- 10 and IFN-y can be used to assess or monitor responsiveness (e.g., early responsiveness) to the TNF- a inhibition aspect of the combined IL-6 / TNF- a inhibitor therapy.Biomarker(s) Associated with Responsiveness to IL-6 Inhibitor Therapy

[0333] In some embodiments, the method is for assessing or monitoring the responsiveness of a subject having rheumatoid arthritis to an interleukin-6 inhibitor therapy, the method comprising determining, in a sample from a subject having rheumatoid arthritis and receiving an IL-6 inhibitor therapy, a change in expression level from a reference level (e.g. a reference level as described herein, such as in one embodiment a respective baseline level in a subject prior to administration of an IL-6 inhibitor therapy) of at least one biomarker (including, e.g., at least two, at least three, at least four, at least five, at least six, at least seven, at least eight or at least nine biomarkers) from Table 1, wherein the change in expression level from the reference level of the at least one biomarker is an indication of the likelihood of early responsiveness to the IL-6 inhibitor therapy.

[0334] In some embodiments, at least one biomarker (including, e.g., at least two, at least three, at least four, at least five, at least six, at least seven, at least eight or at least nine biomarkers) that is used in accordance with methods described herein involving an IL-6 inhibitor therapy is shown in Table 1. In some embodiments, at least one biomarker as shown in Table 1 is used to determine or monitor responsiveness (e.g., early responsiveness) to an IL-6 inhibitor therapy. In some embodiments, at least one biomarker comprising AZU1 is used to determine or monitor responsiveness (e.g., early responsiveness) to an IL-6 inhibitor therapy. In some embodiments, at least one biomarker comprising TNFSF14 can be used to determine or monitor responsiveness (e.g., early responsiveness) to an IL-6 inhibitor therapy. In some embodiments, at least one biomarker comprising MMP-9 is used to determine or monitor responsiveness (e.g., early responsiveness) to an IL-6 inhibitor therapy. In some embodiments, at least one biomarker comprising MMP-1 is used to determine or monitor responsiveness (e.g., early responsiveness) to an IL-6 inhibitor therapy. In some embodiments, at least one biomarker comprising Ep-CAM is used to determine or monitor responsiveness (e.g., early-56-Attorney Docket No. 768830: SA9-910PC responsiveness) to an IL-6 inhibitor therapy. In some embodiments, at least one biomarker comprising CCL4 is used to determine or monitor responsiveness (e.g., early responsiveness) to an IL-6 inhibitor therapy. In some embodiments, at least one biomarker comprising LDL- receptor is used to determine or monitor responsiveness (e.g., early responsiveness) to an IL-6 inhibitor therapy. In some embodiments, at least one biomarker comprising Flt3L is used to determine or monitor responsiveness (e.g., early responsiveness) to an IL-6 inhibitor therapy. In some embodiments, at least one biomarker comprising OSM is used to determine or monitor responsiveness (e.g., early responsiveness) to an IL-6 inhibitor therapy.

[0335] In some embodiments, at least one biomarker comprising Ep-CAM, CCL4, LDL- receptor, or Flt3L that shows an increased expression can be used to predict or monitor responsiveness to an IL-6 inhibitor therapy. In some embodiments, an increase in expression level of at least one biomarker comprising Ep-CAM, CCL4, LDL-receptor, or Flt3L is at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or higher, relative to a reference level (e.g. a reference level as described herein, such as in one embodiment a respective baseline level in a subject prior to administration of an IL-6 inhibitor therapy). In some embodiments, an increase in expression level of at least one biomarker comprising Ep-CAM, CCL4, LDL-receptor, or Flt3L is from about 15% to 50%, 15%to 99%, 20% to 99%, 25% to 99%, 30% to 99%, 35% to 99%, 40% to 99%, 45% to 99%, 50% to99%, 55% to 99%, 60% to 99%, 65% to 99%, 70% to 99%, 75% to 99%, 80% to 99%, 85% to 99%, 90% to 99%, 95% to 99%, or higher, relative to a reference level (e.g. a reference level as described herein, such as in one embodiment a respective baseline level in a subject prior to administration of an IL-6 inhibitor therapy).

[0336] In some embodiments, an increase in expression level of at least one biomarker comprising Ep-CAM, CCL4, LDL-receptor, or Flt3L is at least 1.1-fold, at least 1.5-fold, at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 6-fold, at least 7-fold, at least 8-fold, at least 9-fold, or at least 10-fold, relative to a reference level (e.g. a reference level as described herein, such as in one embodiment a respective baseline level in a subject prior to administration of an IL-6 inhibitor therapy). In some embodiments, an increase in expression level of at least one biomarker comprising Ep-CAM, CCL4, LDL-receptor, or Flt3L is 1.1 -fold to 10 fold, 1.5-fold to 10-fold, 2-fold to 10-fold, 3 -fold to 10-fold, 4-fold to 10-fold, 5-fold to-57-Attorney Docket No. 768830: SA9-910PC10-fold, 6-fold to 10-fold, 7-fold to 10-fold, 8-fold to 10-fold, 9-fold to 10-fold, relative to a reference level (e.g. a reference level as described herein, such as in one embodiment a respective baseline level in a subject prior to administration of an IL-6 inhibitor therapy).

[0337] In some embodiments, at least one biomarker comprising AZU1, MMP9, MMP1, OSM, or TNFSF14 that show a reduced expression can be used to predict or monitor responsiveness to an IL-6 inhibitor therapy. In some embodiments, a decrease in expression level of at least one biomarker comprising AZU1, MMP9, MMP1, OSM, or TNFSF14 is at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or higher, relative to a reference level. In some embodiments, a decrease in expression level of at least one biomarker comprising AZU1, MMP9, MMP1, OSM, or TNFSF14 is from about 15% to 50%, 15% to 99%, 20% to 99%, 25% to 99%, 30% to 99%, 35% to 99%, 40% to 99%, 45% to 99%, 50% to 99%, 55% to 99%, 60% to 99%, 65% to 99%, 70% to 99%, 75% to 99%, 80% to 99%, 85% to 99%, 90% to 99%, 95% to 99%, or higher, relative to a reference level (e.g. a reference level as described herein, such as in one embodiment a respective baseline level in a subject prior to administration of an IL-6 inhibitor therapy.

[0338] In some embodiments, a decrease in expression level of at least one biomarker comprising AZU1, MMP9, MMP1, OSM, or TNFSF14 is at least 1.1-fold, at least 1.5-fold, at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 6-fold, at least 7-fold, at least 8-fold, at least 9-fold, or at least 10-folder, relative to a reference level (e.g. a reference level as described herein, such as in one embodiment a respective baseline level in a subject prior to administration of an IL-6 inhibitor therapy). In some embodiments, a decrease in expression level of at least one biomarker comprising AZU1, MMP9, MMP1, OSM, or TNFSF14 is 1.1- fold tolO fold, 1.5-fold to 10-fold, 2-fold to 10-fold, 3-fold to 10-fold, 4-fold to 10-fold, 5-fold to 10-fold, 6-fold to 10-fold, 7-fold to 10-fold, 8-fold to 10-fold, 9-fold to 10-fold, relative to a reference level (e.g. a reference level as described herein, such as in one embodiment a respective baseline level in a subject prior to administration of an IL-6 inhibitor therapy).

[0339] In some embodiments, the at least one biomarker (including, e.g., at least two, at least three, at least four, at least five, at least six, at least seven, at least eight or at least nine biomarkers) as described herein is used in accordance with one or more methods described-58-Attorney Docket No. 768830: SA9-910PC herein. In some embodiments, a change in expression level of at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, biomarkers are used in accordance with one or more methods described herein. In some embodiments the change in expression level of 2, 3, 4, 5, 6, 7, 8, 9 biomarkers are determined to indicate responsiveness to an IL-6 inhibitor therapy. In some embodiments the change in expression level of 2-4, 3-5, 4-6, 5-8, 6- 9, 2-9, 3-9, 4-9, 5-9, 6-9, 7-9, or 8-9, biomarkers are determined to indicate responsiveness to an IL-6 inhibitor therapy.

[0340] In some embodiments, more than one biomarker used in accordance with one or more methods described herein comprises a 2 -biomarker combination shown in Table 3 for a subject who is receiving an IL-6 inhibitor therapy. As shown in Table 3, the possible arrangement of a set of two biomarkers selected from Table 3 of a total of nine biomarkers are shown. For example, the following selections of two biomarkers include selecting one biomarker from first column and one biomarker from the topmost row to provide a 2 -biomarker combination as follows: [AZU1, MMP1], [AZU1, MMP9], [AZU1, OSM], [AZU1, TNFSF14], [AZU1, Ep- CAM], [AZU1, CCL4], [AZU1, LDL-receptor], and [AZU1, Flt3L], Similarly, in some embodiments, the 2 -biomarker is as follows: [MMP1, MMP9], [MMP1, OSM], [MMP1, TNFSF14], [MMP1, Ep-CAM], [MMP1, CCL4], [MMP1, LDL-receptor], and [MMP1, Flt3L] and so on and so forth. For example, in some embodiments, responsiveness to an IL-6 inhibitor therapy can be determined or monitored based on at least one biomarker (as described above) that shows an increased expression level relative to a reference level, and at least one biomarker (as described above) that shows a decreased expression level relative to a reference level. In some embodiments, responsiveness to an IL-6 inhibitor therapy can be determined or monitored based on at least two biomarkers that each shows an increased expression level relative to a reference level, and / or at least two biomarkers that each shows a decreased expression level relative to a reference level.Table 3: 2 -biomarker combinations associated with responsiveness to an IL-6 inhibitor therapy.-59-Attorney Docket No. 768830: SA9-910PC

[0341] In some embodiments, at least one biomarker used in any one of the methods described herein is selected from: AZU1, TNFSF14, OSM, and MMP-9. In some embodiments, at least one biomarker used in any one of the methods described herein comprises at least two biomarkers (including, e.g., at least three biomarkers, at least four biomarkers) selected from: AZU1, TNFSF14, OSM, and MMP-9.

[0342] In some embodiments, at least one biomarker used in any one of the methods described herein comprises at least two biomarkers that includes AZU1 and MMP-9.

[0343] In some embodiments, at least one biomarker used in any one of the methods described herein comprises at least two biomarkers that includes AZU1 and TNFSF14.

[0344] In some embodiments, three biomarker combinations, four biomarker combinations are used, five biomarker combinations, six biomarker combinations, seven biomarker combinations, eight biomarker combinations and nine biomarker combinations are used in accordance with one or more methods described herein. For example, in some embodiments, at least one biomarker used in any one of the methods described herein comprises at least three biomarkers that includes AZU1, TNFSF14, and OSM.

[0345] In some embodiments, a biomarker as described herein is determined to show a change in expression level at Week 2 (during a course of IL-6 inhibitor treatment) relative to a reference level (e.g., in one embodiment a respective baseline level in a subject prior to administration of an IL-6 inhibitor therapy) as shown in Fig. 5B. In some embodiments, a biomarker as described herein is determined to show a 20% change in expression level at Week 2, Week 3, Week 4, Week 4, Week 5, Week 6, Week 7, Week 8, Week 9, Week 10, Week 11, or Week 12 (during a course of an IL-6 inhibitor treatment) relative to a reference level (e.g., in one embodiment a respective baseline level in a subject prior to administration of an IL-6 inhibitor therapy). In some embodiments, a biomarker as described herein is determined to show a 30% change in expression level at Week 2, Week 3, Week 4, Week 4, Week 5, Week 6, Week 7, Week 8, Week 9, Week 10, Week 11, or Week 12 (during a course of an IL-6 inhibitor treatment) relative to a reference level (e.g., in one embodiment a respective baseline-60-Attorney Docket No. 768830: SA9-910PC level in a subject prior to administration of an IL-6 inhibitor therapy). In some embodiments, a biomarker as described herein is determined to show a 50% change in expression level at Week 2, Week 3, Week 4, Week 4, Week 5, Week 6, Week 7, Week 8, Week 9, Week 10, Week 11, or Week 12 (during a course of an IL-6 inhibitor treatment) relative to a reference level (e.g., in one embodiment a respective baseline level in a subject prior to administration of an IL-6 inhibitor therapy).

[0346] In some embodiments, a biomarker as described herein is determined to show a change in expression level at Week 24 (during a course of IL-6 inhibitor treatment) relative to a reference level (e.g., in one embodiment a respective baseline level in a subject prior to administration of an IL-6 inhibitor therapy) as shown in Fig. 5C.Biomarker(s) Associated with Responsiveness to TNF-a Inhibitor Therapy

[0347] In some embodiments, the method is for assessing or monitoring the responsiveness of a subject having rheumatoid arthritis to TNF-a inhibitor therapy, the method comprising determining, in a sample from a subject having rheumatoid arthritis and receiving a TNF-a inhibitor therapy, a change in expression level from a reference level (e.g. a reference level as described herein, such as in one embodiment a respective baseline level in a subject prior to administration of an TNF-a inhibitor therapy) of at least one biomarker (including, e.g., at least two, at least three, at least four, at least five, at least six, at least seven, at least eight or at least nine biomarkers) in Table 2, wherein the change in expression level from the reference level of the at least one biomarker is an indication of the likelihood of early responsiveness to the TNF-a inhibitor therapy.

[0348] In some embodiments, the at least one biomarker (including, e.g., at least two, at least three, at least four, at least five, at least six, at least seven, at least eight or at least nine biomarkers) used in accordance with methods described herein involving TNF-a inhibitor therapy are shown in Table 2. In some embodiments, at least one biomarker shown in Table 2 is used to monitor responsiveness (e.g., early responsiveness) to TNF-a inhibitor therapy. In some embodiments, at least one biomarker comprising CXCL9 is used to determine or monitor responsiveness (e.g., early responsiveness) to a TNF-a inhibitor therapy. In some embodiments, at least one biomarker comprising EN-RAGE is used to determine or monitor responsiveness (e.g., early responsiveness) to a TNF-a inhibitor therapy. In some embodiments, at least one biomarker comprising CCL20 is used to determine or monitor-61-Attorney Docket No. 768830: SA9-910PC responsiveness (e.g., early responsiveness) to a TNF-a inhibitor therapy. In some embodiments, at least one biomarker comprising CCL4 is used to determine or monitor responsiveness (e.g., early responsiveness) to a TNF-a inhibitor therapy. In some embodiments, at least one biomarker comprising CXCL10. In some embodiments, at least one biomarker comprising OSM is used to determine or monitor responsiveness (e.g., early responsiveness) to a TNF-a inhibitor therapy. In some embodiments, at least one biomarker comprising IL-10 is used to determine or monitor responsiveness (e.g., early responsiveness) to a TNF-a inhibitor therapy.

[0349] In some embodiments, IFN-y is used as a biomarker in combination with at least one biomarker listed in Table 2 to determine or monitor responsiveness (e.g., early responsiveness) to a TNF-a inhibitor therapy. In some embodiments, IFN-y is used as a biomarker in combination with IL-10 to determine or monitor responsiveness (e.g., early responsiveness) to a TNF-a inhibitor therapy.

[0350] In some embodiments, at least one biomarker comprises CCL20, CCL4, CXCL10, CXCL9, EN-RAGE, or OSM that when reduced in expression can be used to predict or monitor responsiveness to TNF-a inhibitor therapy. In some embodiments, a reduced expression level of at least one biomarker comprising CCL20, CCL4, CXCL10, CXCL9, EN-RAGE, or OSM is at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95%, relative to a reference level (e.g. a reference level as described herein, such as in one embodiment a respective baseline level in a subject prior to administration of TNF-a inhibitor therapy). In some embodiments, a decrease in expression level of at least one biomarker comprising CCL20, CCL4, CXCL10, CXCL9, ENRAGE, or OSM is from about 15% to 50%, 15%to 99%, 20% to 99%, 25% to 99%, 30% to 99%, 35% to 99%, 40% to 99%, 45% to 99%, 50% to99%, 55% to 99%, 60% to 99%, 65% to 99%, 70% to 99%, 75% to 99%, 80% to 99%, 85% to 99%, 90% to 99%, 95% to 99%, or higher, relative to a reference level (e.g. a reference level as described herein, such as in one embodiment a respective baseline level in a subject prior to administration of an TNF-a inhibitor therapy).

[0351] In some embodiments, a reduced expression level of at least one biomarker comprising CCL20, CCL4, CXCL10, CXCL9, EN-RAGE, or OSM is at least 1.1-fold, at least 1.5-fold, at-62-Attorney Docket No. 768830: SA9-910PC least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 6-fold, at least 7-fold, at least 8-fold, at least 9-fold, or at least 10-fold, relative to a reference level (e.g. a reference level as described herein, such as in one embodiment a respective baseline level in a subject prior to administration of TNF-a inhibitor therapy). In some embodiments, a reduced expression level of at least one biomarker comprising CCL20, CCL4, CXCL10, CXCL9, EN-RAGE, or OSM is 1.1-fold tolO fold, 1.5-fold to 10-fold, 2-fold to 10-fold, 3-fold to 10-fold, 4-fold to 10-fold, 5-fold to 10-fold, 6-fold to 10-fold, 7-fold to 10-fold, 8-fold to 10-fold, 9-fold to 10-fold, relative to a reference level (e.g. a reference level as described herein, such as in one embodiment a respective baseline level in a subject prior to administration of a TNF-a inhibitor therapy).

[0352] In some embodiments, biomarkers comprise IL-10 or IL-10 and IFN-y that are increased in expression can monitor responsiveness to TNF-a inhibitor therapy. In some embodiments, at the biomarker comprising IL-10 or IFN-y that shows an increased expression can be used to predict or monitor responsiveness to an TNF-a inhibitor therapy. In some embodiments, an increase in expression level of IL-10 or IFN-y is at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or higher, relative to a reference level (e.g. a reference level as described herein, such as in one embodiment a respective baseline level in a subject prior to administration of a TNF-a inhibitor therapy). In some embodiments, an increase in expression level of IL-10 or IFN-y is from about 15% to 50%, 15%to 99%, 20% to 99%, 25% to 99%, 30% to 99%, 35% to 99%, 40% to 99%, 45% to 99%, 50% to99%, 55% to 99%, 60% to 99%, 65% to 99%, 70% to 99%, 75% to 99%, 80% to 99%, 85% to 99%, 90% to 99%, 95% to 99%, or higher, relative to a reference level (e.g. a reference level as described herein, such as in one embodiment a respective baseline level in a subject prior to administration of a TNF-a inhibitor therapy).

[0353] In some embodiments, an increase in expression level of IL-10 or IFN-y is at least 1.1- fold, at least 1.5-fold, at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 6- fold, at least 7-fold, at least 8-fold, at least 9-fold, or at least 10-fold, relative to a reference level (e.g. a reference level as described herein, such as in one embodiment a respective baseline level in a subject prior to administration of a TNF-a inhibitor therapy). In some embodiments, an increase in expression level of IL-10 or IFN-y is 1.1-fold to 10 fold, 1.5-fold-63-Attorney Docket No. 768830: SA9-910PC to 10-fold, 2-fold to 10-fold, 3-fold to 10-fold, 4-fold to 10-fold, 5-fold to 10-fold, 6-fold to 10-fold, 7-fold to 10-fold, 8-fold to 10-fold, 9-fold to 10-fold, relative to a reference level (e.g. a reference level as described herein, such as in one embodiment a respective baseline level in a subject prior to administration of a TNF-a inhibitor therapy).

[0354] In some embodiments, the at least one biomarker as described herein is used in accordance with one or more methods described herein. In some embodiments, a change in expression level of at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, biomarkers are used in accordance with one or more methods described herein. In some embodiments the change in expression level of 2, 3, 4, 5, 6, 7, 8, 9 biomarkers are determined to indicate responsiveness to a rheumatoid arthritis therapy. In some embodiments the change in expression level of 2-4, 3-5, 4-6, 5-8, 6-9, 2-9, 3-9, 4-9, 5-9, 6-9, 7-9, or 8-9, biomarkers are determined to indicate responsiveness to a rheumatoid arthritis therapy

[0355] In some embodiments, more than one biomarker used in accordance with one or more methods described herein comprises a 2 -biomarker combination in Table 4 for a subject who is receiving a TNF-a inhibitor therapy. As shown in Table 4, the possible arrangement of a set of two biomarkers selected from Table 4 of a total of eight biomarkers are shown. For example, the following selections of 2 biomarkers include selecting one biomarker from first column and one biomarker from the topmost row to provide a 2 -biomarker combination as follows: [CCL20, CCL4], [CCL20, CCL10], [CCL20, CXCL9], [CCL20, ENRAGE], [CCL20, OSM], [CCL20, IL-10], [CCL20, IFN-y] and so on and so forth. For example, in some embodiments, responsiveness to a TNF-a inhibitor therapy can be determined or monitored based on at least one biomarker (as described above) that shows an increased expression level relative to a reference level, and at least one biomarker (as described above) that shows a decreased expression level relative to a reference level. In some embodiments, responsiveness to a TNF- a inhibitor therapy can be determined or monitored based on at least two biomarkers that each shows an increased expression level relative to a reference level, and / or at least two biomarkers that each shows a decreased expression level relative to a reference level.Table 4: 2 -biomarker combination relating to TNF a inhibitor therapy.-64-Attorney Docket No. 768830: SA9-910PC

[0356] In some embodiments, at least one biomarker used in any one of the methods described herein is selected from: CXCL9, EN-RAGE, CCL4, CXCL10, and CCL20. In some embodiments, at least one biomarker used in any one of the methods described herein comprises at least two biomarkers (including, e.g., at least three biomarkers, at least four biomarkers, at least five biomarkers) selected from: CXCL9, EN-RAGE, CCL4, CXCL10, and CCL20.

[0357] In some embodiments, at least one biomarker used in any one of the methods described herein comprises at least two biomarkers that includes CXCL9 and CCL4.

[0358] In some embodiments, at least one biomarker used in any one of the methods described herein comprises at least two biomarkers that includes CXCL9 and EN-RAGE.

[0359] In some embodiments, three biomarker combinations, four biomarker combinations are used, five biomarker combinations, six biomarker combinations, seven biomarker combinations, and eight biomarker combinations are used in accordance with one or more methods described herein. For example, in some embodiments, at least one biomarker used in any one of the methods described herein comprises at least three biomarkers that includes CXCL9, EN-RAGE, and CCL4. In some embodiments, at least one biomarker used in any one of the methods described herein comprises at least three biomarkers that includes CXCL9, ENRAGE, and CXCL10. In some embodiments, at least one biomarker used in any one of the methods described herein comprises at least three biomarkers that includes CXCL9, ENRAGE, and CCL20.

[0360] In some embodiments, a biomarker as described herein is determined to show a change in expression level at week 2 (during a course of TNF a inhibitor treatment) relative to a reference level (e.g., in one embodiment a respective baseline level in a subject prior to administration of a TNF a inhibitor therapy) as shown in Fig. 5B. In some embodiments, a-65-Attorney Docket No. 768830: SA9-910PC biomarker as described herein is determined to show a 20% change in expression level at week 2, week 3, week 4, week 4, week 5, week 6, week 7, week 8, week 9, week 10, week 11, or week 12 (during a course of an TNF a inhibitor treatment) relative to a reference level (e.g., in one embodiment a respective baseline level in a subject prior to administration of a TNF a inhibitor therapy). In some embodiments, a biomarker as described herein is determined to show a 30% change in expression level at week 2, week 3, week 4, week 4, week 5, week 6, week 7, week 8, week 9, week 10, week 11, or week 12 (during a course of a TNF a inhibitor treatment) relative to a reference level (e.g., in one embodiment a respective baseline level in a subject prior to administration of a TNF a inhibitor therapy). In some embodiments, a biomarker as described herein is determined to show a 50% change in expression level at week 2, week 3, week 4, week 4, week 5, week 6, week 7, week 8, week 9, week 10, week 11, or week 12 (during a course of a TNF a inhibitor treatment) relative to a reference level (e.g., in one embodiment a respective baseline level in a subject prior to administration of a TNF a inhibitor therapy).

[0361] In some embodiments, a biomarker as described herein is determined to show a change in expression level at week 24 (during a course of a TNF a inhibitor treatment) relative to a reference level (e.g., in one embodiment a respective baseline level in a subject prior to administration of a TNF a inhibitor therapy) as shown in Fig. 5C.Methods of Treating

[0362] The identification of at least one biomarker as described herein allow not only determining or monitoring of the responsiveness of a subject to a rheumatoid arthritis therapy but also allows for treating rheumatoid arthritis in a subject. For example, in some embodiments, a change in expression level of at least one biomarker (including, e.g., at least two, at least three, at least four, at least five, at least six, at least seven, at least eight or at least nine biomarkers) as described herein can be used to evaluate, select, or modify a rheumatoid arthritis treatment plan for a subject in need thereof. In some embodiments, when a subject after initiation with a rheumatoid arthritis therapy is evaluated at least on the basis of at least one biomarker described herein as showing early responsiveness to the rheumatoid arthritis therapy, the subject can continue to be administered the rheumatoid arthritis therapy. On the other hand, when a subject after initiation with a rheumatoid arthritis therapy is evaluated at-66-Attorney Docket No. 768830: SA9-910PC least on the basis of at least one biomarker described herein as not showing any early responsiveness to the rheumatoid arthritis therapy, the subject can be instructed to stop the rheumatoid arthritis therapy. In some such embodiments, a different rheumatoid arthritis therapy can be selected and administered to the subject. In some embodiments, a different rheumatoid arthritis therapy is a rheumatoid arthritis therapy that is different from the original or prior rheumatoid arthritis therapy, for example, in some embodiments, a rheumatoid arthritis therapy that is based on a different mechanism of action, or in some embodiments a rheumatoid arthritis therapy that incorporates another drug for a combined therapy, or in some embodiments a rheumatoid arthritis therapy that is based on modifying the dose and / or dosing regimen of the original or prior rheumatoid arthritis therapy.

[0363] In some embodiments, a method for treating of a subject having rheumatoid arthritis comprises determining in a sample obtained from the subject having rheumatoid arthritis and receiving rheumatoid arthritis therapy a change in expression level from a reference level of at least one biomarker (including, e.g., at least two, at least three, at least four biomarker(s) and so forth) shown in Tables 1 or 2 (wherein biomarker(s) is / are selected based on the rheumatoid arthritis therapy being received or having been received by the subject prior to the measurement) wherein a change in expression level from the reference level of the at least one biomarker is an indication of the responsiveness to a rheumatoid arthritis therapy. In some embodiments, such a change (e.g., increase or decrease) in expression level of a biomarker is at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or higher, relative to a reference level. In some embodiments, such a change (e.g., increase or decrease) in expression level of a biomarker is from about 15% to 50%, 15% to 99%, 20% to 99%, 25% to 99%, 30% to 99%, 35% to 99%, 40% to 99%, 45% to 99%, 50% to 99%, 55% to 99%, 60% to 99%, 65% to 99%, 70% to 99%, 75% to 99%, 80% to 99%, 85% to 99%, 90% to 99%, at least 95% to 99%, or higher, relative to a reference level (e.g. a reference level as described herein, such as in one embodiment a respective baseline level in a subject prior to administration of rheumatoid arthritis therapies (e.g., an IL-6 inhibitor therapy or an TNF-a inhibitor therapy). In some embodiments, such a change (e.g., increase or decrease) in expression level of a biomarker is at least 1.1 -fold, at least 1.5-fold, at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 6-fold, at-67-Attorney Docket No. 768830: SA9-910PC least 7-fold, at least 8-fold, at least 9-fold, or at least 10-folder, relative to a reference level. In some embodiments, such a change (e.g., increase or decrease) in expression level of a biomarker is l. lto fold-10 fold, 1.5-fold to 10-fold, 2-fold to 10-fold, 3-fold to 10-fold, 4-fold to 10-fold, 5-fold to 10-fold, 6-fold to 10-fold 7-fold to 10-fold, 8-fold to 10-fold, 9-fold to 10- fold, relative to a reference level (e.g. a reference level as described herein, such as in one embodiment a respective baseline level in a subject prior to administration of rheumatoid arthritis therapies (e.g., an IL-6 inhibitor therapy or an TNF-a inhibitor therapy).

[0364] In some embodiments where a rheumatoid arthritis therapy comprises an IL-6 inhibitor therapy and a TNF-a inhibitor therapy (a “combined IL-6 / TNF- a inhibitor therapy”; e.g., in some embodiments where an antibody agent is a bispecific antibody agent that targets IL-6 and TNF-a, or in some embodiments where a subject is receiving an IL-6 inhibitor and a TNF- a inhibitor as individual compositions concurrently or sequentially), methods as described herein that involve one or more biomarkers associated with responsiveness to an IL-6 inhibitor therapy can be combined with methods as described herein that involve one or more biomarkers associated with responsiveness to a TNF-a inhibitor therapy. For examples, in some embodiments, at least one biomarker from Table 1 and at least one biomarker from Table 2 can be used in a method of treating rheumatoid arthritis as described herein, for example, to evaluate, select, or modify a combined IL-6 / TNF-a inhibitor therapy being administered to a subject. In some embodiments, at least one biomarker selected from: AZU1, TNFSF14, OSM, and MMP-9 can be used to assess or monitor responsiveness (e.g., early responsiveness) to the IL-6 inhibition aspect of a combined IL-6 / TNF- a inhibitor therapy, while at least one biomarker selected from: CXCL9, EN-RAGE, CCL4, CXCL10, and CCL20 can be used to assess or monitor responsiveness (e.g., early responsiveness) to the TNF-a inhibition aspect of the combined IL-6 / TNF-a inhibitor therapy, so that the treatment plan can be evaluated, selected or modified accordingly.

[0365] In some embodiments, at least one biomarker selected from: AZU1, TNFSF14, OSM, and MMP-9 can be used to assess or monitor responsiveness (e.g., early responsiveness) to the IL-6 inhibition aspect of a combined IL-6 / TNF- a inhibitor therapy, while at least one biomarker selected from IL- 10 or IL- 10 and FFN-y can be used to assess or monitor responsiveness (e.g., early responsiveness) to the TNF-a inhibition aspect of the combined IL- 6 / TNF-a inhibitor therapy, so that the treatment plan can be evaluated, selected or modified-68-Attorney Docket No. 768830: SA9-910PC accordingly. In some embodiments, at least one biomarker selected from: Ep-CAM, LDL- receptor, and Flt3L can be used to assess or monitor responsiveness (e.g., early responsiveness) to the IL-6 inhibition aspect of a combined IL-6 / TNF- a inhibitor therapy, while at least one biomarker selected from: CXCL9, EN-RAGE, CCL4, CXCL10, and CCL20 can be used to assess or monitor responsiveness (e.g., early responsiveness) to the TNF-a inhibition aspect of the combined IL-6 / TNF-a inhibitor therapy, so that the treatment plan can be evaluated, selected or modified accordingly. In some embodiments, at least one biomarker selected from: Ep-CAM, LDL-receptor, and Flt3L can be used to assess or monitor responsiveness (e.g., early responsiveness) to the IL-6 inhibition aspect of a combined IL-6 / TNF- a inhibitor therapy, while at least one biomarker selected from: IL- 10 or IL- 10 and IFN-y can be used to assess or monitor responsiveness (e.g., early responsiveness) to the TNF-a inhibition aspect of the combined IL-6 / TNF-a inhibitor therapy, so that the treatment plan can be evaluated, selected or modified accordingly.

[0366] In some embodiments are described use of at least one biomarker (including, e.g., at least two, at least three, at least four, at least five, at least six, at least seven, at least eight or at least nine biomarkers) shown in Table 1 or 2 or any combinations of biomarkers as shown in Table 3 or 4 in the manufacture of a kit for determining the treatment of rheumatoid arthritis in a subject, wherein the subject is determined to have rheumatoid arthritis.Biomarker(s) Associated with Responsiveness to IL-6 Inhibitor Therapy

[0367] In some embodiments is described a method of treating rheumatoid arthritis, the method comprising determining, in a sample of a subject having rheumatoid arthritis and receiving an IL-6 inhibitor therapy, a change (e.g. increase or decrease) in expression level from a reference level, of at least one biomarker comprising Ep-CAM, CCL4, LDL-receptor, or Flt3L; and continuing the IL-6 inhibitor therapy if the expression level of the at least one biomarker is increased relative to the reference level; or stopping the IL-6 inhibitor therapy and optionally selecting a different rheumatoid arthritis therapy if the expression level of the at least one biomarker is reduced or is not substantially changed relative to the reference level. In some embodiments, a different rheumatoid arthritis therapy is a therapy that is not an IL-6 inhibitor therapy.

[0368] In some embodiments is described a method of treating rheumatoid arthritis, the method comprising determining, in a sample of a subject having rheumatoid arthritis and receiving an-69-Attorney Docket No. 768830: SA9-910PCIL-6 inhibitor therapy, a change in expression level from a reference level, of at least one biomarker comprising AZU1, MMP9, MMP1, OSM, TNFSF14, or any combinations thereof; and continuing the IL-6 inhibitor therapy if the expression level of the at least one biomarker is reduced relative to the reference level; or stopping the IL-6 inhibitor therapy and optionally selecting a different rheumatoid arthritis therapy if the expression level of the at least one biomarker(s) is increased or is not substantially changed relative to the reference level.

[0369] In some embodiments is described a method of treating rheumatoid arthritis, the method comprising selecting a subject having rheumatoid arthritis and receiving an IL-6 inhibitor therapy and showing a change in expression level from a reference level, of at least one biomarker comprising Ep-CAM, CCL4, LDL-receptor, Flt3L, or any combinations thereof; and continuing with the subject the IL-6 inhibitor therapy if the expression level of the at least one biomarker is increased relative to the reference level; or stopping the IL-6 inhibitor therapy and optionally selecting a different rheumatoid arthritis therapy if the expression level of the at least one biomarker is reduced or is not substantially changed, relative to the reference level. In some embodiments, a different rheumatoid arthritis therapy is a therapy that is not an IL-6 inhibitor therapy.

[0370] In some embodiments is a method of treating rheumatoid arthritis, the method comprising: selecting a subject having rheumatoid arthritis and receiving an IL-6 inhibitor therapy and who is determined to have a change in expression level from a reference level, of at least one biomarker comprising AZU1, MMP9, MMP1, OSM, TNFSF14, or any combinations thereof; and continuing the IL-6 inhibitor therapy if the expression level of the at least one biomarker is reduced relative to the reference level; or stopping the IL-6 inhibitor therapy and optionally selecting a different rheumatoid arthritis therapy if the expression level of the at least one biomarker is increased or is not substantially changed relative to the reference level. In some embodiments, a different rheumatoid arthritis therapy is a therapy that is not an IL-6 inhibitor therapy.

[0371] In some embodiments is described a method of treating rheumatoid arthritis, the method comprising: determining in a sample of a subject having rheumatoid arthritis and receiving an IL-6 inhibitor therapy, a change in expression level from a reference level, of at least one biomarker comprising AZU1, MMP9, MMP1, OSM, TNFSF14, Ep-CAM, CCL4, LDL- receptor, Flt3L, or any combinations thereof; and continuing the IL-6 inhibitor therapy if:-70-Attorney Docket No. 768830: SA9-910PC(a) the expression level of at least one biomarker comprising Ep-CAM, CCL4, LDL-receptor, or Flt3L is increased relative to its respective reference level; or(b) the expression level of at least one biomarker comprising AZU1, MMP9, MMP1, OSM, TNFSF14, or any combinations thereof is reduced relative to its respective reference level; or(c) both (a) and (b); or stopping the IL-6 inhibitor therapy and optionally selecting a different rheumatoid arthritis therapy if:(d) the expression level of at least one biomarker Ep-CAM, CCL4, LDL-receptor, Flt3L, or any combinations thereof is reduced or is not substantially changed, relative to its respective reference level; or(e) the expression level of at least one biomarker comprising AZU1, MMP9, MMP1, OSM, TNFSF 14, or any combinations thereof is increased or is not substantially changed, relative to its respective reference level; or(f) both (d) and (e).In some embodiments, a different rheumatoid arthritis therapy is a therapy that is not an IL-6 inhibitor therapy.

[0372] In some embodiments is described a method of treating rheumatoid arthritis, the method comprising modifying or continuing a rheumatoid arthritis treatment for a subject having rheumatoid arthritis and receiving an IL-6 inhibitor therapy, at least in part on the basis of a change in expression level from a reference level in a sample from the subject, of at least one biomarker comprising Ep-CAM, CCL4, LDL-receptor, Flt3L, or any combinations thereof, wherein:- if the expression level of the at least one biomarker is increased relative to the reference level, administration of the IL-6 inhibitor therapy to the subject is continued; or- if the expression level of the at least one biomarker is reduced or is not substantially changed relative to the reference level, administration of the IL-6 inhibitor therapy to the subject is stopped and optionally a different rheumatoid arthritis therapy is selected for the subject. In some embodiments, a different rheumatoid arthritis therapy is a therapy that is not an IL-6 inhibitor therapy.

[0373] In some embodiments is described a method of treating rheumatoid arthritis, the method comprising modifying or continuing a rheumatoid arthritis treatment for a subject having-71-Attorney Docket No. 768830: SA9-910PC rheumatoid arthritis and receiving an IL-6 inhibitor therapy, at least in part on the basis of a change in expression level from a reference level in a sample from the subject, of at least one biomarker comprising AZU1, MMP9, MMP1, OSM, TNFSF14, or any combinations thereof, wherein:- if the expression level of the at least one biomarker is decreased relative to the reference level, administration of the IL-6 inhibitor therapy to the subject is continued; or- if the expression level of the at least one biomarker is increased or is not substantially changed relative to the reference level, administration of the IL-6 inhibitor therapy to the subject is stopped and optionally a different rheumatoid arthritis therapy is selected for the subject. In some embodiments, a different rheumatoid arthritis therapy is a therapy that is not an IL-6 inhibitor therapy.

[0374] In some embodiments is described a method of treating rheumatoid arthritis, the method comprising: modifying or continuing a rheumatoid arthritis treatment for a subject having rheumatoid arthritis and receiving an IL-6 inhibitor therapy, at least in part on the basis of a change in expression level from a reference level in a sample from the subject, of at least one biomarker comprising AZU1, MMP9, MMP1, OSM, TNFSF14, Ep-CAM, CCL4, LDL- receptor, Flt3L, or any combinations thereof; and continuing the IL-6 inhibitor therapy if:(a) the expression level of at least one biomarker comprising Ep-CAM, CCL4, LDL-receptor, Flt3L, or any combinations thereof is increased relative to its respective reference level; or(b) the expression level of at least one biomarker comprising AZU1, MMP9, MMP1, OSM, TNFSF14, or any combinations thereof is reduced relative to its respective reference level; or(c) both (a) and (b); or stopping the IL-6 inhibitor therapy and optionally selecting a different rheumatoid arthritis therapy if:(d) the expression level of at least one biomarker Ep-CAM, CCL4, LDL-receptor, Flt3L, or any combinations thereof is reduced or is not substantially changed, relative to its respective reference level; or(e) the expression level of at least one biomarker comprising AZU1, MMP9, MMP1, OSM, TNFSF14, or any combinations thereof is increased or is not substantially changed, relative to its respective reference level; or(f) both (d) and (e).-72-Attorney Docket No. 768830: SA9-910PCIn some embodiments, a different rheumatoid arthritis therapy is a therapy that is not an IL-6 inhibitor therapy.

[0375] In still some embodiments is described a method of treating rheumatoid arthritis, the method comprising: if a sample of a subject, who has rheumatoid arthritis and is receiving an IL-6 inhibitor therapy, is determined to have an increased expression level of at least one biomarker comprising Ep-CAM, CCL4, LDL-receptor, Flt3L, or any combinations thereof, as compared to a reference level, continuing administration of the IL-6 inhibitor therapy to the subject; or if a sample of a subject, who has rheumatoid arthritis and is receiving an IL-6 inhibitor therapy, is determined to have a reduced or substantially the same expression level of at least one biomarker comprising Ep-CAM, CCL4, LDL-receptor, Flt3L, or any combinations thereof as compared to a reference level, stopping administration of the IL-6 inhibitor therapy to the subject and optionally selecting a different rheumatoid arthritis therapy. In some embodiments, a different rheumatoid arthritis therapy is a therapy that is not an IL-6 inhibitor therapy.

[0376] In some embodiments is a method of treating rheumatoid arthritis, the method comprising: if a sample of a subject, who has rheumatoid arthritis and is receiving an IL-6 inhibitor therapy, is determined to have a reduced expression level of at least one biomarker comprising AZU1, MMP9, MMP1, OSM, or TNFSF14, or any combinations thereof as compared to a reference level, continuing administration of the IL-6 inhibitor therapy to the subject; or if a sample of a subject, who has rheumatoid arthritis and is receiving an IL-6 inhibitor therapy, is determined to have an increased or substantially the same expression level of at least one biomarker comprising AZU1, MMP9, MMP1, OSM, TNFSF14, or any combinations thereof as compared to a reference level, stopping administration of the IL-6 inhibitor therapy to the subject and optionally selecting a different rheumatoid arthritis therapy. In some embodiments, a different rheumatoid arthritis therapy is a therapy that is not an IL-6 inhibitor therapy.

[0377] In some embodiments are described use of at least one biomarker (including, e.g., at least two, at least three, at least four, at least five, at least six, at least seven, at least eight or at least nine biomarkers) shown in Table 1 or any biomarker combination as shown in Table 3 in the manufacture of a kit for determining the treatment of rheumatoid arthritis in a subject treated with an IL-6 inhibitor therapy, wherein the subject is determined to have rheumatoid arthritis.-73-Attorney Docket No. 768830: SA9-910PC

[0378] In some embodiments, a change in expression level of at least one biomarker comprising Ep-CAM, CCL4, LDL-receptor, or Flt3L that shows an increased expression, can be used as described herein can be used to monitor, select, or modify a rheumatoid arthritis therapy (e.g. an IL-6 inhibitor therapy) plan for a subject in need thereof In some embodiments, a change in expression level (e.g. an increase in expression level) of at least one biomarker comprising Ep-CAM, CCL4, LDL-receptor, or Flt3L is at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or higher, relative to a reference level (e.g. a reference level as described herein, such as in one embodiment a respective baseline level in a subject prior to administration of an IL-6 inhibitor therapy). In some embodiments, such a change (e.g., increase) in expression level of at least one biomarker comprising Ep-CAM, CCL4, LDL-receptor, or Flt3L is from about 15% to 50%, 15%to 99%, 20% to 99%, 25% to 99%, 30% to 99%, 35% to 99%, 40% to 99%, 45% to 99%, 50% to99%, 55% to 99%, 60% to 99%, 65% to 99%, 70% to 99%, 75% to 99%, 80% to 99%, 85% to 99%, 90% to 99%, 95% to 99%, or higher, relative to a reference level (e.g. a reference level as described herein, such as in one embodiment a respective baseline level in a subject prior to administration of an IL-6 inhibitor therapy.

[0379] In some embodiments, an increase in expression level of at least one biomarker comprising Ep-CAM, CCL4, LDL-receptor, or Flt3L is at least 1.1-fold, at least 1.5-fold, at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 6-fold, at least 7-fold, at least 8-fold, at least 9-fold, or at least 10-fold, relative to a reference level (e.g. a reference level as described herein, such as in one embodiment a respective baseline level in a subject prior to administration of an IL-6 inhibitor therapy). In some embodiments, an increase in expression level of at least one biomarker comprising Ep-CAM, CCL4, LDL-receptor, or Flt3L is 1.1 -fold tolO fold, 1.5-fold to 10-fold, 2-foldto 10-fold, 3-fold to 10-fold, 4-fold to 10-fold, 5-fold to 10-fold, 6-fold to 10-fold, 7-fold to 10-fold, 8-fold to 10-fold, 9-fold to 10-fold, relative to a reference level (e.g. a reference level as described herein, such as in one embodiment a respective baseline level in a subject prior to administration of an IL-6 inhibitor therapy).

[0380] A change in expression level of at least one biomarker comprising AZU1, MMP9, MMP1, OSM, or TNFSF14 that shows a decreased expression, can be used as described herein to monitor, select, or modify a rheumatoid arthritis therapy (e.g. an IL-6 inhibitor therapy) plan-74-Attorney Docket No. 768830: SA9-910PC for a subject in need thereof. In some embodiments, a decrease in expression level of at least one biomarker comprising AZU1, MMP9, MMP1, OSM, or TNFSF14 is at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or higher, relative to a reference level. In some embodiments, such a change (e.g., decrease) in expression level of at least one biomarker comprising AZU1, MMP9, MMP1, OSM, or TNFSF14 is from about 15% to 50%, 15%to 99%, 20% to 99%, 25% to 99%, 30% to 99%, 35% to 99%, 40% to 99%, 45% to 99%, 50% to99%, 55% to 99%, 60% to 99%, 65% to 99%, 70% to 99%, 75% to 99%, 80% to 99%, 85% to 99%, 90% to 99%, 95% to 99%, or higher, relative to a reference level (e.g. a reference level as described herein, such as in one embodiment a respective baseline level in a subject prior to administration of an IL-6 inhibitor therapy. In some embodiments, a decrease in expression level of at least one biomarker comprising AZU1, MMP9, MMP1, OSM, or TNFSF14 is at least 1.1 -fold, at least 1.5-fold, at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 6-fold, at least 7-fold, at least 8-fold, at least 9-fold, or at least 10-folder, relative to a reference level (e.g. a reference level as described herein, such as in one embodiment a respective baseline level in a subject prior to administration of an IL-6 inhibitor therapy). In some embodiments, a decrease in expression level of at least one biomarker comprising AZU1, MMP9, MMP1, OSM, or TNFSF14 is 1.1- fold tolO fold, 1.5-fold to 10-fold, 2-foldto 10-fold, 3-fold to 10-fold, 4-fold to 10-fold, 5-fold to 10-fold, 6-fold to 10-fold, 7-fold to 10-fold, 8-fold to 10-fold, 9-fold to 10-fold, relative to a reference level (e.g. a reference level as described herein, such as in one embodiment a respective baseline level in a subject prior to administration of an IL-6 inhibitor therapy).

[0381] In some embodiments, the at least one biomarker as described herein is used in accordance with one or more methods described herein. In some embodiments, a change in expression level of at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, biomarkers are used in accordance with one or more methods described herein. In some embodiments the change in expression level of 2, 3, 4, 5, 6, 7, 8, 9 biomarkers are determined to indicate responsiveness to an IL-6 inhibitor therapy, thereby evaluating, selecting, or modifying the rheumatoid arthritis treatment plan for a subject in need thereof. In some embodiments the change in expression level of 2-4, 3-5, 4-6, 5-8, 6-9, 2-9, 3-9, 4-9, 5-9, 6-9, 7-9, or 8-9, biomarkers are determined to indicate responsiveness to an IL-6 inhibitor-75-Attorney Docket No. 768830: SA9-910PC therapy, thereby evaluating, selecting, or modifying the rheumatoid arthritis treatment plan for a subject in need thereofBiomarker(s) Associated with Responsiveness to TNF-q Inhibitor Therapy

[0382] In some embodiments is described a method of treating rheumatoid arthritis, the method comprising determining, in a sample of a subject having rheumatoid arthritis and receiving an TNF-a inhibitor therapy, a change in expression level from a reference level, of at least one biomarker comprising CCL20, CCL4, CXCL10, CXCL9, EN-RAGE, OSM, or any combinations thereof; and continuing the TNF-a inhibitor therapy if the expression level of the at least one biomarker is reduced relative to the reference level; or stopping the TNF-a inhibitor therapy and optionally selecting a different rheumatoid arthritis therapy if the expression level of the at least one biomarker is increased or is not substantially changed relative to the reference level. In some embodiments, a different rheumatoid arthritis therapy is a therapy that is not an TNF-a inhibitor therapy.

[0383] In some embodiments is a method of treating rheumatoid arthritis, the method comprising determining, in a sample of a subject having rheumatoid arthritis and receiving an TNF-a inhibitor therapy, a change in expression level from a reference level, of at least one biomarker comprising IL-10; and continuing the TNF-a inhibitor therapy if the expression level of the at least one biomarker is increased; or stopping the TNF-a inhibitor therapy and optionally selecting a different rheumatoid arthritis therapy if the expression level of the at least one biomarker is reduced or is not substantially changed. In some embodiments, a different rheumatoid arthritis therapy is a therapy that is not an TNF-a inhibitor therapy.

[0384] In still other embodiments is a method of treating rheumatoid arthritis, the method comprising determining, in a sample of a subject having rheumatoid arthritis and receiving an TNF-a inhibitor therapy, a change in expression level from a reference level, of at least one biomarker comprising CCL20, CCL4, CXCL10, CXCL9, EN-RAGE, OSM, IL-10, or any combinations thereof; and continuing the TNF-a inhibitor therapy if:(a) the expression level of at least one biomarker comprising CCL20, CCL4, CXCL10, CXCL9, EN-RAGE, OSM, or any combinations thereof is reduced relative to its respective reference level; or(b) the expression level of at least one biomarker comprising IL-10 is increased relative to its respective reference level; or-76-Attorney Docket No. 768830: SA9-910PC(c) both (a) and (b); or stopping the TNF-a inhibitor therapy and optionally selecting a different rheumatoid arthritis therapy if:(d) the expression level of at least one biomarker CCL20, CCL4, CXCL10, CXCL9, EN-RAGE, OSM, or any combinations thereof is increased or is not substantially changed, relative to its respective reference level; or(e) the expression level of at least one biomarker comprising IL-10 is reduced or is not substantially changed, relative to its respective reference level; or(f) both (d) and (e).In some embodiments, a different rheumatoid arthritis therapy is a therapy that is not an TNF-a inhibitor therapy.

[0385] In some embodiments is described a method of treating rheumatoid arthritis, the method comprising selecting a subject having rheumatoid arthritis and receiving an TNF-a inhibitor therapy and showing a change in expression level from a reference level, of at least one biomarker comprising CCL20, CCL4, CXCL10, CXCL9, EN-RAGE, OSM, or any combinations thereof; and continuing the TNF-a inhibitor therapy if the expression level of the at least one biomarker is reduced relative to the reference level; or stopping the TNF-a inhibitor therapy and optionally selecting a different rheumatoid arthritis therapy if the expression level of the at least one biomarker is increased or is not substantially changed relative to the reference level. In some embodiments, a different rheumatoid arthritis therapy is a therapy that is not an TNF-a inhibitor therapy.

[0386] In still other embodiments is described a method of treating rheumatoid arthritis, the method comprising selecting a subject having rheumatoid arthritis and receiving an TNF-a inhibitor therapy and showing a change in expression level from a reference level, of at least one biomarker comprising IL-10; and continuing the TNF-a inhibitor therapy if the expression level of the at least one biomarker is increased; or stopping the TNF-a inhibitor therapy and optionally selecting a different rheumatoid arthritis therapy if the expression level of the at least one biomarker is reduced or is not substantially changed. In some embodiments, a different rheumatoid arthritis therapy is a therapy that is not an TNF-a inhibitor therapy.

[0387] In some embodiments is a method of treating rheumatoid arthritis, the method comprising modifying or continuing a rheumatoid arthritis treatment for a subject having rheumatoid-77-Attorney Docket No. 768830: SA9-910PC arthritis and receiving an TNF-a inhibitor therapy, at least in part on the basis of a change in expression level from a reference level in a sample from the subject, of at least one biomarker comprising CCL20, CCL4, CXCL10, CXCL9, EN-RAGE, OSM, or any combinations thereof, wherein:- if the expression level of the at least one biomarker is reduced relative to the reference level, administration of the TNF-a inhibitor therapy to the subject is continued; or- if the expression level of the at least one biomarker is increased or is not substantially changed relative to the reference level, administration of the TNF-a inhibitor therapy to the subject is stopped and optionally a different rheumatoid arthritis therapy is selected for the subject.In some embodiments, a different rheumatoid arthritis therapy is a therapy that is not an TNF-a inhibitor therapy.

[0388] In some embodiments is a method of treating rheumatoid arthritis, the method comprising modifying or continuing a rheumatoid arthritis treatment for a subject having rheumatoid arthritis and receiving an TNF-a inhibitor therapy, at least in part on the basis of a change in expression level from a reference level in a sample from the subject, of at least one biomarker comprising IL- 10, wherein:- if the expression level of the at least one biomarker is increased relative to the reference level, administration of the TNF-a inhibitor therapy to the subject is continued; or- if the expression level of the at least one biomarker is reduced or is not substantially changed relative to the reference level, administration of the TNF-a inhibitor therapy to the subject is stopped and optionally a different rheumatoid arthritis therapy is selected for the subject.In some embodiments, a different rheumatoid arthritis therapy is a therapy that is not an TNF-a inhibitor therapy.

[0389] In some embodiments is a method of treating rheumatoid arthritis, the method comprising modifying or continuing a rheumatoid arthritis treatment for a subject having rheumatoid arthritis and receiving an TNF-a inhibitor therapy, at least in part on the basis of a change in expression level from a reference level in a sample from the subject, of at least one biomarker comprising CCL20, CCL4, CXCL10, CXCL9, EN-RAGE, OSM, IL-10, or any combinations thereof; and continuing the TNF-a inhibitor therapy if:-78-Attorney Docket No. 768830: SA9-910PC(a) the expression level of at least one biomarker comprising CCL20, CCL4, CXCL10, CXCL9, EN-RAGE, OSM, or any combinations thereof is reduced relative to its respective reference level; or(b) the expression level of at least one biomarker comprising IL-10 is increased relative to its respective reference level; or(c) both (a) and (b); or stopping the TNF-a inhibitor therapy and optionally selecting a different rheumatoid arthritis therapy if:(d) the expression level of at least one biomarker CCL20, CCL4, CXCL10, CXCL9, ENRAGE, OSM, or any combinations thereof is increased or is not substantially changed, relative to its respective reference level; or(e) the expression level of at least one biomarker comprising IL-10 is reduced or is not substantially changed, relative to its respective reference level; or(f) both (d) and (e).In some embodiments, a different rheumatoid arthritis therapy is a therapy that is not an TNF-a inhibitor therapy.

[0390] In some embodiments is a method of treating rheumatoid arthritis, the method comprising: if a sample of a subject, who has rheumatoid arthritis and is receiving an TNF-a inhibitor therapy, is determined to have an reduced expression level of at least one biomarker comprising CCL20, CCL4, CXCL10, CXCL9, EN-RAGE, OSM, or any combinations thereof, as compared to a reference level, continuing administration of the IL-6 inhibitor therapy to the subject; or if a sample of a subject, who has rheumatoid arthritis and is receiving an TNF-a inhibitor therapy, is determined to have an increased or substantially the same expression level of at least one biomarker comprising CCL20, CCL4, CXCL10, CXCL9, EN-RAGE, OSM, or any combinations thereof as compared to a reference level, stopping administration of the TNF-a inhibitor therapy to the subject and optionally selecting a different rheumatoid arthritis therapy. In some embodiments, a different rheumatoid arthritis therapy is a therapy that is not an TNF-a inhibitor therapy.

[0391] In some embodiments is a method of treating rheumatoid arthritis, the method comprising: if a sample of a subject, who has rheumatoid arthritis and is receiving an TNF-a-79-Attorney Docket No. 768830: SA9-910PC inhibitor therapy, is determined to have an increased expression level of at least one biomarker comprising IL-10, as compared to a reference level, continuing administration of the TNF-a inhibitor therapy to the subject; or if a sample of a subject, who has rheumatoid arthritis and is receiving an TNF-a inhibitor therapy, is determined to have a reduced or substantially the same expression level of at least one biomarker comprising IL-10, as compared to a reference level, stopping administration of the TNF-a inhibitor therapy to the subject and optionally selecting a different rheumatoid arthritis therapy. In some embodiments, a different rheumatoid arthritis therapy is a therapy that is not an TNF-a inhibitor therapy.

[0392] In some embodiments are described use of at least one biomarker (including, e.g., at least two, at least three, at least four, at least five, at least six, at least seven, at least eight or at least nine biomarkers) shown in Table 2 in the manufacture of a kit for determining the treatment of rheumatoid arthritis in a subject treated with TNF- a inhibitor therapy, wherein the subject is determined to have rheumatoid arthritis.

[0393] In some embodiments, the at least one biomarker comprises CCL20, CCL4, CXCL10, CXCL9, EN-RAGE, or OSM that when reduced in expression can be used to predict or monitor responsiveness to TNF-a inhibitor therapy and accordingly be administered TNF-a inhibitor therapy. In some embodiments, a reduced expression level of at least one biomarker comprising CCL20, CCL4, CXCL10, CXCL9, EN-RAGE, or OSM is at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95%, relative to a reference level (e.g. a reference level as described herein, such as in one embodiment a respective baseline level in a subject prior to administration of TNF-a inhibitor therapy). In some embodiments, such a change (e.g., decrease) in expression level of at least one biomarker comprising CCL20, CCL4, CXCL10, CXCL9, EN-RAGE, or OSM is from about 15% to 50%, 15%to 99%, 20% to 99%, 25% to 99%, 30% to 99%, 35% to 99%, 40% to 99%, 45% to 99%, 50% to99%, 55% to 99%, 60% to 99%, 65% to 99%, 70% to 99%, 75% to 99%, 80% to 99%, 85% to 99%, 90% to 99%, 95% to 99%, or higher, relative to a reference level (e.g. a reference level as described herein, such as in one embodiment a respective baseline level in a subject prior to administration of an TNF-a inhibitor therapy).

[0394] In some embodiments, a reduced expression of at least one biomarker comprising CCL20, CCL4, CXCL10, CXCL9, EN-RAGE, or OSM is at least 1.1-fold, at least 1.5-fold, at-80-Attorney Docket No. 768830: SA9-910PC least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 6-fold, at least 7-fold, at least 8-fold, at least 9-fold, or at least 10-folder, relative to a reference level (e.g. a reference level as described herein, such as in one embodiment a respective baseline level in a subject prior to administration of TNF-a inhibitor therapy). In some embodiments, a reduced expression of at least one biomarker comprising CCL20, CCL4, CXCL10, CXCL9, EN-RAGE, or OSM is 1.1- fold tolO fold, 1.5-fold to 10-fold, 2-foldto 10-fold, 3-fold to 10-fold, 4-fold to 10-fold, 5-fold to 10-fold, 6-fold to 10-fold, 7-fold to 10-fold, 8-fold to 10-fold, 9-fold to 10-fold, relative to a reference level (e.g. a reference level as described herein, such as in one embodiment a respective baseline level in a subject prior to administration of TNF-a inhibitor therapy).

[0395] In some embodiments, biomarkers comprise IL-10 or IL-10 and IFN-y that are increased in expression can monitor responsiveness to TNF-a inhibitor therapy. In some embodiments, the biomarker comprising IL-10 or IL-10 and IFN-y that shows an increased expression can be used to monitor, evaluate or modify an TNF-a inhibitor therapy. In some embodiments, an increase in expression level of IL-10 or IFN-y is at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or higher, relative to a reference level (e.g. a reference level as described herein, such as in one embodiment a respective baseline level in a subject prior to administration of a TNF-a inhibitor therapy). In some embodiments, such a change (e.g., increase) in expression level of IL-10 or IFN-y is from about 15% to 50%, 15%to 99%, 20% to 99%, 25% to 99%, 30% to 99%, 35% to 99%, 40% to 99%, 45% to 99%, 50% to99%, 55% to 99%, 60% to 99%, 65% to 99%, 70% to 99%, 75% to 99%, 80% to 99%, 85% to 99%, 90% to 99%, 95% to 99%, or higher, relative to a reference level (e.g. a reference level as described herein, such as in one embodiment a respective baseline level in a subject prior to administration of a TNF-a inhibitor therapy).

[0396] In some embodiments, an increase in expression level of IL-10 or IFN-y is at least 1.1- fold, at least 1.5-fold, at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 6- fold, at least 7-fold, at least 8-fold, at least 9-fold, or at least 10-fold, relative to a reference level (e.g. a reference level as described herein, such as in one embodiment a respective baseline level in a subject prior to administration of a TNF-a inhibitor therapy). In some embodiments, an increase in expression level of IL-10 or IFN-y is 1.1-fold to 10 fold, 1.5-fold to 10-fold, 2-fold to 10-fold, 3-fold to 10-fold, 4-fold to 10-fold, 5-fold to 10-fold, 6-fold to-81-Attorney Docket No. 768830: SA9-910PC10-fold, 7-fold to 10-fold, 8-fold to 10-fold, 9-fold to 10-fold, relative to a reference level (e.g. a reference level as described herein, such as in one embodiment a respective baseline level in a subject prior to administration of a TNF-a inhibitor therapy).

[0397] In some embodiments, the at least one biomarker as described herein is used in accordance with one or more methods described herein. In some embodiments, a change in expression level of at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, biomarkers are used in accordance with one or more methods described herein. In some embodiments the change in expression level of 2, 3, 4, 5, 6, 7, 8, 9 biomarkers are determined to indicate responsiveness to a TNF-a inhibitor therapy, thereby evaluating, selecting, or modifying the rheumatoid arthritis treatment plan for a subject in need thereof. In some embodiments the change in expression level of 2-4, 3-5, 4-6, 5-8, 6-9, 2-9, 3-9, 4-9, 5-9, 6-9, 7-9, or 8-9, biomarkers are determined to indicate responsiveness to a TNF-a inhibitor therapy, thereby evaluating, selecting, or modifying the rheumatoid arthritis treatment plan for a subject in need thereof.Reference Levels

[0398] In some embodiments of various methods described herein, the expression level of at least one biomarker described herein is compared to a reference level.

[0399] In some embodiments, a reference level (e.g., a first reference level or a second reference level, or any additional reference level) used in various methods described herein is expression level of a corresponding biomarker in a sample from a subject whose responsiveness to the rheumatoid arthritis therapy (e.g., an IL-6 inhibitor therapy or an TNF-a inhibitor therapy) is to be determined or monitored in accordance with the present disclosure. In some embodiments, a reference level (e.g., a first reference level or a second reference level, or any additional reference level) used in various methods described herein is the average, mean, or median level of expression level of a corresponding biomarker in a sample from a population of subjects that have rheumatoid arthritis.

[0400] In some embodiments, a reference level (e.g., a first reference level or a second reference level, or any additional reference level) used in various methods described herein is expression level of a corresponding biomarker in a sample from one or more subjects prior to receiving a rheumatoid arthritis therapy (e.g., an IL-6 inhibitor therapy or an TNF-a inhibitor therapy), i.e., baseline expression level. In some embodiments, such a reference level can be obtained-82-Attorney Docket No. 768830: SA9-910PC from a population of RA subjects as described above, or from an individual subject whose responsiveness to the rheumatoid arthritis therapy (e.g., an IL-6 inhibitor therapy or an TNF-a inhibitor therapy) is to be determined or monitored in accordance with the present disclosure.

[0401] In some embodiments where more than one assessment is performed to determine responsiveness to a rheumatoid arthritis therapy (e.g., an IL-6 inhibitor therapy or an TNF-a inhibitor therapy) in a subject, for example, two or more assessments performed at various times during the course of the rheumatoid arthritis therapy, or after a switch to a different rheumatoid arthritis treatment, a reference level of a subsequent assessment can be the same or different from a reference level of a prior assessment. For example, a subject who has been administered a rheumatoid arthritis therapy (e.g., an IL-6 inhibitor therapy or an TNF-a inhibitor therapy) for a period of time (e.g., at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 9 weeks, at least 10 weeks, at least 11 weeks, at least 12 weeks, or longer) may be first assessed to determine if the subject shows any signs of early responsiveness to the rheumatoid arthritis. A reference level used in such a first assessment may be any reference level as described above, e.g., in some embodiment expression level of a corresponding biomarker in a sample from the subject prior to administration of the rheumatoid arthritis therapy.

[0402] If the subject is determined during the first assessment to continue the same rheumatoid arthritis therapy, a second or subsequent assessment may be performed later to continue monitoring the responsiveness of the subject to the same rheumatoid arthritis therapy. In such embodiments, a reference level used in such a second or subsequent assessment can be the same reference level as used in the first or prior assessment, or it can be different from the reference level used in the first or prior assessment, e.g., in some embodiments, such a second or subsequent reference level can be expression level of a corresponding biomarker measured at the first or prior assessment. In some embodiments where a second or subsequent reference level is expression level of a corresponding biomarker measured at the first or prior assessment, a subject may continue the same rheumatoid arthritis therapy if the same directional change in expression level of a subject biomarker as in the first assessment is observed or if expression level of the subject biomarker has stayed substantially the same (e.g., within 10% or less, including, e.g., within 9%, within 8%, within 7%, within 6%, within 5%, or lower, or within 10% to 5% , 8 to 5% or 5 to 1%) since the first or prior assessment.-83-Attorney Docket No. 768830: SA9-910PC

[0403] If the subject is determined during the first assessment to stop the current rheumatoid arthritis therapy because of inadequate responsiveness or non-responsiveness, a second or subsequent assessment may be performed after the subj ect is switched to a different rheumatoid arthritis therapy (e.g., switching from an IL-6 inhibitor therapy to a TNF-a inhibitor therapy, or vice versa) to determine if the subject shows any signs of early responsiveness to the different rheumatoid arthritis treatment. In some such embodiments, a reference level used in such a second or subsequent assessment can be expression level of a relevant biomarker (for the different rheumatoid arthritis treatment) in a sample from one or more RA subjects prior to receiving the different rheumatoid arthritis therapy and optionally prior to receiving the last rheumatoid arthritis therapy that did not work.

[0404] One of skill in the art reading the present disclosure will understand that any of the reference levels described herein may be used as a reference level for determining or monitoring changes in an expression level of at least one biomarker.Biomarker Expression Levels

[0405] Any suitable method for determining biomarker levels (e.g., protein or gene expression) known in the art may be used. In some embodiments, expression level may refer to detecting and quantifying the biomarker expression level, which means measuring mRNA expression level of the selected biomarker. In some embodiments, mRNA expression level may be measured by quantify the copies of a specific mRNA present in a sample, by measuring the amount of hybridization to an mRNA-specific probe. In other embodiments, detection methods may involve amplifying mRNA, or cDNA generated from mRNA, and quantifying the amount of amplicon generated to extrapolate how much mRNA is present in a sample. Yet, in some embodiments, detection methods may involve next-generation sequencing of part or all of mRNA transcripts, or cDNA generated from mRNA, then quantifying the number of sequences detected that correspond to particular gene(s). In some embodiments, detection methods may involve gene expression analysis via oligonucleotide barcodes tagged with antibody agents or in situ hybridization probes. In some embodiments, detection methods may involve gene expression analysis via solution phase hybridization between (i) a capture probe comprising a first oligonucleotide and a target capture agent (e.g., in some embodiments a target capture agent being an antibody agent) and (ii) and a reporter probe comprising a reporter agent (e.g., in some embodiments a fluorescent barcode) and a second oligonucleotide that is capable of-84-Attorney Docket No. 768830: SA9-910PC hybridizing with the first oligonucleotide. In some embodiments, mRNA expression level is measured by quantitative PCR, semi-quantitative PCR, real-time quantitative PCR, nucleotide microarrays, RNA-seq, in situ hybridization or Northern blotting. In some embodiments, biomarker levels can be determined using any one of the methods as described in Example I.

[0406] In some embodiments, expression level may refer to protein expression level of the biomarker. Protein expression level may be measured by detecting proteins present in a sample by using a probe that specifically binds to a particular protein, such as an antibody agent, then detecting the amount of specific binding in a sample. In some embodiments, the method for measuring protein expression may fragment proteins into short peptides, then detect these peptides and quantify how many peptides correspond to the protein(s). In some embodiments, protein expression level is measured by Western blotting, peptide microarray, immunohistochemistry, flow cytometry, mass spectrometry or any combination thereof.

[0407] In some embodiments, the expression levels (of an mRNA or protein) are normalized to the expression level of a reference. Normalizing the expression level of mRNA or protein to a reference enhances reproducibility across samples by factoring differences in sample size and / or mRNA / protein extraction. In some embodiments, multiple references (e.g. genes) may be used, either singly or in aggregate (e.g., by averaging). In some embodiments, expression level of an mRNA or protein may refer to a relative expression level. In some embodiments, expression level of an mRNA or protein may refer to absolute expression level.

[0408] In some embodiments, a reference may be a housekeeping gene. A housekeeping gene is constitutively expressed in a cell in normal and / or pathological states, such as a gene encoding a protein required for basic cellular function and / or maintenance. Housekeeping genes are typically used as a reference to ensure they will be expressed at a detectable and / or reproducible level across multiple samples. Exemplary housekeeping genes and further description of the use of such genes as a reference may be found, for example, in de Kok, J. B., et al. (2005) Lab Invest. 85(1): 154-9. In some embodiments, the housekeeping genes include the beta-actin gene, the RNA18S, the transferrin receptor gene, the GAPDH gene, Ubiquitin C (UBC) gene, ribosomal protein large P0 (RPLPO) gene, beta-2 -microglobulin (B2M), hypoxanthine phosporibosyltransferase 1 (HPRT1) gene, TATA box binding protein (TBP) gene, peptidylprolyl isomerase A (PPIA) gene, glucuronidase beta (GUSB) gene, and phosphoglycerate kinase 1 (PGK1) gene.-85-Attorney Docket No. 768830: SA9-910PCExemplary IL-6 Inhibitor Therapy

[0409] In some embodiments, a rheumatoid arthritis therapy in accordance with the methods described herein is an interleukin-6 (IL-6) inhibitor therapy. As used herein, an IL-6 inhibitor therapy is a therapy comprising an inhibitor that partially or completely blocks an IL-6- associated pathway. In some embodiments, an IL-6 inhibitor is a polypeptide, a polynucleotide, a small molecule, etc. In some embodiments, an IL-6 inhibitor is an antibody agent. In some embodiments, an IL-inhibitor is an antibody of an IgGl subclass.

[0410] In some embodiments, an IL-6 inhibitor therapy comprises an antibody agent (e.g., in some embodiments an antibody of an IgGl subclass) targeting IL-6 cytokine. For example, an exemplary anti-IL-6 antibody agent is or comprises olokizumab, siltuximab, elsilimomab, clazakizumab, sirukumab, or levilimab.

[0411] In some embodiments, an IL-6 inhibitor therapy comprises a soluble polypeptide targeting IL-6 cytokine. For example, such a soluble polypeptide is or comprises olamkicept.

[0412] In some embodiments, an IL-6 inhibitor therapy comprises an antibody agent (e.g., in some embodiments an antibody of an IgGl subclass) targeting IL-6 receptor (IL-6R). For example, an exemplary anti-IL-6R antibody agent is or comprises sarilumab, tocilizumab, or satralizumab.

[0413] In some embodiments, an anti-IL-6 antibody agent is an anti-IL-6R antibody agent as described in U.S. Patent No. 7,521,052, which is incorporated by reference herein in its entirety for the purposes described herein, or an antigen-binding fragment thereof. In some embodiments, an anti-IL-6 antibody agent is an anti-ILR antibody agent (e.g., an anti-human IL-6R antibody) as described in U. S. Patent No. 7,582,298, which is incorporated by reference herein in its entirety for the purposes described herein.

[0414] In some embodiments, an anti-IL-6R antibody agent or antigen-binding fragment thereof that can be used comprises the heavy chain complementarity determining regions (HCDRs) of a HCVR comprising the amino acid sequence of SEQ ID NO: 1 and the light chain complementarity determining regions (LCDRs) of a LCVR comprising the amino acid sequence of SEQ ID NO: 2. In some embodiments, the anti-IL-6R antibody agent or antigenbinding fragment thereof comprises three HCDRs (i.e., HCDR1, HCDR2 and HCDR3) and three LCDRs (i.e., LCDR1, LCDR2 and LCDR3), wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 3; the HCDR2 comprises the amino acid sequence of SEQ ID-86-Attorney Docket No. 768830: SA9-910PCNO: 4; the HCDR3 comprises the amino acid sequence of SEQ ID NO: 5; the LCDR1 comprises the amino acid sequence of SEQ ID NO: 6; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 7; and the LCDRS comprises the amino acid sequence of SEQ ID NO: 8. In yet other embodiments, the anti-IL-6R antibody agent or antigen-binding fragment thereof comprises an HCVR comprising SEQ ID NO: 1 and an LCVR comprising SEQ ID NO: 2. In some embodiments, an anti-IL-6R antibody agent or antigen-binding fragment thereof comprises a heavy chain variable region comprising SEQ ID NO: 1 and a light chain variable region comprising SEQ ID NO: 2. In some embodiments, the anti-IL-6R antibody agent or antigen-binding fragment thereof comprises a heavy chain variable region comprising an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the sequence of SEQ ID NO: 1 and a light chain variable region comprising an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the sequence of SEQ ID NO: 2.

[0415] In some embodiments, an anti-IL-6R antibody agent or antigen-binding fragment thereof comprises a heavy chain comprising SEQ ID NO: 9 and a light chain comprising SEQ ID NO: 10. In some embodiments, the anti-IL-6R antibody agent or antigen-binding fragment thereof comprises a heavy chain comprising an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the sequence of SEQ ID NO: 9 and a light chain comprising an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the sequence of SEQ ID NO: 10.

[0416] The amino acid sequence of SEQ ID NO: 1 is: EVOLVESGGGLVOPGRSLRLSCAAS / OTFPPyAMHWVROAPGKGLEWVSGLSlPiVA G7?IGYADSVI<GRFTISRDNAENSLFL0MNGLRAEDTALYYCAKG7?A$77) / WG0GT MVTVSS(CDR sequences are highlighted: IMGT numbering in bold; Kabat numbering underlined; Chothia numbering italicized).

[0417] The amino acid sequence of SEQ ID NO: 2 is:DIOMTOSPSSVSASVGDRVTITC / MYOG / ASW / .ylWYOOKPGKAPKLLIYGOAS / . / AGV PSRF SGSGSGTDFTLTIS SLOPEDF AS YYC 0(MV5FPF7FGOGTKLEIK(CDR sequences are highlighted: IMGT numbering in bold; Kabat numbering underlined; Chothia numbering italicized).-87-Attorney Docket No. 768830: SA9-910PC

[0418] The amino acid sequence of SEQ ID NO: 3 is RFTFDDYA (CDR-H1 according to IMGT numbering).

[0419] The amino acid sequence of SEQ ID NO: 4 is ISWNSGRI (CDR-H2 according to IMGT numbering).

[0420] The amino acid sequence of SEQ ID NO: 5 is AKGRDSFDI (CDR-H3 according to IMGT numbering).

[0421] The amino acid sequence of SEQ ID NO: 6 is QGISSW (CDR-L1 according to IMGT numbering).

[0422] The amino acid sequence of SEQ ID NO: 7 is GAS (CDR-L2 according to IMGT numbering).

[0423] The amino acid sequence of SEQ ID NO: 8 is QQANSFPYT (CDR-L3 according to IMGT numbering).

[0424] The amino acid sequence of SEQ ID NO: 9 is:EV0LVESGGGLV0PGRSLRLSCAAS / OTFDDFAMHWVR0APGKGLEWVSGLSIPN5GPIGYADSVI<GRFTISRDNAENSLFLOMNGLRAEDTALYYCAKG7? / ),$'F7) / WGOGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQS SGLYSLS S VVTVPS S SLGTQT YICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLG GPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQ YNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPS RDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVD KSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(CDR sequences are highlighted: IMGT numbering in bold; Kabat numbering underlined; Chothia numbering italicized).

[0425] The amino acid sequence of SEQ ID NO: 10 is:DIOMTOSPSSVSASVGDRVTITC / MA'OGTSAW / . / IWYOOKPGKAPKLLIYGAAS / . / AGVPSRFSGSGSGTDFTLTISSLOPEDFASYYCOCMAAFPFTFGOGTKLEIKRTVAAPSVFIFPPSDE QLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLS KADYEKHKVYACEVTHQGLS SP VTKSFNRGEC(CDR sequences are highlighted: IMGT numbering in bold; Kabat numbering underlined; Chothia numbering italicized).-88-Attorney Docket No. 768830: SA9-910PC

[0426] In some embodiments, an anti-IL-6R antibody agent or antigen-binding fragment thereof is sarilumab or an antigen binding fragment thereof, or a bioequivalent thereof. In some embodiments, an anti-IL-6R antibody agent or antigen-binding fragment thereof is an antibody comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 1 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 2. In some embodiments, an anti-IL-6R antibody agent or antigen-binding fragment thereof isan antibody comprising a heavy chain comprising the amino acid sequence of SEQ ID NO: 9 and a light chain comprising the amino acid sequence of SEQ ID NO: 10.

[0427] The term “bioequivalent” as used herein, refers to a molecule having similar bioavailability (rate and extent of availability) after administration at the same molar dose and under similar conditions (e.g., same route of administration), such that the effect, with respect to both efficacy and safety, can be expected to be essentially same as the comparator molecule.

[0428] Two pharmaceutical compositions comprising an antibody agent are bioequivalent if they are pharmaceutically equivalent, meaning they contain the same amount of active ingredient (e.g., IL-6R antibody agent), in the same dosage form, for the same route of administration and meeting the same or comparable standards. Bioequivalence can be determined, for example, by an in vivo study comparing a pharmacokinetic parameter for the two compositions. Parameters commonly used in bioequivalence studies include peak plasma concentration (Cmax) and area under the plasma drug concentration time curve (AUC).

[0429] In some embodiments, an IL-6 inhibitor therapy comprises an IL-6 inhibitor that is a small molecule.

[0430] In some embodiments, an IL-6 inhibitor therapy comprises an IL-6 inhibitor that is an immunoglobulin single variable domain.

[0431] In some embodiments, an IL-6 inhibitor therapy comprises an antibody agent (e.g., a bispecific antibody agent) that targets IL-6 and a different target. For example, in some embodiments, such a bispecific antibody agent targets IL-6 and TNF-a. An exemplary bispecific antibody agent that targets IL-6 and TNF-a is described in WO 2022 / 129572, the content of which is incorporated herein for the purposes described herein.

[0432] The amount of IL-6 inhibitor therapy (e.g., anti-IL-6R antibody agent) is administered to a subject according to the methods described herein is, generally, a therapeutically effective amount. In some embodiments, a therapeutically effective amount of IL-6 inhibitor therapy-89-Attorney Docket No. 768830: SA9-910PC(e.g., anti-IL-6R antibody agent), is from about 0.05 mg to about 700 mg, e.g., about 0.05 mg, about 0.1 mg, about 1.0 mg, about 1.5 mg, about 2.0 mg, about 3.0 mg, about 5.0 mg, about 7.0 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, about 600 mg, about610 mg, about 620 mg, about 630 mg, about 640 mg, about 650 mg, about 660 mg, about670 mg, about 680 mg, about 690 mg, or about 700 mg of the IL-6 inhibitor therapy (e.g., anti-IL-6R antibody agent). In some embodiments, IL-6 inhibitor therapy (e.g., anti-IL-6R antibody agent) is administered at about 150 mg to about 200 mg. In some embodiments, IL-6 inhibitor therapy (e.g., anti-IL-6R antibody agent) is administered at about 150 mg or about200 mg.

[0433] In some embodiments, the IL-6 inhibitor therapy (anti-IL-6R antibody agent) is administered once every two weeks. “Once every two weeks” has the same meaning as “q2w” or “once per two weeks”, viz., that the antibody agent is administered once in a two-week period. In some embodiments, the anti-IL-6R antibody agent (e.g. sarilumab) is administered subcutaneously. In some embodiments, the anti-IL-6R antibody agent (e.g. sarilumab) is administered at about 150 mg to about 200 mg once every two weeks. In some embodiments, the anti-IL-6R antibody agent (e.g. sarilumab) is administered at about 150 mg to about 200 mg once every two weeks subcutaneously. In some embodiments, the anti-IL-6R antibody agent (e.g. sarilumab) is administered at about 150 mg or about 200 mg once every two weeks. In some embodiments, the anti-IL-6R antibody agent (e.g. sarilumab) is administered at about 150 mg or about 200 mg once every two weeks subcutaneously.

[0434] In some embodiments where the anti-IL-6R antibody agent is tocilizumab and it is administered subcutaneously, tocilizumab is administered about 162 mg every other week or-90-Attorney Docket No. 768830: SA9-910PC every week. In some embodiments where the anti-IL-6R antibody agent is tocilizumab and it is administered intravenously, tocilizumab is administered about 4 mg per kg body weight of a subject in need thereof every 4 weeks or about 8 mg per kg body weight of a subject in need thereof every 4 weeks.

[0435] In some embodiments, the amount of an anti-IL-6R antibody agent contained within the individual doses may be expressed in terms of milligrams of antibody agent per kilogram of subject body weight (i.e., mg / kg). For example, the IL-6R antibody agent may be administered to a subject at a dose of about 0.0001 to about 10 mg / kg of subject body weight. For example, the IL-6R antibody agent can be administered at a dose of 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg or 6 mg / kg.

[0436] In some embodiments, two or more (e.g., 2, 3, 4, or 5 or more) doses are administered at the beginning of the treatment regimen as “initial doses” or “loading doses” followed by subsequent doses that are administered on a less frequent basis (e.g., “maintenance doses” or “secondary doses”). In one embodiment, the maintenance dose may be lower than the loading or initial dose.

[0437] In some embodiments, the initial dose is about the same as the loading dose. In certain embodiments, the initial dose is about l. lx, about 1.2x, about 1.3x, about 1.4x, about 1.5x, about 1.6x, about 1.7x, about 1.8x, about 1.9x, abo initial dose about 2. Ox, about 2.5x, about 3. Ox, or more of the loading dose.

[0438] In some embodiments, the IL-6R antibody agent is administered at a dose of about 150 mg or about 200 mg. In some embodiments, the IL-6R antagonist is administered at an initial dose of about 200 mg and one or more secondary doses or maintenance doses of about 200 mg, and the secondary doses are administered every other week (q2w).

[0439] In some embodiments the disclosure comprises administering to the subject one or more additional therapeutic agents in combination with the IL-6R antibody agent. As used herein, the expression “in combination with” means that the additional therapeutic agents are administered before, after, or concurrent with the pharmaceutical composition comprising the IL-6R antibody agent. In some embodiments, the subject is administered the antibody agent with a disease modifying antirheumatic drug (DMARD). In some embodiments, the antibody agent is an IL-6 antibody agent administered with a DMARD. In some embodiments, the-91-Attorney Docket No. 768830: SA9-910PC antibody agent is sarilumab with a DMARD. In some embodiments, the antibody agent is sarilumab administered with methotrexate.Exemplary TNF-a Inhibitor Therapy

[0440] In some embodiments, a rheumatoid arthritis therapy in accordance with the methods described herein is a TNF-a inhibitor therapy. As used herein, a TNF-a inhibitor therapy is a therapy comprising an inhibitor that partially or completely blocks a TNF-a-associated pathway. In some embodiments, an TNF-a inhibitor may be a polypeptide, a polynucleotide, a small molecule, etc. In some embodiments, an TNF-a inhibitor therapy comprises an antibody agent targeting TNF-a. In some embodiments, an IL-inhibitor is an antibody of an IgGl subclass.

[0441] In some embodiments, an TNF-a inhibitor therapy comprises an antibody agent (e.g., in some embodiments an antibody of an IgGl subclass) targeting TNF-a. For example, an exemplary anti-TNF-a antibody agent is or comprises adalimumab (HUMIRA™), certolizumab pegol (CIMZIA™), etanercept (ENBREL™), golimumab (SIMPONI™) or infliximab (REMICADE™). Several biosimilars for adalimumab include AMJEVITA™ HYRIMOZ™, IDACIO™, IMRALDI™ and YUFLYMA™ and for infliximab AVSOLA™, INFLECTRA™, RENFLEXIS™, or biosimilar versions thereof.

[0442] Descriptions of anti-TNF-a antibody agents may be found in U.S. Patent No. 8,092,998, which is incorporated by reference herein in its entirety.

[0443] In some embodiments, the TNF-a antibody agent is adalimumab (HUMIRA™).

[0444] The amino acid sequences of adalimumab are shown below.

[0445] The heavy chain amino acid sequence of SEQ ID NO: 11 is:EVQLVESGGGLVQPGRSLRLSCAASGFTFDDYAMHWVRQAPGKGLEWVSAITWNSGHIDYADSVEGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAKVSYLSTASSLD YWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALT SGVHTFP AVLQS SGLYSLS S VVTVPS S SLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTH TCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVE VHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKG QPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPP VLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

[0446] The light chain amino acid sequence of SEQ ID NO: 12 is:-92-Attorney Docket No. 768830: SA9-910PCDIQMTQSPSSLSASVGDRVTITCRASQGIRNYLAWYQQKPGKAPKLLIYAASTLQSGVPS RFSGSGSGTDFTLTISSLQPEDVATYYCQRYNRAPYTFGQGTKVEIKRTVAAPSVFIFPPS DEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTL TLSKADYEKHKYACEVTHQGS SP VTKSFNRGEC .

[0447] In some embodiments, adalimumab or an antigen binding fragment comprises the heavy chain amino acid sequence of SEQ ID NO: 11 and the light chain amino acid sequence of SEQ ID NO: 12. In some embodiments, the TNF-a antibody agent or antigen-binding fragment thereof comprises a heavy chain comprising an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the sequence of SEQ ID NO: 11 and a light chain comprising an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the sequence of SEQ ID NO: 12.

[0448] The amount of TNF-a inhibitor therapy (e.g., anti- TNF-a antibody agent) is administered to a subject according to the methods described herein is, generally, a therapeutically effective amount. In some embodiments, a therapeutically effective amount of TNF-a inhibitor therapy(e.g., anti- TNF-a antibody agent), is from about 0.05 mg to about 700 mg, e.g., about 0.05 mg, about 0.1 mg, about 1.0 mg, about 1.5 mg, about 2.0 mg, about 3.0 mg, about 5.0 mg, about 7.0 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, about 600 mg, about610 mg, about 620 mg, about 630 mg, about 640 mg, about 650 mg, about 660 mg, about670 mg, about 680 mg, about 690 mg, or about 700 mg of the TNF-a inhibitor therapy (e.g., anti- TNF-a antibody agent). In some embodiments, TNF-a inhibitor therapy (e.g., anti-TNF- a antibody agent) is administered at about 40 mg to about 80 mg. In some embodiments, TNF--93-Attorney Docket No. 768830: SA9-910PC a inhibitor therapy (e.g., anti- TNF-a antibody agent) is administered at about 40 mg or about 80 mg.

[0449] In some embodiments, the TNF-a inhibitor therapy (anti- TNF-a antibody agent) is administered once every two weeks. “Once every two weeks” has the same meaning as “q2w” or “once per two weeks”, viz., that the antibody agent is administered once in a two-week period. In some embodiments, the anti-TNF-a antibody agent (e.g. adalimumab) is administered subcutaneously. In some embodiments, the adalimumab antibody agent is administered at about 40 mg to about 800 mg once every two weeks. In some embodiments, the anti-TNF-a antibody agent (e.g. adalimumab) is administered at about 40 mg to about 80 mg once every two weeks subcutaneously. In some embodiments, the anti-TNF-a antibody agent (e.g. adalimumab) is administered at about 40 mg or about 80 mg once every two weeks. In some embodiments, the anti-TNF-a antibody agent (e.g. adalimumab) is administered at about 40 mg or about 80 mg once every two weeks subcutaneously.

[0450] In some embodiments, two or more (e.g., 2, 3, 4, or 5 or more) doses are administered at the beginning of the treatment regimen as “initial doses” or “loading doses” followed by subsequent doses that are administered on a less frequent basis (e.g., “maintenance doses” or “secondary doses”). In one embodiment, the maintenance dose may be lower than the loading or initial dose.

[0451] In some embodiments, the initial dose is about the same as the loading dose. In certain embodiments, the initial dose is about l. lx, about 1.2x, about 1.3x, about 1.4x, about 1.5x, about 1.6x, about 1.7x, about 1.8x, about 1.9x, abo initial dose about 2. Ox, about 2.5x, about 3. Ox, or more of the loading dose.

[0452] In some embodiments, the anti-TNF-a antibody agent (e.g. adalimumab) is administered at a dose of about 40 mg or about 80 mg. In some embodiments, the anti-TNF-a antibody agent (e.g. adalimumab) is administered at an initial dose of about 40 mg and one or more secondary doses or maintenance doses of about 40 mg, and the secondary doses are administered every other week (q2w).

[0453] In some embodiments the disclosure comprises administering to the subject one or more additional therapeutic agents in combination with the anti-TNF-a antibody agent (e.g. adalimumab). As used herein, the expression “in combination with” means that the additional therapeutic agents are administered before, after, or concurrent with the pharmaceutical-94-Attorney Docket No. 768830: SA9-910PC composition comprising the anti-TNF-a antibody agent (e.g. adalimumab). In some embodiments, the subject is administered the antibody agent with a disease modifying antirheumatic drug (DMARD). In some embodiments, the antibody agent is an anti-TNF-a antibody agent (e.g. adalimumab) administered with a DMARD. In some embodiments, the antibody agent is adalimumab with a DMARD. In some embodiments, the antibody agent is adalimumab administered with methotrexate.

[0454] In some embodiments, a TNF-a inhibitor therapy comprises an orally bioavailable peptide or miniprotein that targets and inhibits activity of TNF receptor 1 (TNFR1). In some embodiments, a TNF-a inhibitor therapy comprises a membrane-permeable peptide (e.g., cyclic peptides) that targets and inhibits TNFR1 .

[0455] In some embodiments, a TNF-a inhibitor therapy comprises a small single-strand oligonucleotide (including e.g., siRNA and antisense oligonucleotide) that specifically targets TNF-a. In some embodiments such small single-strand oligonucleotides can be delivered by lipid nano-crystals.

[0456] In some embodiments, a TNF-a inhibitor therapy comprises a small molecule inhibitor that binds directly to TNF-a and inhibits TNF- a activities. In some embodiments such a small molecule inhibitor is IA-14069 developed by iLab, Inc.

[0457] In some embodiments, a TNF-a inhibitor therapy comprises an oral delivery construct of infliximab. In some embodiments, such a molecule is INT-119 developed by Intract Pharma Ltd.

[0458] In some embodiments, a TNF-a inhibitor therapy comprises an antibody agent modulating sphingosine 1 -phosphate (SIP) receptor. In some embodiments, such an antibody agent is ozanimod.

[0459] In some embodiments, a TNF-a inhibitor therapy comprises an antibody agent (e.g., a bispecific antibody agent) that targets TNF and a different target. For example, in some embodiments, such a bispecific antibody agent targets TNF-a and OX40L. An exemplary bispecific antibody agent that targets TNF-a and OX40L is described in WO 2021 / 110817, the content of which is incorporated herein for the purposes described herein. In some embodiments, a bispecific antibody agent that targets TNF-a and IL-6 can be used in a TNF-a inhibitor therapy. An exemplary bispecific antibody agent that targets TNF-a and IL-6 is-95-Attorney Docket No. 768830: SA9-910PC described in WO 2022 / 129572, the content of which is incorporated herein for the purposes described herein.DMARDs

[0460] Disease modifying antirheumatic drugs (DMARD) are drugs defined by their use in rheumatoid arthritis to slow down disease progression. DMARDs have been classified as synthetic (sDMARD) and biological (bDMARD). Synthetic DMARDs include non- exhaustively methotrexate, sulfasalazine, leflunomide, and hydroxychloroquine. Biological DMARDs include non-exhaustively adalimumab, golimumab, etanercept, abatacept, infliximab, rituximab, and tocilizumab. In some embodiments, no DMARD is administered with an IL-6 inhibitor therapy or TNF-a inhibitor therapy. In some embodiments, at least one DMARD in addition to an IL-6 inhibitor therapy or TNF-a inhibitor therapy is administered to the subject. In some embodiments, the least one other DMARD (other than an IL-6 inhibitor therapy or TNF-a inhibitor therapy) is administered to the subject concurrently with or at the same time as the IL-6 inhibitor therapy or TNF-a inhibitor therapy.Subjects

[0461] The term “subject” means a human subject. In some embodiments, the subject has rheumatoid arthritis. In some embodiments, the subject has rheumatoid arthritis as defined as having at least 6 of 66 swollen joints and 8 of 68 tender joints, as counted by the physician in a typical quantitative swollen and tender joint count examination, high sensitivity C-reactive protein (hs-CRP) >8 mg / L or ESR >28 mm / H- DAS28ESR > 5.1.

[0462] In some embodiments, the subject has “moderately active RA” defined as: at least 8 and at most 26 of 68 tender joints and at least 6 and / or at most 16 of 66 swollen joints in the subject. In some embodiments, “severely active RA” in a subject is defined as: (i) more than 27 of 68 tender joints and / or at least 17 of 66 swollen joints in the subject.

[0463] In some embodiments, the subject, who was previously ineffectively treated for rheumatoid arthritis by administering at least one DMARD different from an IL-6 inhibitor therapy or TNF- a inhibitor therapy described herein, is a subject who was previously ineffectively treated for rheumatoid arthritis by administering a DMARD. In some embodiments, the DMARD is selected from the group consisting of methotrexate, sulfasalazine, leflunomide, and hydroxychloroquine. In various embodiments, the DMARD is methotrexate. In some embodiments, a subject who is considered “ineffectively treated” by his-96-Attorney Docket No. 768830: SA9-910PC or her physician is a subject who either has shown to be intolerant to the one or more DMARD tested by the physician, and / or a subject who has shown an inadequate response to the one or more DMARD tested by the physician, typically a subject who is still considered by the physician to present with, or to have, active rheumatoid arthritis despite the previous one or more DMARD administered.

[0464] In some embodiments, the subject, who was previously ineffectively treated for rheumatoid arthritis by administering one or more DMARD different from an IL-6 inhibitor therapy or TNF- a inhibitor therapy, is a subject who had an inadequate response or intolerance to methotrexate.

[0465] According to the disclosure, for those subjects previously ineffectively treated for rheumatoid arthritis by administering one or more DMARD different from an IL-6 inhibitor therapy or TNF- a inhibitor therapy, the one or more DMARD is / are not administered anymore to the subject, and an IL-6 inhibitor therapy or TNF- a inhibitor therapy is in some embodiments administered alone (e.g. without any other DMARD), in monotherapy to the subject. See International PCT Publication No. WO2017155990, which is incorporated by reference herein in its entirety.

[0466] In some embodiments, the subject is intolerant to the DMARD due to one or more physical reactions, conditions, or symptoms from the treatment with the DMARD. Physical reactions, conditions or symptoms can include allergies, pain, nausea, diarrhea, azotemia, bleeding of the stomach, intestinal bleeding, canker sores, decreased blood platelets, perforation of the intestine, bacterial infection, inflammation of gums or mouth, inflammation of the stomach lining or intestinal lining, bacterial sepsis, stomach ulcer, intestinal ulcer, sun sensitive skin, dizziness, loss of appetite, low energy, and vomiting. In some embodiments, intolerance can be determined by the subject or by a medical professional upon examination of the subject. In various embodiments, the DMARD is selected from the group consisting of methotrexate, sulfasalazine, leflunomide, and hydroxychloroquine. In some embodiments, the DMARD is methotrexate.Kits

[0467] Another aspect described herein relates to kits for use in accordance with any aspects of the methods described herein. In some embodiments, kits are disclosed that may have at least one reagent specific for detecting expression levels of at least one biomarker (including, e.g.,-97-Attorney Docket No. 768830: SA9-910PC at least two, at least three, at least four, at least five, at least six, at least seven, at least eight or at least nine biomarkers) described herein (e.g., as described in Tables 1-4), and may further include instructions for carrying out a method described herein.

[0468] In some embodiments is described a use of one or more agents for determining expression level of at least one biomarker (including, e.g., at least two, at least three, at least four, at least five, at least six, at least seven, at least eight or at least nine biomarkers) as shown in Tables 1- 4 in the manufacture of a kit for use in any aspects of the methods described herein, for example, in some embodiments, for determining or monitoring the efficacy of a rheumatoid arthritis therapy (e.g. IL-6 inhibitor therapy or TNT -a inhibitor therapy) in a subject having rheumatoid arthritis, or for determining or monitoring responsiveness of a subject to a rheumatoid arthritis therapy (e.g. IL-6 inhibitor therapy or TNF-a inhibitor therapy).Kits for use with subjects who are receiving an IL-6 inhibitor therapy

[0469] In some embodiments, kits for use in accordance with certain aspects of the methods described herein are useful to assess or monitor responsiveness (e.g., early responsiveness) to an IL-6 inhibitor therapy in a subject having rheumatoid arthritis.

[0470] In some embodiments, kits for assessing or monitoring responsiveness to or determining continuation of an IL-6 inhibitor therapy in a subject having rheumatoid arthritis, includes at least one agent for detecting in a biological sample from a subject having rheumatoid arthritis and receiving an IL-6 inhibitor therapy expression level of at least one biomarker comprising AZU1, MMP9, MMP1, OSM, TNFSF14, Ep-CAM, CCL4, LDL-receptor, Ftl3L, or any combinations thereof. In some embodiments, a biomarker described herein can be characterized by the respective full sequence provided in Table 5 or a functional fragment thereof. In some embodiments, an agent for detecting a biomarker described herein is capable of binding to a functional fragment of the respective sequence provided in Table 5.

[0471] In some embodiments, the kit includes instructions providing that a decrease in expression level from a reference level of at least one biomarker selected from AZU1, MMP9, MMP1, OSM, and TNFSF14 indicates (i) an increased likelihood of responsiveness to the IL- 6 inhibitor therapy, (ii) a recommended continuation of the IL-6 inhibitor therapy, or (iii) both (i) and (ii).In some embodiments, the kit further includes instructions providing that an increase in or substantially no change in expression level from a reference level of at least one biomarker selected from AZU1, MMP9, MMP1, OSM, TNFSF14, or any combinations thereof indicates-98-Attorney Docket No. 768830: SA9-910PC(i) a decreased likelihood of responsiveness to the IL-6 inhibitor therapy, (ii) a recommended discontinuation of the IL-6 inhibitor therapy, or (iii) both (i) and (ii).

[0472] In some embodiments, at least one biomarker comprising AZU1, MMP9, MMP1, OSM, or TNFSF14 that show a reduced expression can be used to predict or monitor responsiveness to an IL-6 inhibitor therapy. In some embodiments, a decrease in expression level of at least one biomarker comprising AZU1, MMP9, MMP1, OSM, or TNFSF14 is at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or higher, relative to a reference level. In some embodiments, such a change (e.g., decrease) in expression level of at least one biomarker comprising AZU1, MMP9, MMP1, OSM, or TNFSF14 is from about 15% to 50%, 15%to 99%, 20% to 99%, 25% to 99%, 30% to 99%, 35% to 99%, 40% to 99%, 45% to 99%, 50% to99%, 55% to 99%, 60% to 99%, 65% to 99%, 70% to 99%, 75% to 99%, 80% to 99%, 85% to 99%, 90% to 99%, 95% to 99%, or higher, relative to a reference level (e.g. a reference level as described herein, such as in one embodiment a respective baseline level in a subject prior to administration of an IL-6 inhibitor therapy.

[0473] In some embodiments, a decrease in expression level of at least one biomarker comprising AZU1, MMP9, MMP1, OSM, or TNFSF14 is at least 1.1-fold, at least 1.5-fold, at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 6-fold, at least 7-fold, at least 8-fold, at least 9-fold, or at least 10-folder, relative to a reference level (e.g. a reference level as described herein, such as in one embodiment a respective baseline level in a subject prior to administration of an IL-6 inhibitor therapy). In some embodiments, a decrease in expression level of at least one biomarker comprising AZU1, MMP9, MMP1, OSM, or TNFSF14 is 1.1- fold tolO fold, 1.5-fold to 10-fold, 2-fold to 10-fold, 3-fold to 10-fold, 4-fold to 10-fold, 5-fold to 10-fold, 6-fold to 10-fold, 7-fold to 10-fold, 8-fold to 10-fold, 9-fold to 10-fold, relative to a reference level (e.g. a reference level as described herein, such as in one embodiment a respective baseline level in a subject prior to administration of an IL-6 inhibitor therapy).

[0474] In some embodiments, the kit includes instructions providing that an increase in expression level from a reference level of at least one biomarker selected from Ep-CAM, CCL4, LDL-receptor, and Ftl3L, indicates (i) an increased likelihood of responsiveness to the IL-6 inhibitor therapy, (ii) a recommended continuation of the IL-6 inhibitor therapy, or (iii)-99-Attorney Docket No. 768830: SA9-910PC both (i) and (ii). In some embodiments, the kit further includes instructions providing that a decrease in or substantially no change in expression level from a reference level of at least one biomarker selected from Ep-CAM, CCL4, LDL-receptor, and Ftl3L indicates (i) a decreased likelihood of responsiveness to the IL-6 inhibitor therapy, (ii) a recommended discontinuation of the IL-6 inhibitor therapy, or (iii) both (i) and (ii).

[0475] In some embodiments is described a use of one or more agents for determining expression level of at least one biomarker (including, e.g., at least two, at least three, at least four, at least five, at least six, at least seven, at least eight or at least nine biomarkers comprising AZU1, MMP9, MMP1, OSM, TNFSF14, Ep-CAM, CCL4, LDL-receptor, Ftl3L, or any combinations thereof, in the manufacture of a kit for use in any aspects of the methods described herein, for example, in some embodiments, for determining or monitoring the efficacy of an IL-6 inhibitor therapy in a subject having rheumatoid arthritis, or for determining or monitoring responsiveness of a subject to an IL-6 inhibitor therapy. In some embodiments, when such one or more agents detects a change in expression level of at least one biomarker (as described herein) in a sample from a subject receiving an IL-6 inhibitor therapy, from a reference level, the change in the expression level determines the likelihood of responsiveness of the subject to the IL-6 inhibitor therapy in accordance with certain aspects of the methods or kits described herein.

[0476] In some embodiments, the reference level used to measure a change in expression level of the at least one biomarker is the level of at least one biomarker in a biological sample from the subject prior to receiving an IL-6 inhibitor therapy.

[0477] In some embodiments, at least one biomarker comprising Ep-CAM, CCL4, LDL- receptor, Flt3L, or any combinations thereof that shows an increased expression can be used to predict or monitor responsiveness to an IL-6 inhibitor therapy. In some embodiments, an increase in expression level of at least one biomarker comprising Ep-CAM, CCL4, LDL- receptor, or Flt3L, is at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or higher, relative to a reference level (e.g. a reference level as described herein, such as in one embodiment a respective baseline level in a subject prior to administration of an IL-6 inhibitor therapy). In some embodiments, such a change (e.g., increase) in expression level of at least one biomarker-100-Attorney Docket No. 768830: SA9-910PC comprising Ep-CAM, CCL4, LDL-receptor, or Flt3L is from about 15% to 50%, 15%to 99%, 20% to 99%, 25% to 99%, 30% to 99%, 35% to 99%, 40% to 99%, 45% to 99%, 50% to99%, 55% to 99%, 60% to 99%, 65% to 99%, 70% to 99%, 75% to 99%, 80% to 99%, 85% to 99%, 90% to 99%, 95% to 99%, or higher, relative to a reference level (e.g. a reference level as described herein, such as in one embodiment a respective baseline level in a subject prior to administration of an IL-6 inhibitor therapy).

[0478] In some embodiments, an increase in expression level of at least one biomarker comprising Ep-CAM, CCL4, LDL-receptor, or Flt3L is at least 1.1-fold, at least 1.5-fold, at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 6-fold, at least 7-fold, at least 8-fold, at least 9-fold, or at least 10-fold, relative to a reference level (e.g. a reference level as described herein, such as in one embodiment a respective baseline level in a subject prior to administration of an IL-6 inhibitor therapy). In some embodiments, an increase in expression level of at least one biomarker comprising Ep-CAM, CCL4, LDL-receptor, or Flt3L is 1.1 -fold to 10 fold, 1.5-fold to 10-fold, 2-fold to 10-fold, 3 -fold to 10-fold, 4-fold to 10-fold, 5-fold to 10-fold, 6-fold to 10-fold, 7-fold to 10-fold, 8-fold to 10-fold, 9-fold to 10-fold, relative to a reference level (e.g. a reference level as described herein, such as in one embodiment a respective baseline level in a subject prior to administration of an IL-6 inhibitor therapy).Kits for use with subjects who are receiving a TNF-a inhibitor therapy

[0479] In some embodiments, kits for use in accordance with certain aspects of the methods described herein are useful to monitor responsiveness (e.g., early responsiveness) to an TNF- a inhibitor therapy in a subject having rheumatoid arthritis.

[0480] In some embodiments, kits for monitoring responsiveness to or determining continuation of an TNF-a inhibitor therapy in a subject having rheumatoid arthritis, includes at least one agent for detecting in a biological sample from a subject having rheumatoid arthritis and receiving an TNF-a inhibitor therapy expression level of at least one biomarker comprising CCL20, CCL4, CXCL10, CXCL9, EN-RAGE, OSM, IL-10, or IFN-y. In some embodiments, a biomarker described herein can be characterized by the respective full sequence provided in Table 5 or a functional fragment thereof. In some embodiments, an agent for detecting a biomarker described herein is capable of binding to a functional fragment of the respective sequence provided in Table 5.-101-Attorney Docket No. 768830: SA9-910PC

[0481] In some embodiments, the kit includes instructions providing that an increase in expression level from a reference level of at least one biomarker comprising IL-10 or IL-10 and IFN-y indicates (i) an increased likelihood of responsiveness to the TNF-a inhibitor therapy, (ii) a recommended continuation of the TNF-a inhibitor therapy, or (iii) both (i) and(ii). In some embodiments, the kit further includes instructions providing that a decrease in or substantially no change in expression level from a reference level of at least one biomarker comprising IL-10 or IL-10 and IFN-y indicates (i) a decreased likelihood of responsiveness to the TNF-a inhibitor therapy, (ii) a recommended discontinuation of the TNF-a inhibitor therapy, or (iii) both (i) and (ii).

[0482] In some embodiments, the kit includes instructions that a decrease in expression level from a reference level of at least one biomarker selected from CCL20, CCL4, CXCL10, CXCL9, EN-RAGE, and OSM indicates (i) an increased likelihood of responsiveness to the TNF-a inhibitor therapy, (ii) a recommended continuation of the TNF-a inhibitor therapy, or(iii) both (i) and (ii). In some embodiments, the kit further includes instructions providing that an increase in or substantially no change in expression level from a reference level of at least one biomarker selected from CCL20, CCL4, CXCL10, CXCL9, EN-RAGE, and OSM indicates (i) a decreased likelihood of responsiveness to the TNF-a inhibitor therapy, (ii) a recommended discontinuation of the TNF-a inhibitor therapy, or (iii) both (i) and (ii).

[0483] In some embodiments, at least one biomarker comprises CCL20, CCL4, CXCL10, CXCL9, EN-RAGE, or OSM that when reduced in expression can be used to predict or monitor responsiveness to TNF-a inhibitor therapy. In some embodiments, a reduced expression level of at least one biomarker comprising CCL20, CCL4, CXCL10, CXCL9, EN-RAGE, or OSM is at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95%, relative to a reference level (e.g. a reference level as described herein, such as in one embodiment a respective baseline level in a subject prior to administration of TNF-a inhibitor therapy). In some embodiments, such a change (e.g., decrease) in expression level of at least one biomarker comprising CCL20, CCL4, CXCL10, CXCL9, EN-RAGE, or OSM is from about 15% to 50%, 15%to 99%, 20% to 99%, 25% to 99%, 30% to 99%, 35% to 99%, 40% to 99%, 45% to 99%, 50% to99%, 55% to 99%, 60% to 99%, 65% to 99%, 70% to 99%, 75% to 99%, 80% to 99%, 85% to 99%, 90% to 99%, 95%-102-Attorney Docket No. 768830: SA9-910PC to 99%, or higher, relative to a reference level (e.g. a reference level as described herein, such as in one embodiment a respective baseline level in a subject prior to administration of an TNF- a inhibitor therapy). In some embodiments, a reduced expression level of at least one biomarker comprising CCL20, CCL4, CXCL10, CXCL9, EN-RAGE, or OSM is at least 1.1- fold, at least 1.5-fold, at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 6- fold, at least 7-fold, at least 8-fold, at least 9-fold, or at least 10-folder, relative to a reference level (e.g. a reference level as described herein, such as in one embodiment a respective baseline level in a subject prior to administration of TNF-a inhibitor therapy). In some embodiments, a reduced expression level of at least one biomarker comprising CCL20, CCL4, CXCL10, CXCL9, EN-RAGE, or OSM is 1.1-fold tolO fold, 1.5-fold to 10-fold, 2-fold to 10- fold, 3-fold to 10-fold, 4-fold to 10-fold, 5-fold to 10-fold, 6-fold to 10-fold, 7-fold to 10-fold, 8-fold to 10-fold, 9-fold to 10-fold, relative to a reference level (e.g. a reference level as described herein, such as in one embodiment a respective baseline level in a subject prior to administration of a TNF-a inhibitor therapy).

[0484] In some embodiments, biomarkers comprise IL-10 or IL-10 and IFN-y that are increased in expression can monitor responsiveness to TNF-a inhibitor therapy. In some embodiments, at the biomarker comprising IL-10 or IFN-y that shows an increased expression can be used to predict or monitor responsiveness to an TNF-a inhibitor therapy. In some embodiments, an increase in expression level of IL-10 or IFN-y is at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or higher, relative to a reference level (e.g. a reference level as described herein, such as in one embodiment a respective baseline level in a subject prior to administration of a TNF-a inhibitor therapy). In some embodiments, such a change (e.g., increase) in expression level of IL-10 or IFN-y is from about 15% to 50%, 15%to 99%, 20% to 99%, 25% to 99%, 30% to 99%, 35% to 99%, 40% to 99%, 45% to 99%, 50% to99%, 55% to 99%, 60% to 99%, 65% to 99%, 70% to 99%, 75% to 99%, 80% to 99%, 85% to 99%, 90% to 99%, 95% to 99%, or higher, relative to a reference level (e.g. a reference level as described herein, such as in one embodiment a respective baseline level in a subject prior to administration of a TNF-a inhibitor therapy).

[0485] In some embodiments, an increase in expression level of IL-10 or IFN-y is at least 1.1- fold, at least 1.5-fold, at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 6--103-Attorney Docket No. 768830: SA9-910PC fold, at least 7-fold, at least 8-fold, at least 9-fold, or at least 10-fold, relative to a reference level (e.g. a reference level as described herein, such as in one embodiment a respective baseline level in a subject prior to administration of a TNF-a inhibitor therapy). In some embodiments, an increase in expression level of IL-10 or IFN-y is 1.1-fold to 10 fold, 1.5-fold to 10-fold, 2-fold to 10-fold, 3-fold to 10-fold, 4-fold to 10-fold, 5-fold to 10-fold, 6-fold to 10-fold, 7-fold to 10-fold, 8-fold to 10-fold, 9-fold to 10-fold, relative to a reference level (e.g. a reference level as described herein, such as in one embodiment a respective baseline level in a subject prior to administration of a TNF-a inhibitor therapy).

[0486] In some embodiments is described a use of one or more agents for determining expression level of at least one biomarker (including, e.g., at least two, at least three, at least four, at least five, at least six, or at least seven biomarkers comprising CCL20, CCL4, CXCL10, CXCL9, EN-RAGE, OSM, IL-10, or any combinations thereof, in the manufacture of a kit for use in the any aspects of the methods described herein, for example, in some embodiments, for determining or monitoring the efficacy of a TNF-a inhibitor therapy in a subject having rheumatoid arthritis, or for determining or monitoring responsiveness of a subject to a TNF-a inhibitor therapy. In some embodiments, such a kit can further comprises one or more agents for determining expression level of a biomarker IFN-y. In some embodiments, when such one or more agents detects a change in expression level of at least one biomarker (as described herein) in a sample from a subject receiving a TNF-a inhibitor therapy, from a reference level, the change in the expression level determines the likelihood of responsiveness of the subject to the TNF-a inhibitor therapy in accordance with certain aspects of the methods or kits described herein.

[0487] In some embodiments of various kits described herein, primers and primer pairs can be included, which allow the specific amplification of the polynucleotides of at least one biomarker or of any specific parts thereof, and probes that selectively or specifically hybridize to nucleic acid molecules described herein or to any part thereof. Probes may be labeled with a detectable marker, such as, for example, a radioisotope, fluorescent compound, bioluminescent compound, a chemiluminescent compound, metal chelator or enzyme. Such probes and primers can be used to detect the presence of polynucleotides, such as the polynucleotides (e.g., mRNAs) that encodes proteins listed in Tables 1-2, in a sample and as a means for detecting cell expressing proteins encoded by the polynucleotides. As will be-104-Attorney Docket No. 768830: SA9-910PC understood by the skilled artisan, a great many different primers and probes may be prepared based on the sequences provided herein and used effectively to amplify, clone and / or determine the presence and / or levels of mRNAs. In some embodiments, the kits may further comprise a surface or substrate (such as a microarray) for capture probes for detecting of amplified nucleic acids. In some embodiments, the kits comprise at least one pair of primers and a probe specific for detecting at least one biomarker gene expression level using qRT-PCR. In some embodiments, the kits comprise at least one reagent for detecting at least one biomarker gene expression using RNA sequencing. In some embodiments, the kits comprise an oligonucleotide barcode tagged with an antibody agent that is specific for detecting at least one biomarker described herein. In some embodiments, the kits comprise in situ hybridization probes that are specific for detecting at least one biomarker described herein. In some embodiments, the kits comprise (i) a capture probe comprising a first oligonucleotide and a target capture agent (e.g., in some embodiments an antibody agent) that is specific for detecting at least one biomarker described herein and (ii) and a reporter probe comprising a reporter agent (e.g., in some embodiments a fluorescent barcode) and a second oligonucleotide that is capable of hybridizing with the first oligonucleotide.

[0488] In some embodiments, the reagents for detecting the protein expression level of a biomarker may include an antibody agent that specifically binds to the protein encoded by the biomarker.

[0489] In some embodiments, the kits further include a rheumatoid arthritis therapy (e.g., an anti- IL6R antibody agent or an anti-TNF-a antibody agent). The kits may further include instructions for administering rheumatoid arthritis therapy if the subject is identified as responsive to the rheumatoid arthritis therapy.

[0490] The kit can further have a set of instructions and materials for preparing a tissue or cell sample and preparing nucleic acids (such as mRNA) from the sample.Systems

[0491] The present disclosure also relates to systems that may be used in accordance with the methods described herein. The system can include various components or units that help monitor the responsiveness (e.g. early responsiveness) of a subject having rheumatoid arthritis and having received a rheumatoid arthritis therapy (e.g. an IL-6 inhibitor therapy or TNF-a inhibitor therapy).-105-Attorney Docket No. 768830: SA9-910PC

[0492] In some embodiments, the system includes a computing device that includes at least memory and a processor. In some embodiments, the processor can be a general-purpose computer or a portable computing device. Multiple computing devices may be used together such as over a network or other methods of transferring data for performing the one or more steps of the methods described herein. Examples of computing devices include desktop computers, laptop computers personal data assistants (PDA), cellular devices, smart or mobile devices, tablet computers, servers and the like. In general, a processor is capable of executing a plurality of instructions such as program of a software.

[0493] In some embodiments, the processor has or can access memory. Memory is a computer readable medium and can include a single storage device or multiple storage devices located either locally with the computing device or accessible to the computing device across a network.

[0494] In some embodiments software may include program instructions which when executed by the processor of the computing device may perform one or more steps of the methods described herein.

[0495] In some embodiments, the system also includes or has access to databases. The databases store information obtained from or sent to the system. In some embodiments, the databases receive, and store information associated with samples obtained from a subject. The databases also store information about the disclosed biomarkers (such as the ones shown in Tables 1-4 and the respective reference levels.

[0496] In some embodiments the system is shown in FIG. 10, which is a block diagram of a system 1100 that is suitable for use in practicing various embodiments. In the system 1100 of FIG. 10, the server 1110 includes a controller, such as a data processor (DP) 1112 and a computer-readable medium embodied as a memory (MEM) 1114 that stores computer instructions, such as a program (PROG) 1115. Server 1110 may communicate with a client 1120, for example, via the internet 1130.

[0497] Client 1120 includes a controller, such as a data processor (DP) 1122 and a computer- readable medium embodied as a memory (MEM) 1124 that stores computer instructions, such as a program (PROG) 1125. Server 1110 and / or client 1120 may also include a dedicated processor, for example a matrix processor 1113, 1123. Both server 1110 and / or client 1120 may communicate with a remote data processor 1148, for example, via the internet 1130 (as-106-Attorney Docket No. 768830: SA9-910PC shown), and / or via direct communications channels (such as a wireless connection or a physical connection).

[0498] Databases 1142, 1144, 1146 may be connected directly to the server 1110, the client 1144 or the internet 1130. As shown, database 1142 stores the subject’s data 1150, topology overlap matrices 1152 and Bayesian networks 1154; however, this information may be stored separately (or together) in any of the databases 1142, 1144, 1146.

[0499] The programs 1115, 1125 may include program instructions that, when executed by the DP 1112, 1122, enable the server 1110 and / or client 1120 to operate in accordance with an embodiment. That is, various embodiments may be carried out at least in part by computer software executable by the DP 1112 of the server 1110, the DP 1122 of the client 1120, by hardware, or by a combination of software and hardware.

[0500] In general, various embodiments of the server 1110 and / or client 1120 may include tablets and computers, as well as other devices that incorporate combinations of such functions.

[0501] The MEM 1114, 1124 and databases 1142, 1144, 1146 may be of any type suitable to the local technical environment and may be implemented using any suitable data storage technology, such as magnetic memory devices, semiconductor-based memory devices, flash memory, optical memory devices, fixed memory and removable memory. The DP 1112, 1122 may be of any type suitable to the local technical environment, and may include general purpose computers, special purpose computers, microprocessors and multicore processors, as non-limiting examples.

[0502] In some embodiments the system is for assessing or monitoring responsiveness to or determining continuation of an IL-6 inhibitor therapy in a subject having rheumatoid arthritis and receiving an inhibitor therapy, the system comprising at least one database that receives and stores the expression levels of at least one biomarker comprising AZU1, MMP9, MMP1, OSM, TNFSF14, Ep-CAM, CCL4, LDL-receptor, Ftl3L, or any combinations thereof, the expression levels determined from a biological sample from a subject having rheumatoid arthritis and receiving an IL-6 inhibitor therapy; and a computing device comprising at least memory and a processor, wherein the memory is for storing program instructions and the processor is configured to execute the program instructions that when executed perform operations comprising determining a change in expression level of at least one biomarker compared to a reference level, and generating instructions:-107-Attorney Docket No. 768830: SA9-910PC(i) to continue the IL-6 inhibitor therapy if:(a) the expression level of at least one biomarker comprising Ep-CAM, CCL4, LDL- receptor, Flt3L, or any combinations thereof is increased relative to its respective reference level; or(b) the expression level of at least one biomarker comprising AZU1, MMP9, MMP1, OSM, TNFSF14, or any combinations thereof is reduced relative to its respective reference level; or(c) both (a) and (b); or(ii) to discontinue the IL-6 inhibitor therapy and optionally select a different rheumatoid arthritis therapy if:(d) the expression level of at least one biomarker Ep-CAM, CCL4, LDL-receptor, Flt3L, or any combinations thereof is reduced or is not substantially changed, relative to its respective reference level; or(e) the expression level of at least one biomarker comprising AZU1, MMP9, MMP1, OSM, TNFSF14, or any combinations thereof is increased or is not substantially changed, relative to its respective reference level; or(f) both (d) and (e).

[0503] In some embodiments, the system is for determining or monitoring responsiveness to or determining continuation of a TNF-a inhibitor therapy in a subject having rheumatoid arthritis and receiving an inhibitor therapy, the system comprising at least one database that receives and stores the expression levels of at least one biomarker comprising CCL20, CCL4, CXCL10, CXCL9, EN-RAGE, OSM, IL-10, or any combinations thereof; the expression levels determined from a biological sample from a subject having rheumatoid arthritis and receiving a TNF-a inhibitor therapy; and a computing device comprising at least memory and a processor, wherein the memory is for storing program instructions and the processor is configured to execute the program instructions that when executed perform operations comprising: determining a change in expression level of at least one biomarker compared to a reference level, and generating instructions:(i) to continue the TNF-a inhibitor therapy if:-108-Attorney Docket No. 768830: SA9-910PC(a) the expression level of at least one biomarker comprising CCL20, CCL4, CXCL10, CXCL9,EN-RAGE, OSM, or any combinations thereof is reduced relative to its respective reference level; or(b) the expression level of at least one biomarker comprising IL-10 is increased relative to its respective reference level; or(c) both (a) and (b); or(ii) to discontinue the TNF-a inhibitor therapy and optionally select a different rheumatoid arthritis therapy if:(d) the expression level of at least one biomarker CCL20, CCL4, CXCL10, CXCL9, EN-RAGE, OSM, or any combinations thereof is increased or is not substantially changed, relative to its respective reference level; or(e) the expression level of at least one biomarker comprising IL-10 is reduced or is not substantially changed, relative to its respective reference level; or both (d) and (e). In some embodiments, the at least one database further receives and stores the expression level of a biomarker IFN-y.

[0504] The present disclosure is further exemplified in the following non-limiting embodiments:1. A method of assessing or monitoring early responsiveness of a subject having rheumatoid arthritis to an interleukin-6 inhibitor therapy, the method comprising: determining, in a sample from a subject having rheumatoid arthritis and receiving an IL-6 inhibitor therapy, a change in expression level from a reference level of at least one biomarker comprising azurocidin (AZU1), matrix metalloproteinase-9 (MMP-9), matrix metalloproteinase- 1 (MMP-1), oncostatin-M (OSM), tumor necrosis factor ligand superfamily 14 (TNFSF14), epithelial cell adhesion molecule (Ep-CAM), C-C motif chemokine 4 (CCL4), low-density lipoprotein receptors (LDL-receptor), fms-related tyrosine kinase 3 ligand (Flt3L), or any combinations thereof; wherein the change in expression level from the reference level of the at least one biomarker is an indication of the likelihood of early responsiveness to the IL-6 inhibitor therapy.2. A method of treating rheumatoid arthritis, the method comprising:-109-Attorney Docket No. 768830: SA9-910PC determining, in a sample of a subject having rheumatoid arthritis and receiving an IL-6 inhibitor therapy, a change in expression level from a reference level, of at least one biomarker comprising Ep-CAM, CCL4, LDL-receptor, Flt3L, or any combinations thereof; and continuing the IL-6 inhibitor therapy if the expression level of the at least one biomarker is increased relative to the reference level; or stopping the IL-6 inhibitor therapy and optionally selecting a different rheumatoid arthritis therapy if the expression level of the at least one biomarker is reduced or is not substantially changed, relative to the reference level.3. A method of treating rheumatoid arthritis, the method comprising: determining, in a sample of a subject having rheumatoid arthritis and receiving an IL-6 inhibitor therapy, a change in expression level from a reference level, of at least one biomarker comprising AZU1, MMP9, MMP1, OSM, TNFSF14, or any combinations thereof; and continuing the IL-6 inhibitor therapy if the expression level of the at least one biomarker is reduced relative to the reference level; or stopping the IL-6 inhibitor therapy and optionally selecting a different rheumatoid arthritis therapy if the expression level of the at least one biomarker is increased or is not substantially changed relative to the reference level.4. A method of treating rheumatoid arthritis, the method comprising: selecting a subject who is having rheumatoid arthritis and receiving an IL-6 inhibitor therapy and who is determined to show a change in expression level from a reference level, of at least one biomarker comprising Ep-CAM, CCL4, LDL-receptor, Flt3L, or any combinations thereof; and continuing the IL-6 inhibitor therapy if the expression level of the at least one biomarker is increased relative to the reference level; or stopping the IL-6 inhibitor therapy and optionally selecting a different rheumatoid arthritis therapy if the expression level of the at least one biomarker is reduced or is not substantially changed, relative to the reference level.5. A method of treating rheumatoid arthritis, the method comprising: selecting a subject who is having rheumatoid arthritis and receiving an IL-6 inhibitor therapy and who is determined to show a change in expression level from a reference level, of-110-Attorney Docket No. 768830: SA9-910PC at least one biomarker comprising AZU1, MMP9, MMP1, OSM, TNFSF14, or any combinations thereof; and continuing the IL-6 inhibitor therapy if the expression level of the at least one biomarker is reduced relative to the reference level; or stopping the IL-6 inhibitor therapy and optionally selecting a different rheumatoid arthritis therapy if the expression level of the at least one biomarker is increased or is not substantially changed relative to the reference level.6. A method of treating rheumatoid arthritis, the method comprising: determining, in a sample of a subject having rheumatoid arthritis and receiving an IL-6 inhibitor therapy, a change in expression level from a reference level, of at least one biomarker comprising AZU1, MMP9, MMP1, OSM, TNFSF14, Ep-CAM, CCL4, LDL-receptor, Flt3L, or any combinations thereof; and continuing the IL-6 inhibitor therapy if:(a) the expression level of at least one biomarker comprising Ep-CAM, CCL4, LDL- receptor, Flt3L, or any combinations thereof is increased relative to its respective reference level; or(b) the expression level of at least one biomarker comprising AZU1, MMP9, MMP1, OSM, TNFSF14, or any combinations thereof is reduced relative to its respective reference level; or(c) both (a) and (b); or stopping the IL-6 inhibitor therapy and optionally selecting a different rheumatoid arthritis therapy if:(d) the expression level of at least one biomarker Ep-CAM, CCL4, LDL-receptor, Flt3L, or any combinations thereof is reduced or is not substantially changed, relative to its respective reference level; or(e) the expression level of at least one biomarker comprising AZU1, MMP9, MMP1, OSM, TNFSF14, or any combinations thereof is increased or is not substantially changed, relative to its respective reference level; or(f) both (d) and (e).7. A method of treating rheumatoid arthritis, the method comprising:-I l l-Attorney Docket No. 768830: SA9-910PC modifying or continuing a rheumatoid arthritis treatment for a subject having rheumatoid arthritis and receiving an IL-6 inhibitor therapy, at least in part on the basis of a change in expression level from a reference level in a sample from the subject, of at least one biomarker comprising Ep-CAM, CCL4, LDL-receptor, Flt3L, or any combinations thereof, wherein:- if the expression level of the at least one biomarker is increased relative to the reference level, administration of the IL-6 inhibitor therapy to the subject is continued; or- if the expression level of the at least one biomarker is reduced or is not substantially changed relative to the reference level, administration of the IL-6 inhibitor therapy to the subject is stopped and optionally a different rheumatoid arthritis therapy is selected for the subject.8. A method of treating rheumatoid arthritis, the method comprising: modifying or continuing a rheumatoid arthritis treatment for a subject having rheumatoid arthritis and receiving an IL-6 inhibitor therapy, at least in part on the basis of a change in expression level from a reference level in a sample from the subject, of at least one biomarker comprising AZU1, MMP9, MMP1, OSM, TNFSF14, or any combinations thereof, wherein:- if the expression level of the at least one biomarker is decreased relative to the reference level, administration of the IL-6 inhibitor therapy to the subject is continued; or- if the expression level of the at least one biomarker is increased or is not substantially changed relative to the reference level, administration of the IL-6 inhibitor therapy to the subject is stopped and optionally a different rheumatoid arthritis therapy is selected for the subject.9. A method of treating rheumatoid arthritis, the method comprising: if a sample of a subject, who has rheumatoid arthritis and is receiving an IL-6 inhibitor therapy, is determined to have an increased expression level of at least one biomarker comprising Ep-CAM, CCL4, LDL-receptor, Flt3L, or any combinations thereof, as compared to a reference level, continuing administration of the IL-6 inhibitor therapy to the subject; or if a sample of a subject, who has rheumatoid arthritis and is receiving an IL-6 inhibitor therapy, is determined to have a reduced or substantially the same expression level of at least one biomarker comprising Ep-CAM, CCL4, LDL-receptor, Flt3L, or any combinations thereof as compared to a reference level, stopping administration of the IL-6 inhibitor therapy to the subject and optionally selecting a different rheumatoid arthritis therapy.10. A method of treating rheumatoid arthritis, the method comprising:-112-Attorney Docket No. 768830: SA9-910PC if a sample of a subject, who has rheumatoid arthritis and is receiving an IL-6 inhibitor therapy, is determined to have a reduced expression level of at least one biomarker comprising AZU1, MMP9, MMP1, OSM, TNFSF14, or any combinations thereof, as compared to a reference level, continuing administration of the IL-6 inhibitor therapy to the subject; or if a sample of a subject, who has rheumatoid arthritis and is receiving an IL-6 inhibitor therapy, is determined to have an increased or substantially the same expression level of at least one biomarker comprising AZU1, MMP9, MMP1, OSM, TNFSF14, or any combinations thereof, as compared to a reference level, stopping administration of the IL-6 inhibitor therapy to the subject and optionally selecting a different rheumatoid arthritis therapy.11. The method of any one of embodiments 1-10, wherein the IL-6 inhibitor therapy comprises an IL-6 receptor (IL-6R) inhibitor.12. The method of embodiment 11, wherein the IL-6R inhibitor comprises an anti-IL-6R antibody agent.13. The method of embodiment 12, wherein the anti-IL-6R antibody agent comprises three heavy chain complementarity determining regions (CDRs) corresponding to the CDRs of a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 1, and three light chain complementarity determining regions (CDRs) corresponding to the CDRs of a light chain variable region comprising the amino acid sequence of SEQ ID NO: 2.14. The method of embodiment 12, wherein the anti-IL-6R antibody agent comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 1, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 2.15. The method of embodiment 12, wherein the anti-IL-6R antibody agent comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 9, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 10.16. The method of embodiment 12, wherein the anti-IL-6R antibody agent comprises or is sarilumab or an antigen binding fragment thereof.17. The method of any one of embodiments 13-16, wherein the anti-IL-6R antibody agent is administered to the subject: at a dose of about 100 mg every two weeks to about 200 mg every two weeks, at a dose of about 150 mg every two weeks to about 200 mg every two weeks, at a dose of about 150 mg every two weeks, or at a dose of about 200 mg every two weeks.-113-Attorney Docket No. 768830: SA9-910PC18. The method of any one of embodiments 1-17, further comprising determining, in a second sample from the subject who is determined to continue to receive the IL-6 inhibitor therapy, a second change in expression level from a second reference level of at least one biomarker comprising AZU1, MMP9, MMP1, OSM, TNFSF14, Ep-CAM, CCL4, LDL-receptor, Flt3L, or combinations thereof, wherein the second change in expression level is measured after the subject is determined to continue to receive the IL-6 inhibitor therapy.19. The method of embodiment 18, wherein the at least one biomarker used for determining the second change in expression level is the same as the at least one biomarker used for determining a first change in expression level.20. The method of embodiment 18, wherein the at least one biomarker used for determining the second change in expression level is different from the at least one biomarker used for determining a first change in expression level.21. The method of any one of embodiments 1-20, wherein the reference level or a first reference level is expression level of the at least one biomarker in a sample from the subject prior to receiving the IL-6 inhibitor therapy.22. The method of any one of embodiments 18-21, wherein the second reference level is the same as the first reference level.23. The method of any one of embodiments 18-21 , wherein the second reference level is different from a first reference level.24. A method of assessing or monitoring early responsiveness of a subject having rheumatoid arthritis to a tumor necrosis factor- a (TNF-a) inhibitor therapy, the method comprising: determining, in a sample from a subject having rheumatoid arthritis and receiving a TNF- a inhibitor therapy, a change in expression level from a reference level of at least one biomarker comprising C-C motif chemokine 20 (CCL20), C-C motif chemokine 4 (CCL4), C-X-C motif chemokine 10 (CXCL10), C-X-C motif chemokine 9 (CXCL9), protein S100-A12 (ENRAGE), oncostatin-M (OSM), interleukin- 10 (IL-10), or any combinations thereof, wherein the change in expression level from the reference level of the at least one biomarker is an indication of the likelihood of early responsiveness to the TNF-a inhibitor therapy.25. A method of treating rheumatoid arthritis, the method comprising:-114-Attorney Docket No. 768830: SA9-910PC determining, in a sample of a subject having rheumatoid arthritis and receiving a TNF-a inhibitor therapy, a change in expression level from a reference level, of at least one biomarker comprising CCL20, CCL4, CXCL10, CXCL9, EN-RAGE, OSM, or any combinations thereof; and continuing the TNF-a inhibitor therapy if the expression level of the at least one biomarker is reduced relative to the reference level; or stopping the TNF-a inhibitor therapy and optionally selecting a different rheumatoid arthritis therapy if the expression level of the at least one biomarker is increased or is not substantially changed relative to the reference level.26. A method of treating rheumatoid arthritis, the method comprising: determining, in a sample of a subject having rheumatoid arthritis and receiving a TNF-a inhibitor therapy, a change in expression level from a reference level, of at least one biomarker comprising IL-10; and continuing the TNF-a inhibitor therapy if the expression level of the at least one biomarker is increased; or stopping the TNF-a inhibitor therapy and optionally selecting a different rheumatoid arthritis therapy if the expression level of the at least one biomarker is reduced or is not substantially changed.27. A method of treating rheumatoid arthritis, the method comprising: selecting a subject who is having rheumatoid arthritis and receiving a TNF-a inhibitor therapy and who is determined to show a change in expression level from a reference level, of at least one biomarker comprising CCL20, CCL4, CXCL10, CXCL9, EN-RAGE, OSM, or any combinations thereof; and continuing the TNF-a inhibitor therapy if the expression level of the at least one biomarker is reduced relative to the reference level; or stopping the TNF-a inhibitor therapy and optionally selecting a different rheumatoid arthritis therapy if the expression level of the at least one biomarker is increased or is not substantially changed relative to the reference level.28. A method of treating rheumatoid arthritis, the method comprising:-115-Attorney Docket No. 768830: SA9-910PC selecting a subject who is having rheumatoid arthritis and receiving a TNF-a inhibitor therapy and who is determined to show a change in expression level from a reference level, of at least one biomarker comprising IL-10; and continuing the TNF-a inhibitor therapy if the expression level of the at least one biomarker is increased; or stopping the TNF-a inhibitor therapy and optionally selecting a different rheumatoid arthritis therapy if the expression level of the at least one biomarker is reduced or is not substantially changed.29. A method of treating rheumatoid arthritis, the method comprising: determining, in a sample of a subject having rheumatoid arthritis and receiving a TNF-a inhibitor therapy, a change in expression level from a reference level, of at least one biomarker comprising CCL20, CCL4, CXCL10, CXCL9, EN-RAGE, OSM, IL-10, or any combinations thereof; and continuing the TNF-a inhibitor therapy if:(a) the expression level of at least one biomarker comprising CCL20, CCL4, CXCL10, CXCL9, EN-RAGE, OSM, or any combinations thereof is reduced relative to its respective reference level; or(b) the expression level of at least one biomarker comprising IL-10 is increased relative to its respective reference level; or(c) both (a) and (b); or stopping the TNF-a inhibitor therapy and optionally selecting a different rheumatoid arthritis therapy if:(g) the expression level of at least one biomarker CCL20, CCL4, CXCL10, CXCL9, EN-RAGE, OSM, or any combinations thereof is increased or is not substantially changed, relative to its respective reference level; or(h) the expression level of at least one biomarker comprising IL-10 is reduced or is not substantially changed, relative to its respective reference level; or(i) both (d) and (e).30. A method of treating rheumatoid arthritis, the method comprising: modifying or continuing a rheumatoid arthritis treatment for a subject having rheumatoid arthritis and receiving a TNF-a inhibitor therapy, at least in part on the basis of a change in-116-Attorney Docket No. 768830: SA9-910PC expression level from a reference level in a sample from the subject, of at least one biomarker comprising CCL20, CCL4, CXCL10, CXCL9, EN-RAGE, OSM, or any combinations thereof, wherein:- if the expression level of the at least one biomarker is reduced relative to the reference level, administration of the TNF-a inhibitor therapy to the subject is continued; or- if the expression level of the at least one biomarker is increased or is not substantially changed relative to the reference level, administration of the TNF-a inhibitor therapy to the subject is stopped and optionally a different rheumatoid arthritis therapy is selected for the subject.31. A method of treating rheumatoid arthritis, the method comprising: modifying or continuing a rheumatoid arthritis treatment for a subject having rheumatoid arthritis and receiving a TNF-a inhibitor therapy, at least in part on the basis of a change in expression level from a reference level in a sample from the subject, of at least one biomarker comprising IL- 10, wherein:- if the expression level of the at least one biomarker is increased relative to the reference level, administration of the TNF-a inhibitor therapy to the subject is continued; or- if the expression level of the at least one biomarker is reduced or is not substantially changed relative to the reference level, administration of the TNF-a inhibitor therapy to the subject is stopped and optionally a different rheumatoid arthritis therapy is selected for the subject.32. A method of treating rheumatoid arthritis, the method comprising: if a sample of a subject, who has rheumatoid arthritis and is receiving a TNF-a inhibitor therapy, is determined to have a reduced expression level of at least one biomarker comprising CCL20, CCL4, CXCL10, CXCL9, EN-RAGE, OSM, or any combinations thereof, as compared to a reference level, continuing administration of the IL-6 inhibitor therapy to the subject; or if a sample of a subject, who has rheumatoid arthritis and is receiving an TNF-a inhibitor therapy, is determined to have an increased or substantially the same expression level of at least one biomarker comprising CCL20, CCL4, CXCL10, CXCL9, EN-RAGE, OSM, or any combinations thereof, as compared to a reference level, stopping administration of the TNF-a inhibitor therapy to the subject and optionally selecting a different rheumatoid arthritis therapy.33. A method of treating rheumatoid arthritis, the method comprising: if a sample of a subject, who has rheumatoid arthritis and is receiving a TNF-a inhibitor therapy, is determined to have an increased expression level of at least one biomarker comprising-117-Attorney Docket No. 768830: SA9-910PCIL-10, as compared to a reference level, continuing administration of the TNF-a inhibitor therapy to the subject; or if a sample of a subject, who has rheumatoid arthritis and is receiving an TNF-a inhibitor therapy, is determined to have a reduced or substantially the same expression level of at least one biomarker comprising IL-10, as compared to a reference level, stopping administration of the TNF- a inhibitor therapy to the subject and optionally selecting a different rheumatoid arthritis therapy.34. The method of any one of embodiments 24-33, wherein the at least one biomarker further comprises a biomarker IFN-y.35. The method of any one of embodiments 24-34, wherein the TNF-a inhibitor therapy comprises an anti-TNF-a antibody agent.36. The method of embodiment 35, wherein the anti-TNF-a antibody agent comprises or is adalimumab or an antigen-binding fragment thereof.37. The method of embodiment 36, wherein the adalimumab or an antigen-binding fragment thereof is administered to the subject at a dose of about 40 mg every two weeks.38. The method of any one of embodiments 24-34, wherein the TNF- a inhibitor therapy comprises a small molecule TNF- a inhibitor.39. The method of any one of embodiments 24-34, wherein the TNF-a inhibitor therapy comprises a TNFR1 signaling inhibitor.40. The method of any one of embodiments 24-39, further comprising determining, in a second sample from the subject who is determined to continue to receive the TNF- a inhibitor therapy, a second change in expression level from a second reference level of at least one biomarker comprising CCL20, CCL4, CXCL10, CXCL9, EN-RAGE, OSM IL-10, or any combinations thereof, wherein the second change in expression level is measured after the subject is determined to continue to receive the TNF- a inhibitor therapy.41. The method of embodiment 40, wherein the at least one biomarker used for determining the second change in expression level is the same as the at least one biomarker used for determining a first change in expression level.42. The method of embodiment 40, wherein the at least one biomarker used for determining the second change in expression level is different from the at least one biomarker used for determining a first change in expression level.-118-Attorney Docket No. 768830: SA9-910PC43. The method of any one of embodiments 24-42, wherein the reference level or a first reference level is expression level of the at least one biomarker in a sample from the subject prior to receiving the TNF- a inhibitor therapy.44. The method of any one of embodiments 40-43, wherein the second reference level is the same as the first reference level.45. The method of any one of embodiments 40-43, wherein the second reference level is different from a first reference level.46. The method of any one of embodiments 1-45, wherein the determining comprises measuring the expression level of the at least one biomarker and comparing the measured expression level with the respective reference level.47. The method of any one of embodiments 1-46, wherein the sample comprises a serum or blood sample.48. The method of any one of embodiments 1-47, wherein the sample is from the subject after receiving the therapy (the IL-6 inhibitor therapy or the TNF- a inhibitor therapy) for about two weeks to about twelve weeks.49. The method of any one of embodiments 1-48, wherein the change in expression level is an mRNA expression level.50. The method of any one of embodiments 1-48, wherein the change in expression level is a protein expression level.51. The method of any one of embodiments 1-50, wherein the subject was previously administered at least one disease modifying antirheumatic drug (DMARD) other than the IL-6 inhibitor therapy or the TNF- a inhibitor therapy, which is being received by the subject.52. The method of embodiment 51, wherein the subject had an inadequate response to or did not tolerate the at least one DMARD.53. The method of embodiment 51 or 52 wherein the at least one DMARD comprises a synthetic DMARD, optionally wherein the synthetic DMARD is or comprises methotrexate (MTX).54. A kit for assessing or monitoring early responsiveness to or determining continuation of an IL-6 inhibitor therapy in a subject having rheumatoid arthritis, the kit comprising at least one agent for detecting in a biological sample from a subject having rheumatoid arthritis and receiving an IL-6 inhibitor therapy expression level of at least one biomarker comprising AZU1, MMP9, MMP1, OSM, TNFSF14, Ep-CAM, CCL4, LDL-receptor, Ftl3L, or any combinations thereof.-119-Attorney Docket No. 768830: SA9-910PC55. The kit of embodiment 54, further comprising an instruction providing that a decrease in expression level from a reference level of at least one biomarker comprising AZU1, MMP9, MMP1, OSM, TNFSF14, or any combinations thereof indicates (i) an increased likelihood of responsiveness to the IL-6 inhibitor therapy, (ii) a recommended continuation of the IL-6 inhibitor therapy, or (iii) both (i) and (ii).56. The kit of embodiment 54 or 55, further comprising an instruction providing that an increase in expression level from a reference level of at least one biomarker comprising Ep-CAM, CCL4, LDL-receptor, Ftl3L, or any combinations thereof indicates (i) an increased likelihood of responsiveness to the IL-6 inhibitor therapy, (ii) a recommended continuation of the IL-6 inhibitor therapy, or (iii) both (i) and (ii).57. The kit of embodiment 55 or 56, wherein the reference level is expression level of the at least one biomarker in a biological sample from the subject prior to receiving the IL-6 inhibitor therapy.58. A kit for assessing or monitoring early responsiveness to or determining continuation of an TNF-a inhibitor therapy in a subject having rheumatoid arthritis, the kit comprising at least one agent for detecting in a biological sample from a subject having rheumatoid arthritis and receiving an TNF-a inhibitor therapy expression level of at least one biomarker comprising CCL20, CCL4, CXCL10, CXCL9, EN-RAGE, OSM, IL-10, or any combinations thereof.59. The kit of embodiment 58, further comprising an instruction providing that an increase in expression level from a reference level of at least one biomarker comprising IL- 10 indicates (i) an increased likelihood of responsiveness to the TNF-a inhibitor therapy, (ii) a recommended continuation of the TNF-a inhibitor therapy, or (iii) both (i) and (ii).60. The kit of embodiment 58 or 59, further comprising an instruction providing that a decrease in expression level from a reference level of at least one biomarker comprising CCL20, CCL4, CXCL10, CXCL9, EN-RAGE, OSM, or any combinations thereof indicates (i) an increased likelihood of responsiveness to the TNF-a inhibitor therapy, (ii) a recommended continuation of the TNF-a inhibitor therapy, or (iii) both (i) and (ii).61. The kit of any one of embodiments 54-60, further comprising at least one agent for detecting in a biological sample from a subject having rheumatoid arthritis and receiving an TNF-a inhibitor therapy expression level of a biomarker IFN-y.62. The kit of embodiment 61, further comprising an instruction providing that an increase in expression level from a reference level of the biomarker IFN-y indicates (i) an increased likelihood-120-Attorney Docket No. 768830: SA9-910PC of responsiveness to the TNF-a inhibitor therapy, (ii) a recommended continuation of the TNF-a inhibitor therapy, or (iii) both (i) and (ii).63. The kit of any one of embodiments 58-62, wherein the reference level is expression level of the at least one biomarker in a biological sample from the subject prior to receiving the TNF-a inhibitor therapy.64. The kit of any one of embodiments 54-63, wherein the biological sample comprises a serum or blood sample.65. The kit of any one of embodiments 54-64, wherein the biological sample is from the subject after receiving the therapy for about two weeks to about twelve weeks.66. The kit of any one of embodiments 54-65, wherein the expression level is an mRNA expression level.67. The kit of any one of embodiments 54-65, wherein the expression level is a protein expression level.68. A system for assessing or monitoring early responsiveness to or determining continuation of an IL-6 inhibitor therapy in a subject having rheumatoid arthritis and receiving the IL-6 inhibitor therapy, the system comprising: at least one database that receives and stores expression levels of at least one biomarker comprising AZU1, MMP9, MMP1, OSM, TNFSF14, Ep-CAM, CCL4, LDL-receptor, Ftl3L, or any combinations thereof, the expression levels determined from a biological sample from a subject having rheumatoid arthritis and receiving an IL-6 inhibitor therapy; and a computing device comprising at least memory and a processor, wherein the memory is for storing program instructions and the processor is configured to execute the program instructions that when executed perform operations comprising: determining a change in expression level of the at least one biomarker compared to a reference level, and generating instructions:(i) to continue the IL-6 inhibitor therapy if:(a) expression level of at least one biomarker comprising Ep-CAM, CCL4, LDL-receptor, or Flt3L is increased relative to its respective reference level; or-121-Attorney Docket No. 768830: SA9-910PC(b) expression level of at least one biomarker comprising AZU1, MMP9, MMP1, OSM, TNFSF14, or any combinations thereof is reduced relative to its respective reference level; or(c) both (a) and (b); or(ii) to stop the IL-6 inhibitor therapy and optionally to select or identify a different rheumatoid arthritis therapy if:(d) expression level of at least one biomarker comprising Ep-CAM, CCL4, LDL-receptor, Flt3L, or any combinations thereof is reduced or is not substantially changed, relative to its respective reference level; or(e) expression level of at least one biomarker comprising AZU1, MMP9, MMP1, OSM, TNFSF14, or any combinations thereof is increased or is not substantially changed, relative to its respective reference level; or(f) both (d) and (e).69. The system of embodiment 68, wherein the reference level is expression level of the at least one biomarker in a biological sample from the subject prior to receiving the IL-6 inhibitor therapy.70. A system for assessing or monitoring early responsiveness to or determining continuation of a TNF-a inhibitor therapy in a subject having rheumatoid arthritis and receiving the TNF-a inhibitor therapy, the system comprising: at least one database that receives and stores expression levels of at least one biomarker comprising CCL20, CCL4, CXCL10, CXCL9, EN-RAGE, OSM, IL-10, or any combinations thereof; the expression levels determined from a biological sample from a subject having rheumatoid arthritis and receiving a TNF-a inhibitor therapy; and a computing device comprising at least memory and a processor, wherein the memory is for storing program instructions and the processor is configured to execute the program instructions that when executed perform operations comprising: determining a change in expression level of the at least one biomarker compared to a reference level, and generating instructions:(i) to continue the TNF-a inhibitor therapy if:-122-Attorney Docket No. 768830: SA9-910PC(a) expression level of at least one biomarker comprising CCL20, CCL4, CXCL10, CXCL9, EN-RAGE, OSM, or any combinations thereof is reduced relative to its respective reference level; or(b) expression level of at least one biomarker comprising IL- 10 is increased relative to its respective reference level; or(c) both (a) and (b); or(ii) to stop the TNF-a inhibitor therapy and optionally to select or identify a different rheumatoid arthritis therapy if:(g) expression level of at least one biomarker CCL20, CCL4, CXCL10, CXCL9, EN-RAGE, OSM, or any combinations thereof is increased or is not substantially changed, relative to its respective reference level; or(h) expression level of at least one biomarker comprising IL-10 is reduced or is not substantially changed, relative to its respective reference level; or(i) both (d) and (e).71. The system of embodiment 70, wherein the reference level is expression level of the at least one biomarker in a biological sample from the subject prior to receiving the TNF-a inhibitor therapy.72. The system of embodiment 70 or 71, wherein the at least one database further receives and stores expression level of a biomarker IFN-y.73. The system of any one of embodiments 68-72, wherein the at least one database further receives and stores respective reference level(s) of the at least one biomarker.74. The system of any one of embodiments 68-73, wherein the biological sample comprises a serum or blood sample.75. The system of any one of embodiments 68-74, wherein the biological sample is from the subject after receiving the therapy for about two weeks to about twelve weeks.76. The system of any one of embodiments 68-75, wherein the expression level is an mRNA expression level.77. The system of any one of embodiments 68-75, wherein the expression level is a protein expression level.-123-Attorney Docket No. 768830: SA9-910PC78. A method for treating rheumatoid arthritis in a patient in need thereof, the method comprising: determini...

Claims

Attorney Docket No. 768830: SA9-910PCCLAIMSWhat is claimed is:

1. A method of assessing or monitoring early responsiveness of a subject having rheumatoid arthritis to an interleukin-6 inhibitor therapy, the method comprising: determining, in a sample from a subject having rheumatoid arthritis and receiving an IL-6 inhibitor therapy, a change in expression level from a reference level of at least one biomarker comprising azurocidin (AZU1), matrix metalloproteinase-9 (MMP-9), matrix metalloproteinase- 1 (MMP-1), oncostatin-M (OSM), tumor necrosis factor ligand superfamily 14 (TNFSF14), epithelial cell adhesion molecule (Ep-CAM), C-C motif chemokine 4 (CCL4), low-density lipoprotein receptors (LDL-receptor), fms-related tyrosine kinase 3 ligand (Flt3L), or any combinations thereof; wherein the change in expression level from the reference level of the at least one biomarker is an indication of the likelihood of early responsiveness to the IL-6 inhibitor therapy.

2. A method of treating rheumatoid arthritis, the method comprising: determining, in a sample of a subject having rheumatoid arthritis and receiving an IL-6 inhibitor therapy, a change in expression level from a reference level, of at least one biomarker comprising Ep-CAM, CCL4, LDL-receptor, Flt3L, or any combinations thereof; and continuing the IL-6 inhibitor therapy if the expression level of the at least one biomarker is increased relative to the reference level; or stopping the IL-6 inhibitor therapy and optionally selecting a different rheumatoid arthritis therapy if the expression level of the at least one biomarker is reduced or is not substantially changed, relative to the reference level.

3. A method of treating rheumatoid arthritis, the method comprising: determining, in a sample of a subject having rheumatoid arthritis and receiving an IL-6 inhibitor therapy, a change in expression level from a reference level, of at least one biomarker comprising AZU1, MMP9, MMP1, OSM, TNFSF14, or any combinations thereof; and-161-Attorney Docket No. 768830: SA9-910PC continuing the IL-6 inhibitor therapy if the expression level of the at least one biomarker is reduced relative to the reference level; or stopping the IL-6 inhibitor therapy and optionally selecting a different rheumatoid arthritis therapy if the expression level of the at least one biomarker is increased or is not substantially changed relative to the reference level.

4. The method of any one of claims 1-3, wherein the IL-6 inhibitor therapy comprises:(i) an IL-6 receptor (IL-6R) inhibitor;(ii) an IL-6R inhibitor that comprises an anti-IL-6R antibody agent;(iii) sarilumab or an antigen-binding fragment thereof; or(iv) sarilumab or an antigen-binding fragment thereof at a dose of about 100 mg every two weeks to about 200 mg every two weeks.

5. The method of any one of claims 1-4, further comprising determining, in a second sample from the subject who is determined to continue to receive the IL-6 inhibitor therapy, a second change in expression level from a second reference level of at least one biomarker comprising AZU1, MMP9, MMP1, OSM, TNFSF14, Ep-CAM, CCL4, LDL-receptor, Flt3L, or combinations thereof, wherein the second change in expression level is measured after the subject is determined to continue to receive the IL-6 inhibitor therapy, optionally wherein the at least one biomarker used for determining the second change in expression level is the same as the at least one biomarker used for determining a first change in expression level.

6. The method of any one of claims 1-5, wherein:(i) the reference level or a first reference level is expression level of the at least one biomarker in a sample from the subject prior to receiving the IL-6 inhibitor therapy;(ii) the second reference level is the same as the first reference level; or(iii) the second reference level is different from the first reference level.

7. A method of assessing or monitoring early responsiveness of a subject having rheumatoid arthritis to a tumor necrosis factor-(TNF-a) inhibitor therapy, the method comprising:-162-Attorney Docket No. 768830: SA9-910PC determining, in a sample from a subject having rheumatoid arthritis and receiving a TNF- a inhibitor therapy, a change in expression level from a reference level of at least one biomarker comprising C-C motif chemokine 20 (CCL20), C-C motif chemokine 4 (CCL4), C-X-C motif chemokine 10 (CXCL10), C-X-C motif chemokine 9 (CXCL9), protein S100-A12 (ENRAGE), oncostatin-M (OSM), interleukin- 10 (IL-10), or any combinations thereof, wherein the change in expression level from the reference level of the at least one biomarker is an indication of the likelihood of early responsiveness to the TNF-a inhibitor therapy.

8. A method of treating rheumatoid arthritis, the method comprising: determining, in a sample of a subject having rheumatoid arthritis and receiving a TNF-a inhibitor therapy, a change in expression level from a reference level, of at least one biomarker comprising CCL20, CCL4, CXCL10, CXCL9, EN-RAGE, OSM, or any combinations thereof; and continuing the TNF-a inhibitor therapy if the expression level of the at least one biomarker is reduced relative to the reference level; or stopping the TNF-a inhibitor therapy and optionally selecting a different rheumatoid arthritis therapy if the expression level of the at least one biomarker is increased or is not substantially changed relative to the reference level.

9. A method of treating rheumatoid arthritis, the method comprising: determining, in a sample of a subject having rheumatoid arthritis and receiving a TNF-a inhibitor therapy, a change in expression level from a reference level, of at least one biomarker comprising IL-10; and continuing the TNF-a inhibitor therapy if the expression level of the at least one biomarker is increased; or stopping the TNF-a inhibitor therapy and optionally selecting a different rheumatoid arthritis therapy if the expression level of the at least one biomarker is reduced or is not substantially changed.-163-Attorney Docket No. 768830: SA9-910PC10. The method of any one of claims 7-9, wherein the at least one biomarker further comprises a biomarker IFN-y.

11. The method of any one of claims 7-10, wherein the TNF-a inhibitor therapy comprises:(i) an anti-TNF-a antibody agent;(ii) adalimumab or an antigen-binding fragment thereof;(iii) adalimumab or an antigen-binding fragment thereof at a dose of about 40 mg every two weeks;(iv) a small molecule TNF- a inhibitor; or(v) a TNFR1 signaling inhibitor.

12. The method of any one of claims 7-11, further comprising determining, in a second sample from the subject who is determined to continue to receive the TNF- a inhibitor therapy, a second change in expression level from a second reference level of at least one biomarker comprising CCL20, CCL4, CXCL10, CXCL9, EN-RAGE, OSM IL-10, or any combinations thereof, wherein the second change in expression level is measured after the subject is determined to continue to receive the TNF- a inhibitor therapy, optionally wherein the at least one biomarker used for determining the second change in expression level is the same as the at least one biomarker used for determining a first change in expression level.

13. The method of any one of claims 7-12, wherein:(i) the reference level or a first reference level is expression level of the at least one biomarker in a sample from the subject prior to receiving the TNF- a inhibitor therapy;(ii) the second reference level is the same as the first reference level; or(iv) the second reference level is different from the first reference level.

14. The method of any one of claims 1-13, wherein:(i) the determining comprises measuring the expression level of the at least one biomarker and comparing the measured expression level with the respective reference level;(ii) the sample comprises a serum or blood sample;-164-Attorney Docket No. 768830: SA9-910PC(iii) the sample is from the subject after receiving the therapy for about two weeks to about twelve weeks;(iv) both (ii) and (iii), or(v) any combination of (i)-(iii).

15. The method of any one of claims 1-14, wherein the change in expression level is an mRNA expression level or a protein expression level.

16. The method of any one of claims 1-15, wherein:(i) the subject was previously administered at least one disease modifying antirheumatic drug (DMARD) other than the IL-6 inhibitor therapy or the TNF-a inhibitor therapy, which is being received by the subject; and / or(ii) the subject had an inadequate response to or did not tolerate the at least one DMARD, optionally wherein the at least one DMARD comprises methotrexate (MTX).

17. A kit for assessing or monitoring early responsiveness to or determining continuation of an IL-6 inhibitor therapy in a subject having rheumatoid arthritis, the kit comprising at least one agent for detecting in a biological sample from a subject having rheumatoid arthritis and receiving an IL-6 inhibitor therapy expression level of at least one biomarker comprising AZU1, MMP9, MMP1, OSM, TNFSF14, Ep-CAM, CCL4, LDL-receptor, Ftl3L, or any combinations thereof.

18. The kit of claim 17, further comprising an instruction providing that:(A) a decrease in expression level from a reference level of at least one biomarker comprising AZU1, MMP9, MMP1, OSM, TNFSF14, or any combinations thereof indicates (i) an increased likelihood of responsiveness to the IL-6 inhibitor therapy, (ii) a recommended continuation of the IL-6 inhibitor therapy, or (iii) both (i) and (ii); and / or(B) an increase in expression level from a reference level of at least one biomarker comprising Ep-CAM, CCL4, LDL-receptor, Ftl3L, or any combinations thereof indicates (i) an increased likelihood of responsiveness to the IL-6 inhibitor therapy, (ii) a recommended continuation of the IL-6 inhibitor therapy, or (iii) both (i) and (ii).-165-Attorney Docket No. 768830: SA9-910PC19. The kit of claim 17 or 18, wherein the reference level is expression level of the at least one biomarker in a biological sample from the subject prior to receiving the IL-6 inhibitor therapy.

20. A kit for assessing or monitoring early responsiveness to or determining continuation of an TNF-a inhibitor therapy in a subject having rheumatoid arthritis, the kit comprising at least one agent for detecting in a biological sample from a subject having rheumatoid arthritis and receiving an TNF-a inhibitor therapy expression level of at least one biomarker comprising CCL20, CCL4, CXCL10, CXCL9, EN-RAGE, OSM, IL-10, or any combinations thereof.

21. The kit of claim 20, further comprising an instruction providing that:(A) an increase in expression level from a reference level of at least one biomarker comprising IL-10 indicates (i) an increased likelihood of responsiveness to the TNF-a inhibitor therapy, (ii) a recommended continuation of the TNF-a inhibitor therapy, or (iii) both (i) and (ii); and / or(B) a decrease in expression level from a reference level of at least one biomarker comprising CCL20, CCL4, CXCL10, CXCL9, EN-RAGE, OSM, or any combinations thereof indicates (i) an increased likelihood of responsiveness to the TNF-a inhibitor therapy, (ii) a recommended continuation of the TNF-a inhibitor therapy, or (iii) both (i) and (ii).

22. The kit of claim 20 or 21, further comprising at least one agent for detecting in a biological sample from a subject having rheumatoid arthritis and receiving an TNF-a inhibitor therapy expression level of a biomarker IFN-y, optionally wherein the kit comprises instructions providing that an increase in expression level from a reference level of the biomarker IFN-y indicates (i) an increased likelihood of responsiveness to the TNF-a inhibitor therapy, (ii) a recommended continuation of the TNF-a inhibitor therapy, or (iii) both (i) and (ii).

23. The kit of claim 20 or 21, wherein the reference level is expression level of the at least one biomarker in a biological sample from the subject prior to receiving the TNF-a inhibitor therapy.

24. The kit of any one of claims 17-23, wherein the biological sample comprises:-166-Attorney Docket No. 768830: SA9-910PC(i) a serum or blood sample; and / or(ii) the subject after receiving the therapy for about two weeks to about twelve weeks.

25. The kit of any one of claims 17-24, wherein the expression level is an mRNA expression level or a protein expression level.

26. A system for assessing or monitoring early responsiveness to or determining continuation of an IL-6 inhibitor therapy in a subject having rheumatoid arthritis and receiving the IL-6 inhibitor therapy, the system comprising: at least one database that receives and stores expression levels of at least one biomarker comprising AZU1, MMP9, MMP1, OSM, TNFSF14, Ep-CAM, CCL4, LDL-receptor, Ftl3L, or any combinations thereof, the expression levels determined from a biological sample from a subject having rheumatoid arthritis and receiving an IL-6 inhibitor therapy; and a computing device comprising at least memory and a processor, wherein the memory is for storing program instructions and the processor is configured to execute the program instructions that when executed perform operations comprising: determining a change in expression level of the at least one biomarker compared to a reference level, and generating instructions:(i) to continue the IL-6 inhibitor therapy if:(a) expression level of at least one biomarker comprising Ep-CAM, CCL4, LDL-receptor, or Flt3L is increased relative to its respective reference level; or(b) expression level of at least one biomarker comprising AZU1, MMP9, MMP1, OSM, TNFSF14, or any combinations thereof is reduced relative to its respective reference level; or(c) both (a) and (b); or(ii) to stop the IL-6 inhibitor therapy and optionally to select or identify a different rheumatoid arthritis therapy if:-167-Attorney Docket No. 768830: SA9-910PC(d) expression level of at least one biomarker Ep-CAM, CCL4, LDL- receptor, Flt3L, or any combinations thereof is reduced or is not substantially changed, relative to its respective reference level; or(e) expression level of at least one biomarker comprising AZU1, MMP9, MMP1, OSM, TNFSF14, or any combinations thereof is increased or is not substantially changed, relative to its respective reference level; or(f) both (d) and (e).

27. The system of claim 26, wherein the reference level is expression level of the at least one biomarker in a biological sample from the subject prior to receiving the IL-6 inhibitor therapy.

28. A system for assessing or monitoring early responsiveness to or determining continuation of a TNF-a inhibitor therapy in a subject having rheumatoid arthritis and receiving the TNF-a inhibitor therapy, the system comprising: at least one database that receives and stores expression levels of at least one biomarker comprising CCL20, CCL4, CXCL10, CXCL9, EN-RAGE, OSM, IL-10, or any combinations thereof; the expression levels determined from a biological sample from a subject having rheumatoid arthritis and receiving a TNF-a inhibitor therapy; and a computing device comprising at least memory and a processor, wherein the memory is for storing program instructions and the processor is configured to execute the program instructions that when executed perform operations comprising: determining a change in expression level of the at least one biomarker compared to a reference level, and generating instructions:(i) to continue the TNF-a inhibitor therapy if:(a) expression level of at least one biomarker comprising CCL20, CCL4, CXCL10, CXCL9, EN-RAGE, OSM, or any combinations thereof is reduced relative to its respective reference level; or(b) expression level of at least one biomarker comprising IL- 10 is increased relative to its respective reference level; or(c) both (a) and (b); or-168-Attorney Docket No. 768830: SA9-910PC(ii) to stop the TNF-a inhibitor therapy and optionally to select or identify a different rheumatoid arthritis therapy if:(d) expression level of at least one biomarker CCL20, CCL4, CXCL10, CXCL9, EN-RAGE, OSM, or any combinations thereof is increased or is not substantially changed, relative to its respective reference level; or(e) expression level of at least one biomarker comprising IL-10 is reduced or is not substantially changed, relative to its respective reference level; or(f) both (d) and (e).

29. The system of claim 28, wherein:(i) the reference level is expression level of the at least one biomarker in a biological sample from the subject prior to receiving the TNF-a inhibitor therapy; and / or(ii) the at least one database further receives and stores expression level of a biomarker IFN-y.

30. The system of any one of claims 26-29, wherein the at least one database further receives and stores respective reference level(s) of the at least one biomarker.

31. The system of any one of claims 26-30, wherein (i) the biological sample comprises a serum or blood sample; and / or (ii) the subject after receiving the therapy (the IL-6 inhibitor therapy or the TNF- a inhibitor therapy) for about two weeks to about twelve weeks.

32. The system of any one of claims 26-31, wherein the expression level is an mRNA expression level or a protein expression level.-169-

Images