Compositions and methods for treating rheumatoid arthritis

Abstract

Composition and methods for treating rheumatoid arthritis are provided herein using compositions comprising anti-FcRn agents and optionally in combination with anti-TNF agents.

Description

[0001] COMPOSITIONS AND METHODS FOR TREATING RHEUMATOID ARTHRITIS

[0002] CROSS REFERNENCE TO RELATED APPLICATIONS

[0003] The present application claims priority to and the benefit of United States patent application no. 63 / 596,362, “COMPOSITIONS AND METHODS FOR TREATING RHEUMATOID ARTHRITIS,” which was filed on November 6, 2023, the disclosure of which is hereby incorporated by reference in its entirety.

[0004] SEQUENCE LISITNG

[0005] The instant application contains a Sequence Listing which is being submitted herewith electronically in XML format and is hereby incorporated by reference in its entirety. Said XML copy, created on October 31, 2024, is named 103693006077_Sequencelisting.xml and is 43 kilobytes in size.

[0006] FIELD

[0007] The present application relates to treating or reducing severity of rheumatoid arthritis in a subject.

[0008] BACKGROUND

[0009] Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disorder of unknown etiology that occurs in approximately 1% of the population (Alamanos Y, Drosos A. Epidemiology of adult rheumatoid arthritis. Autoimmunity Reviews. 2005;4(3): 130-136.2015). In all populations, RA is more prevalent among women than men and usually develops in the fourth or fifth decades of life, with 80% of the total cases occurring between the ages of 35 and 50. Joint inflammation underlies the cardinal manifestations of this disease, which include pain, stiffness, swelling, and tenderness in the joints followed by cartilage destruction, bone erosion, and subsequent deformities, resulting in impaired physical function. There may also be associated morbidity from non-articular manifestations of RA, including fever, malaise, and pulmonary, ocular, and hematologic effects. Patients with RA experience a shorter life expectancy than the general population, and the increased mortality rates in RA are associated with clinical disease activity. The embodiments provided for herein fulfil these needs as well as others.

[0010] SUMMARY

[0011] Provided herein are methods of treating or reducing severity of rheumatoid arthritis in a subject in need thereof, the method comprising administering an anti-neonatal Fc receptor (FcRn) agent to the subject, wherein, prior to the subject receiving an initial administration of the anti-FcRn agent, an anti-citrullinated protein antibody (ACPA) level in a blood sample from the subject is or has been found to be higher than an ACPA reference level. In some embodiments, the anti-FcRn agent is nipocalimab.

[0012] Also provided herein are methods of treating or reducing severity of rheumatoid arthritis in a subject in need thereof, the method comprising

[0013] (a) determining an ACPA level in a blood sample from the subject; and

[0014] (b) administering an anti-neonatal Fc receptor (FcRn) agent to the subject if the ACPA level determined in step (a) is higher than an ACPA reference level. In some embodiments, the anti- FcRn agent is nipocalimab.

[0015] In some embodiments, the blood sample is serum sample.

[0016] In some embodiments, the ACPA reference level is within a range from about 100- 1000 U / ml.

[0017] In some embodiments, the ACPA reference level is about 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 525, 550, 575, 600, 625, 650, 675, 700, 725, 750, 775, 800, 825, 850, 875, 900, 925, 950, 975, or 1000 U / ml.

[0018] In some embodiments, the ACPA reference level is within a range from about 400-600 U / ml.

[0019] In some embodiments, the ACPA level in the blood sample is determined using an ELISA assay. In some embodiments, the ACPA level in the blood sample is determined using a cyclic citrullinated peptides (CCP) assay.

[0020] In some embodiments, the ACPA level in the blood sample is determined using a CCP2 assay.

[0021] In some embodiments, the ACPA level in the blood sample is determined using a CCP3 assay.

[0022] In some embodiments, the subject has not been previously treated with a diseasemodifying antirheumatic drug (DMARD). In some embodiments, the subject demonstrated inadequate response to or is intolerant to at least one disease-modifying antirheumatic drug (DMARD). In some embodiments, the DMARD is an anti-tumor necrosis factor (TNF) agent. In some embodiments, the anti-TNF agent is adalimumab, certolizumab pegol, etanercept, golimumab, or infliximab. In some embodiments, the anti-TNF agent is adalimumab, etanercept, golimumab, or infliximab. In some embodiments, the DMARD is a JAK inhibitor. In some embodiments, the JAK inhibitor is tofacitinib, baricitinib, or upadacitinib. In some embodiments, the DMARD is an anti-interleukin-6 (IL-6) agent. In some embodiments, the anti-IL-6 agent is tocilizumab. In some embodiments, the DMARD is an anti-CD20 agent. In some embodiments, the anti-CD20 agent is rituximab. In some embodiments, the DMARD is a T-cell costimulation inhibitor. In some embodiments, the T-cell costimulation inhibitor is abatacept. In some embodiments, the DMARD is an anti- inter leukin- 1 (IL-1) agent. In some embodiments, the anti- IL-1 agent is anakinra.

[0023] In some embodiments, the subject has at least a 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 110%, or 120% higher chance of achieving DAS28-CRP remission within 12 weeks of initiation of said administering compared to subjects having an ACPA level lower than the ACPA reference level prior to receiving an initial administration of the anti-FcRn agent.

[0024] In some embodiments, the method provides a clinical benefit as measured by a decrease in DAS28-CRP in the subject by more than 0.7 from baseline within 12 weeks of initiation of said administering. In some embodiments, the subject achieves DAS28-CRP remission within 12 weeks of initiation of said administering.

[0025] In some embodiments, the method provides a clinical benefit as measured by a decrease in Clinical Disease Activity Index (CD Al) in the subject by more than 10 from baseline within 12 weeks of initiation of said administering.

[0026] In some embodiments, the method provides a clinical benefit as measured by a decrease in Health Assessment Questionnaire-Disability Index (HAQ-DI) in the subject by more than 0.4 from baseline within 12 weeks of initiation of said administering.

[0027] In some embodiments, the method further comprises administering at least one conventional synthetic disease modifying anti-rheumatic drug (csDMARD).

[0028] In some embodiments, the method provides a clinical benefit as measured by a decrease in DAS28-CRP in the subject by more than 0.9 from baseline within 8 weeks, 9 weeks, 10 weeks, 11 weeks, or 12 weeks of initiation of said administering the at least one csDMARD. In some embodiments, the method provides a clinical benefit as measured by a decrease in DAS28- CRP in the subject by more than 1.2 from baseline within 10 weeks, 11 weeks, or 12 weeks of initiation of said administering the at least one csDMARD. In some embodiments, the method provides a clinical benefit as measured by a decrease in Clinical Disease Activity Index (CD Al) in the subject by more than 10 from baseline within 12 weeks of initiation of said administering the at least one csDMARD. In some embodiments, the csDMARD is methotrexate, hydroxychloroquine, leflunomide, or sulfasalazine.

[0029] In some embodiments, the subject achieves an ACR50 response within 12 weeks of initiation of said administering.

[0030] In some embodiments, the subject achieves an ACR70 response within 12 weeks of initiation of said administering.

[0031] In some embodiments, the subject achieves an ACR90 response within 12 weeks of initiation of said administering. In some embodiments, the anti-FcRn agent is administered every week or every two weeks.

[0032] In some embodiments, the anti-FcRn agent is administered intravenously or subcutaneously.

[0033] In some embodiments, the anti-FcRn agent is administered at a therapeutically effective dose.

[0034] In some embodiments, the anti-FcRn agent is administered at a therapeutically effective dose for a period sufficient to treat or reduce severity of rheumatoid arthritis in the subject.

[0035] In some embodiments, the anti-FcRn agent is nipocalimab, rozanolixizumab, batoclimab, IMVT-1402, efgartigimod, onlanolimab, SYNT002, ABY- 039, or DX-2507.

[0036] In some embodiments, the anti-FcRn agent is an anti-FcRn antibody comprising: (a) a light chain, which comprises a CDRL1 comprising an amino acid sequence of SEQ ID NO: 3, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 4, and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 5; and (b) a heavy chain, which comprises a CDR Hl comprising an amino acid sequence of SEQ ID NO: 6, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 7, and a CDR H3 comprising an amino acid sequence of SEQ ID NO: 8. In some embodiments, (a) the light chain of the anti-FcRn antibody comprises a light chain variable region comprising an amino acid sequence of SEQ ID NO: 9; and (b) the heavy chain of the anti-FcRn antibody comprises a heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 10. In some embodiments, (a) the light chain of the anti-FcRn antibody comprises an amino acid sequence of SEQ ID NO: 1; and (b) the heavy chain of the anti-FcRn antibody comprises an amino acid sequence of SEQ ID NO: 2.

[0037] In some embodiments, the anti-FcRn agent is Nipocalimab.

[0038] In some embodiments, the anti-FcRn agent is administered intravenously at about 15 mg / kg to about 30 mg / kg based on the weight of the subject.

[0039] In some embodiments, the method further comprises administering an anti-tumor necrosis factor (TNF) agent to the subject. In some embodiments, the subject demonstrated inadequate response to or is intolerant to a previous anti-TNF agent, which is different from the TNF agent administered to the subject. In some embodiments, the anti-FcRn agent is administered separately, simultaneously, or sequentially with the anti-TNF agent. In some embodiments, the anti-FcRn agent is administered sequentially with the anti-TNF agent. In some embodiments, the anti-FcRn agent is administered simultaneously with the anti-TNF agent. In some embodiments, the anti-TNF agent is administered intravenously or subcutaneously. In some embodiments, the anti-TNF agent is administered every week, every 2 weeks, every 3 weeks, every 4 weeks, every 6 weeks, or every 8 weeks. In some embodiments, the anti-TNF agent is adalimumab, certolizumab pegol, etanercept, golimumab, or infliximab. In some embodiments, the anti-TNF agent is an anti-TNF antibody comprises: (a) a light chain, which comprises a CDR LI comprising an amino acid sequence of SEQ ID NO: 42, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 43, a CDR L3 comprising an amino acid sequence of SEQ ID NO: 44; and (b) a heavy chain, which comprises a CDR Hl comprising an amino acid sequence of SEQ ID NO: 45, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 46, and a CDR H3 comprising an amino acid sequence of SEQ ID NO: 47. In some embodiments, (a) the light chain of the anti-TNF antibody comprises a light chain variable region comprising an amino acid sequence of SEQ ID NO: 48; and (b) the heavy chain of the anti-TNF antibody comprises a heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 49. In some embodiments, (a) the light chain of the anti-TNF antibody comprises an amin acid sequence of SEQ ID NO: 40; and (b) the heavy chain of the anti-TNF antibody comprises an amino acid sequence of SEQ ID NO: 41. In some embodiments, the anti- TNF agent is golimumab. In some embodiments, the anti-TNF agent is an anti-TNF antibody comprising (a) a light chain comprising an amino acid sequence of SEQ ID NO: 29; and (b) a heavy chain comprising an amino acid sequence of SEQ ID NO: 30. In some embodiments, the anti-TNF agent is certolizumab pegol. In some embodiments, the method provides a clinical benefit as measured by a decrease in DAS28-CRP by more than 0.8, more than 1, more than 1.2, more than 1.4, more than 1.6, more than 1.8, more than 2, more than 2.2, more than 2.4, more than 2.6, more than 2.8, more than 3, more than 3.2, more than 3.4, more than 3.6, more than 3.8, more than 4, more than 4.2, more than 4.4, more than 4.6, more than 4.8, more than 5, more than 5.2, more than 5.4, more than 5.6, more than 5.8, or more than 6 from baseline within 12 weeks of initiation of said administering. In some embodiments, the subject achieved DAS28-CRP LDA within 12 weeks of initiation of said administering. In some embodiments, the method provides a clinical benefit as measured by a decrease in Clinical Disease Activity Index (CD Al) by more than 11, more than 13, more than 15, more than 17, more than 19, more than 21, more than 23, more than 25, more than 27, more than 29, more than 31, more than 33, more than 35, more than 37, more than 39, more than 41, more than 43, more than 45, more than 47, more than 49, more than 51, more than 53, more than 55, more than 57, more than 59, more than 61, more than 63, more than 65, more than 67, more than 69, or more than 70 from baseline within 12 weeks of initiation of said administering. In some embodiments, the method provides a clinical benefit as measured by a decrease in Health Assessment Questionnaire-Disability Index (HAQ- DI) by more than 0.5, more than 0.6, more than 0.7, more than 0.8, more than 0.9 more than 1, more than 1.1, more than 1.2, more than 1.3, more than 1.4, more than 1.5, more than 1.6, more than 1.7, more than 1.8, more than 1.9, or more than 2 from baseline within 12 weeks of initiation of said administering.

[0040] Further provided herein is an anti-FcRn agent for use in a method of treating or reducing severity of rheumatoid arthritis in a subject in need thereof, the method comprising administering the anti-FcRn agent to the subject, wherein, prior to the subject receiving an initial administration of the anti-FcRn agent, an anti-cyclic citrullinated peptide autoantibody (ACPA) level in a blood sample from the subject is or has been found to be higher than an ACPA reference level.

[0041] Yet further provided herein is an anti-FcRn agent for use in a method of treating or reducing severity of rheumatoid arthritis in a subject in need thereof, the method comprising (a) determining an ACPA level in a blood sample from the subject; and (b) administering an anti- neonatal Fc receptor (FcRn) agent to the subject if the ACPA level determined in step (a) is higher than an ACPA reference level.

[0042] In some embodiments, the blood sample is serum sample.

[0043] In some embodiments, the ACPA reference level is within a range from about 100- 1000 U / ml.

[0044] In some embodiments, the ACPA reference level is about 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 525, 550, 575, 600, 625, 650, 675, 700, 725, 750, 775, 800, 825, 850, 875, 900, 925, 950, 975, or 1000 U / ml. In some embodiments, the ACPA reference level is within a range from about 400-600

[0045] U / ml.

[0046] In some embodiments, the ACPA level in the blood sample is determined using an ELISA assay.

[0047] In some embodiments, the ACPA level in the blood sample is determined using a cyclic citrullinated peptides (CCP) assay.

[0048] In some embodiments, the ACPA level in the blood sample is determined using a CCP2 assay.

[0049] In some embodiments, the ACPA level in the blood sample is determined using a CCP3 assay.

[0050] In some embodiments, the subject has not been previously treated with a diseasemodifying antirheumatic drug (DMARD). In some embodiments, the subject demonstrated inadequate response to or is intolerant to at least one disease-modifying antirheumatic drug (DMARD). In some embodiments, the DMARD is an anti-tumor necrosis factor (TNF) agent. In some embodiments, the anti-TNF agent is adalimumab, certolizumab pegol, etanercept, golimumab, or infliximab. In some embodiments, the anti-TNF agent is adalimumab, etanercept, golimumab, or infliximab. In some embodiments, the DMARD is a JAK inhibitor. In some embodiments, the JAK inhibitor is tofacitinib, baricitinib, or upadacitinib. In some embodiments, the DMARD is an anti-interleukin-6 (IL-6) agent. In some embodiments, the anti-IL-6 agent is tocilizumab. In some embodiments, the DMARD is an anti-CD20 agent. In some embodiments, the anti-CD20 agent is rituximab. In some embodiments, the DMARD is a T-cell costimulation inhibitor. In some embodiments, the T-cell costimulation inhibitor is abatacept. In some embodiments, the DMARD is an anti- inter leukin- 1 (IL-1) agent. In some embodiments, the anti- IL-1 agent is anakinra.

[0051] In some embodiments, the subject has at least a 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 110%, or 120% higher chance of achieving DAS28-CRP remission in the subject. In some embodiments, the method provides a clinical benefit as measured by a decrease in DAS28-CRP in the subject by more than 0.7 from baseline within 12 weeks of initiation of said administering.

[0052] In some embodiments, the subject achieves DAS28-CRP remission within 12 weeks of initiation of said administering.

[0053] In some embodiments, the method provides a clinical benefit as measured by a decrease in Clinical Disease Activity Index (CD Al) in the subject by more than 10 from baseline within 12 weeks of initiation of said administering.

[0054] In some embodiments, the method provides a clinical benefit as measured by a decrease in Health Assessment Questionnaire-Disability Index (HAQ-DI) in the subject by more than 0.4 from baseline within 12 weeks of initiation of said administering.

[0055] In some embodiments, the method further comprises administering at least one conventional synthetic disease modifying anti-rheumatic drug (csDMARD). In some embodiments, the method provides a clinical benefit as measured by a decrease in DAS28-CRP in the subject by more than 0.9 from baseline within 8 weeks, 9 weeks, 10 weeks, 11 weeks, or 12 weeks of initiation of said administering the at least one csDMARD. In some embodiments, the method provides a clinical benefit as measured by a decrease in DAS28-CRP in the subject by more than 1.2 from baseline within 10 weeks, 11 weeks, or 12 weeks of initiation of said administering the at least one csDMARD. In some embodiments, the method provides a clinical benefit as measured by a decrease in Clinical Disease Activity Index (CD Al) in the subject by more than 10 from baseline within 12 weeks of initiation of said administering the at least one csDMARD. In some embodiments, the csDMARD is methotrexate, hydroxychloroquine, leflunomide, or sulfasalazine.

[0056] In some embodiments, the subject achieves an ACR50 response within 12 weeks of initiation of said administering.

[0057] In some embodiments, the subject achieves an ACR70 response within 12 weeks of initiation of said administering. In some embodiments, the subject achieves an ACR90 response within 12 weeks of initiation of said administering.

[0058] In some embodiments, the anti-FcRn agent is administered every week or every two weeks.

[0059] In some embodiments, the anti-FcRn agent is administered intravenously or subcutaneously.

[0060] In some embodiments, the anti-FcRn agent is administered at a therapeutically effective dose.

[0061] In some embodiments, the anti-FcRn agent is administered at a therapeutically effective dose for a period sufficient to treat or reduce severity of rheumatoid arthritis in the subject.

[0062] In some embodiments, the anti-FcRn agent is nipocalimab, rozanolixizumab, batoclimab, IMVT-1402, efgartigimod, onlanolimab, SYNT002, ABY- 039, or DX-2507.

[0063] In some embodiments, the anti-FcRn agent is an anti-FcRn antibody comprising: (a) a light chain, which comprises a CDRL1 comprising an amino acid sequence of SEQ ID NO: 3, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 4, and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 5; and (b) a heavy chain, which comprises a CDR Hl comprising an amino acid sequence of SEQ ID NO: 6, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 7, and a CDR H3 comprising an amino acid sequence of SEQ ID NO: 8. In some embodiments, (a) the light chain of the anti-FcRn antibody comprises a light chain variable region comprising an amino acid sequence of SEQ ID NO: 9; and (b) the heavy chain of the anti-FcRn antibody comprises a heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 10. In some embodiments, (a) the light chain of the anti-FcRn antibody comprises an amino acid sequence of SEQ ID NO: 1; and (b) the heavy chain of the anti-FcRn antibody comprises an amino acid sequence of SEQ ID NO: 2.

[0064] 112. The anti-FcRn agent for use according to any one of claims 66-111 , wherein the anti- FcRn agent is nipocalimab. In some embodiments, the anti-FcRn agent is administered intravenously at about 15 mg / kg to about 30 mg / kg based on the weight of the subject.

[0065] In some embodiments, the method further comprises administering an anti-tumor necrosis factor (TNF) agent to the subject. In some embodiments, the subject demonstrated inadequate response to or is intolerant to a previous anti-TNF agent, which is different from the TNF agent administered to the subject. In some embodiments, the anti-FcRn agent is administered separately, simultaneously, or sequentially with the anti-TNF agent. In some embodiments, the anti-FcRn agent is administered sequentially with the anti-TNF agent. In some embodiments, the anti-FcRn agent is administered simultaneously with the anti-TNF agent. In some embodiments, the anti-TNF agent is administered intravenously or subcutaneously. In some embodiments, the anti-TNF agent is administered every week, every 2 weeks, every 3 weeks, every 4 weeks, every 6 weeks, or every 8 weeks. In some embodiments, the anti-TNF agent is adalimumab, certolizumab pegol, etanercept, golimumab, or infliximab. In some embodiments, the anti-TNF agent is an anti-TNF antibody comprises: (a) a light chain, which comprises a CDR LI comprising an amino acid sequence of SEQ ID NO: 42, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 43, a CDR L3 comprising an amino acid sequence of SEQ ID NO: 44; and (b) a heavy chain, which comprises a CDR Hl comprising an amino acid sequence of SEQ ID NO: 45, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 46, and a CDR H3 comprising an amino acid sequence of SEQ ID NO: 47. In some embodiments, (a) the light chain of the anti-TNF antibody comprises a light chain variable region comprising an amino acid sequence of SEQ ID NO: 48; and (b) the heavy chain of the anti-TNF antibody comprises a heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 49. In some embodiments, (a) the light chain of the anti-TNF antibody comprises an amin acid sequence of SEQ ID NO: 40; and (b) the heavy chain of the anti-TNF antibody comprises an amino acid sequence of SEQ ID NO: 41. In some embodiments, the anti-TNF agent is golimumab. In some embodiments, the anti-TNF agent is an anti-TNF antibody comprising (a) a light chain comprising an amino acid sequence of SEQ ID NO: 29; and (b) a heavy chain comprising an amino acid sequence of SEQ ID NO: 30. In some embodiments, the anti-TNF agent is certolizumab pegol. In some embodiments, the method provides a clinical benefit as measured by a decrease in DAS28-CRP by more than 0.8, more than 1, more than 1.2, more than 1.4, more than 1.6, more than 1.8, more than 2, more than 2.2, more than 2.4, more than 2.6, more than 2.8, more than 3, more than 3.2, more than 3.4, more than 3.6, more than 3.8, more than 4, more than 4.2, more than 4.4, more than 4.6, more than 4.8, more than 5, more than 5.2, more than 5.4, more than 5.6, more than 5.8, or more than 6 from baseline within 12 weeks of initiation of said administering. In some embodiments, the subject achieves DAS28-CRP LDA within 12 weeks of initiation of said administering.

[0066] In some embodiments, the method provides a clinical benefit as measured by a decrease in Clinical Disease Activity Index (CD Al) by more than 11, by more than 13, more than 15, more than 17, more than 19, more than 21, more than 23, more than 25, more than 27, more than 29, more than 31, more than 33, more than 35, more than 37, more than 39, more than 41, more than 43, more than 45, more than 47, more than 49, more than 51, more than 53, more than 55, more than 57, more than 59, more than 61, more than 63, more than 65, more than 67, more than 69, or more than 70 from baseline within 12 weeks of initiation of said administering.

[0067] In some embodiments, the method provides a clinical benefit as measured by a decrease in Health Assessment Questionnaire-Disability Index (HAQ-DI) by more than 0.4, more than 0.5, more than 0.6, more than 0.7, more than 0.8, more than 0.9 more than 1, more than 1.1, more than 1.2, more than 1.3, more than 1.4, more than 1.5, more than 1.6, more than 1.7, more than 1.8, more than 1.9, or more than 2 from baseline within 12 weeks of initiation of said administering.

[0068] Yet further provided herein is a combination of an anti-FcRn agent and an anti-TNF agent for use in a method as defined above.

[0069] Yet further provided herein is a kit comprising an anti-neonatal Fc receptor (FcRn) agent and an anti -tumor necrosis factor (TNF) agent to the subject.

[0070] In some embodiments, the components of the kit are disposed separately.

[0071] In some embodiments, the anti-FcRn agent and the anti-TNF agent are for separate, simultaneous or sequential administration.

[0072] In some embodiments, the anti-FcRn agent is an anti-FcRn agent as defined in any one of claims 43-47. In some embodiments, the anti-TNF agent is an anti-TNF agent as defined in any one of claims 56-61.

[0073] In some embodiments, the kit further comprises instructions for use.

[0074] In some embodiments, the kit further comprises instructions for a method of treating or reducing severity of rheumatoid arthritis in a subject. In some embodiments, the method is a method as defined above.

[0075] BRIEF DESCRIPTION OF THE DRAWINGS

[0076] FIG. 1 depicts a schematic overview of a clinical trial study to evaluate the efficacy and safety of anti-FcRn antibodies for treatment of rheumatoid arthritis.

[0077] FIGs. 2A-2C are graphs showing changes in pharmacodynamic biomarkers. FIG. 2A depicts percent change in IgG levels. FIG. 2B depicts percent change in circulating immune complex (CIC) levels. FIG. 2C depicts percent change in anti-cyclic citrullinated peptide antibody (anti-CCP antibody, also known as anti-citrullinated protein antibodies (ACPA)) levels. Values after treatment failure reported as missing; for change in anti-CCP analyses, patients with baseline anti-CCP below lower limit of quantitation excluded. Geometric mean (GMean) and 95% confidence interval (CI) based on ratio of value at visit over baseline value, with y-axes transformed to corresponding % change value (= 100% * [ratio - 1]).

[0078] FIG. 3 depicts a schematic overview of a clinical trial study to evaluate the efficacy and safety of a combination of anti-FcRn antibodies and anti-TNF antibodies for treatment of rheumatoid arthritis.

[0079] FIG. 4 is a chart showing proportions of patients achieving DAS28-CRP remission at weekl2 among patients in nipocalimab group, patients in placebo group, patients in nipocalimab group and having baseline ACPA above median, and patients in placebo group and having baseline ACPA above median.

[0080] FIG. 5 is a chart showing proportions of patients achieving ACR50 response at week 12 among patients in nipocalimab group, patients in placebo group, patients in nipocalimab group and having baseline ACPA above median, and patients in placebo group and having baseline ACPA above median.

[0081] DETAILED DESCRIPTION

[0082] The present disclosure provides for embodiments for methods of treating or reducing the severity of rheumatoid arthritis (RA) and related symptoms or pathologies associated with the same. In some embodiments, the methods of treating or reducing severity of rheumatoid arthritis in a subject in need thereof, comprises administering an agent against human neonatal Fc receptor (FcRn) to the subject. In some embodiments, prior to the subject receiving an initial administration of the anti -FcRn agent, an anti-citrullinated protein antibody (ACPA) level in a blood sample from the subject is or has been found to be higher than an ACPA reference level.

[0083] Anti -FcRn agents are useful, for example, to promote clearance of autoantibodies in a subject, to suppress antigen presentation in a subject, to block an immune response, such as blocking an immune complex- based activation of the immune response in a subject, or to treat immunological diseases (e.g., autoimmune diseases) in a subject. In some embodiments, the anti- FcRn agent is an anti-FcRn antibody.

[0084] The term “antibody” herein is used in the broadest sense and encompasses various antibody structures, including but not limited to monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), scFV, nanobodies, VHH, and antibody fragments so long as they exhibit FcRn antigen-binding activity.

[0085] Additionally, antibody or antibody molecule, as that term is used herein, refers to a polypeptide, e.g., an immunoglobulin chain or fragment thereof, comprising at least one functional immunoglobulin variable domain sequence. An antibody molecule encompasses antibodies (e.g., full-length antibodies) and antibody fragments. In some embodiments, an antibody molecule comprises an antigen binding or functional fragment of a full-length antibody, or a full-length immunoglobulin chain. For example, a full-length antibody is an immunoglobulin (Ig) molecule (e.g., an IgG antibody) that is naturally occurring or formed by normal immunoglobulin gene fragment recombinatorial processes). In embodiments, an antibody molecule refers to an immunologically active, antigen-binding portion of an immunoglobulin molecule, such as an antibody fragment. An antibody fragment, e.g., functional fragment, comprises a portion of an antibody, e.g., Fab, Fab', F(ab')2, F(ab)2, variable fragment (Fv), domain antibody (dAb), or single chain variable fragment (scFv). A functional antibody fragment binds to the same antigen as that recognized by the intact (e.g., full-length) antibody. The terms “antibody fragment” or “functional fragment” also include isolated fragments consisting of the variable regions, such as the “Fv” fragments consisting of the variable regions of the heavy and light chains or recombinant single chain polypeptide molecules in which light and heavy variable regions are connected by a peptide linker (“scFv proteins”). In some embodiments, an antibody fragment does not include portions of antibodies without antigen binding activity, such as Fc fragments or single amino acid residues. Exemplary antibody molecules include full length antibodies and antibody fragments, e.g., dAb (domain antibody), single chain, Fab, Fab’, and F(ab’)2 fragments, and single chain variable fragments (scFvs).

[0086] Immunoglobulin chains exhibit the same general structure of relatively conserved framework regions (FR) joined by three hypervariable regions, also called complementarity determining regions or CDRs. The CDRs from the two chains of each pair are aligned by the framework regions, enabling binding to a specific epitope. From N-terminus to C-terminus, both light and heavy chains comprise the domains FR1, CDR1, FR2, CDR2, FR3, CDR3 and FR4. The assignment of amino acids to each domain is in accordance with the definitions of Kabat Sequences of Proteins of Immunological Interest (National Institutes of Health, Bethesda, Md. (1987 and 1991)), or Chothia & Lesk J. Mol. Biol. 196:901-917 (1987); Chothia et al. Nature 342:878-883 (1989). In some embodiments, the antibodies provided herein comprise the same FRs and different CDRs. In some embodiments, the antibodies provided herein comprise the same CDRs and different FRs. In some embodiments, mutations in the FR are in the heavy chain. In some embodiments, mutations in the FR are in the FR1 of the heavy chain. In some embodiments, mutations in the FR are in the FR2 of the heavy chain. In some embodiments, mutations in the FR are in the FR3 of the heavy chain. In some embodiments, mutations in the FR are in the FR4 of the heavy chain. In some embodiments, mutations in the FR are in the light chain. In some embodiments, mutations in the FR are in the FR1 of the light chain. In some embodiments, mutations in the FR are in the FR2 of the light chain. In some embodiments, mutations in the FR are in the FR3 of the light chain. In some embodiments, mutations in the FR are in the FR4 of the light chain. In some embodiments, mutations in the FR are in the heavy and light chains. In some embodiments, mutations in the FR are in any one or more of the FRs of the heavy and light chains.

[0087] The term “antibody molecule” also encompasses whole or antigen binding fragments of domain, or single domain, antibodies, which can also be referred to as “sdAb” or “VHH.” Domain antibodies comprise either VH or VL that can act as stand-alone, antibody fragments. Additionally, domain antibodies include heavy-chain-only antibodies (HCAbs). Domain antibodies also include a CH2 domain of an IgG as the base scaffold into which CDR loops are grafted. It can also be generally defined as a polypeptide or protein comprising an amino acid sequence that is comprised of four framework regions interrupted by three complementarity determining regions. This is represented as FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4. sdAbs can be produced in camelids such as llamas, but can also be synthetically generated using techniques that are well known in the art. The numbering of the amino acid residues of a sdAb or polypeptide is according to the general numbering for VH domains given by Kabat et al. ("Sequence of proteins of immunological interest," US Public Health Services, NIH Bethesda, MD, Publication No. 91, which is hereby incorporated by reference in its entirety). According to this numbering, FR1 of a sdAb comprises the amino acid residues at positions 1-30, CDR1 of a sdAb comprises the amino acid residues at positions 31-36, FR2 of a sdAb comprises the amino acids at positions 36-49, CDR2 of a sdAb comprises the amino acid residues at positions 50-65, FR3 of a sdAb comprises the amino acid residues at positions 66- 94, CDR3 of a sdAb comprises the amino acid residues at positions 95-102, and FR4 of a sdAb comprises the amino acid residues at positions 103-113. Domain antibodies are also described in WO 2004 / 041862 and WO 2016 / 065323, each of which is hereby incorporated by reference in its entirety.

[0088] In some embodiments, as provided for herein, antibody molecules can be monospecific (e.g., monovalent or bivalent), bispecific (e.g., bivalent, trivalent, tetravalent, pentavalent, or hexavalent), trispecific (e.g., trivalent, tetravalent, pentavalent, hexavalent), or with higher orders of specificity (e.g., tetraspecific) and / or higher orders of valency beyond hexavalency. An antibody molecule can comprise a functional fragment of a light chain variable region and a functional fragment of a heavy chain variable region, or heavy and light chains may be fused together into a single polypeptide. As used herein, the term “fused” or “linked” when used in reference to a protein having different domains or heterologous sequences means that the protein domains are part of the same peptide chain that are connected to one another with either peptide bonds or other covalent bonding. The domains or section can be linked or fused directly to one another, or another domain or peptide sequence can be between the two domains or sequences and such sequences would still be considered fused or linked to one another. In some embodiments, the various domains or proteins provided for herein are linked or fused directly to one another or a linker sequence(s), such as a glycine / serine, glycine / alanine linker or other types of peptide linkers generally known to link the two domains together. Two peptide sequences are linked directly if they are directly connected to one another or indirectly if there is a linker or other structure that links the two regions. A linker can be directly linked to two different peptide sequences or domains.

[0089] As used herein, the terms “variable region” and “variable domain” refer to the portions of the light and heavy chains of an antibody that include amino acid sequences of complementary determining regions (CDRs, e g., CDRL1, CDR L2, CDRL3, CDR H1, CDR H2, and CDR H3) and framework regions (FRs). According to the methods used in this disclosure, the amino acid positions assigned to CDRs and FRs are defined according to Kabat (Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD. (1991)). Using this numbering system, the actual linear amino acid sequence may contain fewer or additional amino acids corresponding to a shortening of, or insertion into, a CDR (defined further herein) or FR (defined further herein) of the variable region. For example, a heavy chain variable region may include a single inserted residue (i.e., residue 52a according to Kabat) after residue 52 of CDRH2 and inserted residues (i.e., residues 82a, 82b, 82c, etc. according to Kabat) after residue 82 of heavy chain FR. The Kabat numbering of residues may be determined for a given antibody by alignment at regions of homology of the sequence of the antibody with a “standard” Kabat numbered sequence.

[0090] As used herein, the terms “complementary determining regions” and “CDRs” refer to the regions of an antibody variable domain or variable region which are hypervariable in sequence and / or form structurally defined loops. A CDR is also known as a hypervariable region. The light chain and heavy chain variable regions each have three CDRs. The light chain variable region contains CDR LI, CDR L2, and CDR L3. The heavy chain variable region contains CDR Hl, CDR H2, and CDR H3. Each CDR may include amino acid residues from a complementarity determining region as defined by Kabat (i.e., about residues 24-34 (CDR LI), 50-56 (CDR L2) and 89-97 (CDRL3) in the light chain variable region and about residues 31-35 (CDR Hl), SO- 65 (CDR H2) and 95-102 (CDR H3) in the heavy chain variable region).

[0091] As used herein, the term “FcRn” refers to a neonatal Fc receptor that binds to the Fc region of an IgG antibody, e.g., an IgGl antibody. An exemplary FcRn is human FcRn having UniProt ID No. P55899, which is hereby incorporated by reference in its entirety. Human FcRn is believed to be responsible for maintaining the half-life of IgG by binding and trafficking constitutively internalized IgG back to the cell surface for the recycling of IgG.

[0092] In some embodiments, the anti -FcRn antibody comprises a heavy chain and a light chain. In some embodiments, the anti-FcRn antibody comprises variable domains of a heavy chain and a light chain in a scFv format. In some embodiments, the heavy and light chain are linked with a peptide linker, such a glycine / serine or glycine / alanine linker.

[0093] In some embodiments, the anti-FcRn antibody is nipocalimab (nipo, also known as M281), a fully human, anti-FcRn antibody. In some embodiments, nipocalimab is described in U.S. Patent No. 10,676,526, which is incorporated herein by reference in its entirety. In some embodiments, nipocalimab comprises or consists of a light chain comprising or consisting of the sequence:

[0094] QSALTQPASVSGSPGQSITISCTGTGSDVGSYNLVSWYQQHPGKAPKLMIYGDSERPSGV SNRFSGSKSGNTASLTISGLQAEDEADYYCSSYAGSGIYVFGTGTKVTVLGQPKAAPSVT LFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAAS SYLSLTPEQWKSHKSYSCQVTHEGSTVEKTVAPTECS (SEQ ID NO: 1); and a heavy chain comprising or consisting of the sequence:

[0095] EVQLLESGGGLVQPGGSLRLSCAASGFTFSTYAMGWVRQAPGKGLEWVSSIGASGSQT RYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARLAIGDSYWGQGTMVTVSS ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS GLYSLS S WTVPS S SLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCP APELLGG PSVFLFPPI<PI<DTLMISRTPEVTCVVVDVSHEDPEVI<FNWYVDGVEVHNAI<TI<PREEQY ASTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR EEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDK SRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO: 2).

[0096] In some embodiments, the antibody comprises or consists of: (a) a light chain sequence comprising or consisting of SEQ ID NO: 1 or a light chain sequence comprising or consisting of a sequence that is at least 95%, 96%, 97% 98%, 99% identical to SEQ ID NO: 1, wherein the CDRL1 comprises the sequence TGTGSDVGSYNLVS (SEQ ID NO: 3), the CDRL2 comprises the sequence GDSERPS (SEQ ID NO: 4), the CDRL3 comprises the sequence SSYAGSGIYV (SEQ ID NO: 5); and (b) a heavy chain sequence comprising or consisting of SEQ ID NO: 2 or a heavy chain sequence comprising or consisting of a sequence that is at least 95%, 96%, 97% 98%, or 99% identical to SEQ ID NO: 2, wherein the CDR Hl comprises the sequence TYAMG (SEQ ID NO: 6), the CDR H2 comprises the sequence SIGASGSQTRYADS (SEQ ID NO: 7), and the CDR H3 comprises the sequence LAIGDSY (SEQ ID NO: 8).

[0097] In some embodiments, the antibody comprises a light chain variable region comprising an amino acid sequence that is at least 95%, 97%, 99%, or 100% identical to: QSALTQPASVSGSPGQSITISCTGTGSDVGSYNLVSWYQQHPGKAPKLMIYGDSERPSGV SNRFSGSKSGNTASLTISGLQAEDEADYYCSSYAGSGIYVFGTGTKVTVL (SEQ ID NO: 9). In some embodiments, the light chain variable region comprises a CDR LI having the sequence of SEQ ID NO: 3, a CDR L2 comprising the sequence of SEQ ID NO: 4, and a CDR L3 comprising the sequence of SEQ ID NO: 5.

[0098] In some embodiments, the antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 95%, 97%, 99%, or 100% identical to: EVQLLESGGGLVQPGGSLRLSCAASGFTFSTYAMGWVRQAPGKGLEWVSSIGASGSQT RYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARLAIGDSYWGQGTMVTVSS (SEQ ID NO: 10). In some embodiments, the heavy chain variable region comprises a CDR Hl comprising the sequence of SEQ ID NO: 6, a CDR H2 comprising the sequence of SEQ ID NO: 7, and a CDRH3 comprising the sequence of SEQ ID NO: 8. In some embodiments, the anti-FcRn antibody is efgartigimod (also known as ARGX- 113), a modified human IgGl -derived Fc fragment that binds FcRn. In some embodiments, efgartigimod is described in U.S. Patent No. 10,316,073, which is incorporated herein by reference in its entirety. In some embodiments, efgartigimod comprises or consists of a first subunit comprising or consisting of the sequence:

[0099] DI<THTC PPC PAPELLGGPSVFLFPPI<PI<DTLYITREPEVTCVVVDVSHEDPEVI<FNWYVD GVEVHNAI<TI<PREEQYNSTYRVVSVLTVLHQDWLNGI<EYI<CT<VSNI<ALPAPIEI<TISI< AKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPV LDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALKFHYTQKSLSLSPGK (SEQ ID NO:

[0100] 11); and a second subunit comprising or consisting of the sequence:

[0101] DI<THTC PPC PAPELLGGPSVFLFPPI<PI<DTLYITREPEVTCVVVDVSHEDPEVI<FNWYVD GVEVHNAI<TI<PREEQYNSTYRVVSVLTVLHQDWLNGI<EYI<CT<VSNI<ALPAPIEI<TISI< AKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPV LDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALKFHYTQKSLSLSPGK (SEQ ID NO:

[0102] 12).

[0103] In some embodiments, the anti-FcRn antibody is rozanolixizumab (also known as UCB7665), a humanized anti-FcRn antibody. In some embodiments, rozanolixizumab is described in U.S. Patent No. 10,233,243, which is incorporated herein by reference in its entirety. In some embodiments, rozanolixizumab comprises or consists of a light chain comprising or consisting of the sequence:

[0104] DIQMTQSPSSLSASVGDRVTITCKSSQSLVGASGKTYLYWLFQKPGKAPKRLIYLVSTLD SGIPSRFSGSGSGTEFTLHSSLQPEDFATYYCLQGTHFPHTFGQGTKLEIKRTVAAPSVFIF PPSDEQLKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSS TLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 13); and a heavy chain comprising or consisting of the sequence: EVPLVESGGGLVQPGGSLRLSCAVSGFTFSNYGMVWVRQAPGKGLEWVAYIDSDGDN TYYRDSVKGRFTISRDNAKSSLYLQMNSLRAEDTAVYYCTTGIVRPFLYWGQGTLVTVS SASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQS SGLYSLS S V VT VPS S SLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCP APEFLGGPS VFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNS TYRWSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEE MTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSR WQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 14).

[0105] In some embodiments, the anti-FcRn antibody is batoclimab (also known as IMVT-1401, RVT1401, HL161BKN, and HBM9161), a fully human, anti-FcRn antibody. In some embodiments, batoclimab is described in U.S. Patent No. 10,544,226, which is incorporated herein by reference in its entirety. In some embodiments, batoclimab comprises or consists of a light chain comprising or consisting of the sequence:

[0106] SYVLTQSPSVSVAPGQTARITCGGNNIGSKSVHWYQQKPGQAPVLWYDDSDRPSGIPE RFSASNSGNTATLTISRVEAGDEADYYCQVWDSSSDHWFGGGTKLTVLGQPKAAPSV TLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAA SSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS (SEQ ID NO: 15); and a heavy chain comprising or consisting of the sequence:

[0107] QLLLQESGPGLVKPSETLSLTCTVSGGSLSSSFSYWVWIRQPPGKGLEWIGTIYYSGNTY YNPSLKSRLTISVDTSKNHFSLKLSSVTAADTAVYYCARRAGILTGYLDSWGQGTLVTV SSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQ SSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAA GGPSVFLFPPI<PI<DTLMISRTPEVTCVVVDVSHEDPEVI<FNWYVDGVEVHNAI<TI<PREE QYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPP SREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO: 16).

[0108] In some embodiments, the anti-FcRn antibody is IMVT-1402 (also known as HL161ANS), a fully human, anti-FcRn antibody. In some embodiments, the anti-FcRn antibody is orilanolimab (also known as ALXN1830 and SYNT001), a humanized anti-FcRn antibody. In some embodiments, orilanolimab is described in U.S. Patent No. 10,626,175, which is incorporated herein by reference in its entirety. In some embodiments, orilanolimab comprises or consists of a light chain variable region comprising or consisting of the sequence:

[0109] DIQMTQSPSSLSASVGDRVTITCKASDHINNWLAWYQQKPGQAPRLLISGATSLETGVPS RFSGSGTGKDYTLTISSLQPEDFATYYCQQYWSTPYTFGGGTKVEIK (SEQ ID NO: 19); and a heavy chain variable region comprising or consisting of the sequence:

[0110] QVQLVQSGAELKKPGASVKLSCKASGYTFTSYGISWVKQATGQGLEWIGEIYPRSGNTY YNEKFKGRATLTADKSTSTAYMELRSLRSEDSAVYFCARSTTVRPPGIWGTGTTVTVSS (SEQ ID NO: 20).

[0111] In some embodiments, the anti-FcRn antibody is SYNT002, a humanized anti-FcRn antibody. In some embodiments, SYNT002 is described in U.S. Patent No. 10,822,417, which is incorporated herein by reference in its entirety. In some embodiments, SYNT002 comprises or consists of a light chain variable region comprising or consisting of the sequence:

[0112] DIVMTQSPDSLSASVGDRVTITCKASQSVSNDVAWYQQKPGQPPKLLIYYASNRYTGVP DRFSGSGYGTDFTLTISSLQAEDVAVYFCQQDYSSLTFGQGTKLEIK (SEQ ID NO: 21); and a heavy chain variable region comprising or consisting of the sequence:

[0113] EVQLVESGGGLVKPGGSLKLSCAASGFTFSDYGMHWVRQAPGKGLEWVAYISSGSSTI YYADTVKGRFTISRDNAKNTLYLQMNSLRAEDTAMYYCARAESTTTVGDYWGQGTSV TVSS (SEQ ID NO: 22).

[0114] In some embodiments, the anti-FcRn antibody is ABY-039 (also known as Affibody AB), a bivalent antibody-mimetic targeting FcRn. In some embodiments, ABY-039 is described in U.S. Patent No. 10,323,066, which is incorporated herein by reference in its entirety.

[0115] In some embodiments, the anti-FcRn antibody is DX-2507, a fully human anti-FcRn monoclonal antibody. In some embodiments, DX-2507 is described in U.S. Patent No. 9,862,768, which is incorporated herein by reference in its entirety. In some embodiments, DX- 2507 comprises or consists of a light chain comprising or consisting of the sequence:

[0116] QSALTQPASVSGSPGQSITISCTGTGSDVGSYNLVSWYQQHPGKAPKLMITGDSQRPSGV SNRFSGSKSGNTASLTISGLQAEDEADYYCASTAGSGITVFGTGTKVTVLGQPKANPTVT LFPPSSEELQANKATLVCLISDFYPGAVTVAWKADGSPVKAGVETTKPSKQSNNKYAAS SYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS (SEQ ID NO: 25); and a heavy chain comprising or consisting of the sequence:

[0117] EVQLLESGGGLVQPGGSLRLSCAASGFTFSEYAMGWVRQAPGKGLEWVSSIGSSGGQT I<YADSVI<GRFTISRDNSI<NTLYLQMNSLRAEDTAVYYC ARLAIGDSYWGQGTMVTVSS ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS GLYSLS S WTVPS S SLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCP APELLGG PSVFLFPPI<PI<DTLMISRTPEVTCVVVDVSHEDPEVI<FNWYVDGVEVHNAI<TI<PREEQY NSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSA rqEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVD KSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO: 26).

[0118] In some embodiments of all the methods described herein, the Fc domain of the antibody is not fucosy lated. In some embodiments of all the methods described herein, the Fc domain of the antibody is not glycosylated. In some embodiments of all the methods described herein, the antibody lacks effector function. In some embodiments of all the methods described herein, the antibody is an IgGl antibody.

[0119] In some embodiments, antibodies described herein may comprise mutations (e.g., amino acid substitutions, additions, and / or deletions) outside of the CDRs (i.e., in framework regions (FRs)). An amino acid substitution, addition, and / or deletion can be a substitution, addition, and / or deletion of one or more amino acids (e.g., 1, 2, 3, 4, 5, 6, 7, 8, or more). An amino acid substitution, addition, and / or deletion can be a substitution, addition, and / or deletion of eight or fewer, seven or fewer, six or fewer, five or fewer, four or fewer, three or fewer, or two or fewer single amino acids. In some embodiments, antibodies described herein may include amino acid substitutions, additions, and / or deletions in the constant regions (e.g., Fc region) of the antibody that, e.g., lead to decreased effector function, e.g., decreased complement-dependent cytolysis (CDC), antibody-dependent cell-mediated cytolysis (ADCC), antibody-dependent cell-mediated phagocytosis (ADCP), and / or decreased B-cell killing. The constant regions are not involved directly in binding an antibody to its target, but exhibit various effector functions, such as participation of the antibody in antibody-dependent cellular toxicity. In some embodiments, the antibodies described herein are characterized by decreased binding (or in some cases absence of binding) to human complement factor Clq and / or human Fc receptor on natural killer (NK) cells. In other embodiments, the antibodies are characterized by decreased binding (or in some cases absence of binding) to human FcyRI, FcyRIIA, and / or FcyRIIIA. In some embodiments, anti- FcRn antibodies described herein contain asparagine (N) at position 297 (numbering according to the EU System). In some embodiments, anti-FcRn antibodies described herein are aglycosylated at position 297 (numbering according to the EU System). In some cases, anti-FcRn antibodies described herein do not have an N at position 297 (EU numbering) in any one of SEQ ID NOs: 2 and 23-26, such that the antibody is aglycosylated at that position. The resulting effectorless antibody shows very little binding to complement or Fc receptors (i.e., complement Clq binding), indicating low CDC potential. In some embodiments, the Fc region is an effectorless Fc region.

[0120] In some embodiments, the heavy chain of the antibody comprises a sequence having no more than 5, 4, 3, 2, or 1 single amino acid substitutions relative to the amino acid sequence of SEQ ID NO: 2. In some embodiments, the light chain of the isolated antibody comprises a sequence having no more than 5, 4, 3, 2 or 1 single amino acid substitutions relative to the sequence of SEQ ID NO: 1.

[0121] As used herein, the term “percent (%) identity” refers to the percentage of amino acid (or nucleic acid) residues of a candidate sequence, e.g., an anti-FcRn antibody of the present disclosure, that are identical to the amino acid (or nucleic acid) residues of a reference sequence, e.g., a wild-type anti-FcRn antibody, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent identity (i.e., gaps can be introduced in one or both of the candidate and reference sequences for optimal alignment and non-homologous sequences can be disregarded for comparison purposes). Alignment for purposes of determining percent identity can be achieved in various ways that are within the skill in the art, for instance, using publicly available computer software such as BLAST, ALIGN, or Megalign (DNASTAR) software. Those skilled in the art can determine appropriate parameters for measuring alignment, including any algorithms needed to achieve maximal alignment over the full length of the sequences being compared. In some embodiments, the percent amino acid (or nucleic acid) sequence identity of a given candidate sequence to, with, or against a given reference sequence (which can alternatively be phrased as a given candidate sequence that has or includes a certain percent amino acid (or nucleic acid) sequence identity to, with, or against a given reference sequence) is calculated as follows:

[0122] 100 x (fraction of A / B) where A is the number of amino acid (or nucleic acid) residues scored as identical in the alignment of the candidate sequence and the reference sequence, and where B is the total number of amino acid (or nucleic acid) residues in the reference sequence. In some embodiments where the length of the candidate sequence does not equal to the length of the reference sequence, the percent amino acid (or nucleic acid) sequence identity of the candidate sequence to the reference sequence would not equal to the percent amino acid (or nucleic acid) sequence identity of the reference sequence to the candidate sequence.

[0123] In some embodiments, a reference sequence aligned for comparison with a candidate sequence may show that the candidate sequence exhibits from 50% to 100% identity across the full length of the candidate sequence or a selected portion of contiguous amino acid (or nucleic acid) residues of the candidate sequence. The length of the candidate sequence aligned for comparison purpose is at least 30%, e.g., at least 40%, e.g., at least 50%, 60%, 70%, 80%, 90%, or 100% of the length of the reference sequence. When a position in the candidate sequence is occupied by the same amino acid (or nucleic acid) residue as the corresponding position in the reference sequence, then the molecules are identical at that position. A position may be altered by a substitution, deletion, or insertion. A substitution, deletion, or insertion may comprise a certain number of amino acids (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or more). When describing a substitution, deletion, or insertion of no more than n amino acids, this is meant that the substitution, deletion, or insertion comprises, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or n amino acids. The number or substitutions, deletions, or insertions can comprise a percent of the total sequence (e.g., 1%, 5%, 10%, 15%, 20%, or more) where the number of substitutions, deletions, or insertions alters 5%, 10%, 15%, 20% or more, of the amino acids in the total sequence.

[0124] The most specific autoimmunity known for rheumatoid arthritis is reflected by generation of ACPA. Presence of ACPA in established rheumatoid arthritis is associated with disease severity, while generation of ACPA at early developmental phases of rheumatoid arthritis can have a strong predictive value for progressing to the full-blown disease. Thus, development of ACPA may be of crucial importance to the pathogenesis of RA. In this application, the inventors discovered that the administration of anti-FcRn agent (e.g., anti-FcRn antibody) has particularly therapeutic efficacy in rheumatoid arthritis patients with an ACPA level above certain ACPA reference levels.

[0125] While the general association of ACPA positivity and rheumatoid arthritis severity was reported, the association between baseline ACPA level and rheumatoid arthritis treatment response is unknown and unpredictable. For example, the treatment response to anti-TNF, the most widely used class of bDMARD, is not associated with ACPA positivity or level. There is no clear data for anti-IL6 treatment response and baseline ACPA positivity or level. For JAKi, abatacept, and rituximab, there are post-hoc analysis data to suggest that ACPA positive (vs negative) patients may respond better to these drugs. However, within the ACPA positive patients, there is no clear data for the association between the ACPA baseline level and response.

[0126] The present discovery that anti-FcRn treatment efficacy is more pronounced in ACPA- positive patients with higher ACPA baseline level is new and unexpected. Anti-FcRn is a novel mechanism that has never been tested in rheumatoid arthritis patients. The mechanism is different from all existing standard of care (SOCs), and therefore what we know for the existing SOCs cannot be directly extrapolated to anti-FcRn. In the present disclosure, the inventors defined specific and novel ACPA baseline thresholds that are not just positive / negative, which has not been disclosed for other mechanisms of actions. In some embodiments, the ACPA reference level used herein is within a range from about 100-1000 U / ml. In some embodiments, the ACPA reference level is within a range from about 100-110, 110-120, 120-130, 130-140, 140-150, 150-160, 160-170, 170-180, 180-190, 190- 200, 200-210, 210-220, 220-230, 230-240, 240-250, 250-260, 260-270, 270-280, 280-290, 290-

[0127] 300, 300-310, 310-320, 320-330, 330-340, 340-350, 350-360, 360-370, 370-380, 380-390, 390-

[0128] 400, 400-410, 410-420, 420-430, 430-440, 440-450, 450-460, 460-470, 470-480, 480-490, 490-

[0129] 500, 500-510, 510-520, 520-530, 530-540, 540-550, 550-560, 560-570, 570-580, 580-590, 590-

[0130] 600, 600-610, 610-620, 620-630, 630-640, 640-650, 650-660, 660-670, 670-680, 680-690, 690-

[0131] 700, 700-710, 710-720, 720-730, 730-740, 740-750, 750-760, 760-770, 770-780, 780-790, 790-

[0132] 800, 800-810, 810-820, 820-830, 830-840, 840-850, 850-860, 860-870, 870-880, 880-890, 890-

[0133] 900, 900-910, 910-920, 920-930, 930-940, 940-950, 950-960, 960-970, 970-980, 980-990, or

[0134] 990-1000 U / ml. In some embodiments, the ACPA reference level used herein is within a range from about 400-600 U / ml. In some embodiments, the ACPA reference level is about 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 525, 550, 575, 600, 625, 650, 675, 700, 725, 750, 775, 800, 825, 850, 875, 900, 925, 950, 975, or 1000 U / ml. In a preferred embodiment, the ACPA reference level is within a range from about 400-600 U / ml.

[0135] ACPA level can be determined using blood sample from the subject / patient. Over the years, various assays for determining ACPA levels have been developed. Any known or yet to be developed assays can be used herein to determine the ACPA level for the subject / patient. For example, the ACPA level can be determined using an ELISA assay, such as a cyclic citrullinated peptides (CCP) assay. Currently, three (3) generation of CCP assay have been developed, CCP1, CCP2, and CCP3. Exemplary assays useful herein for determining ACAP level in subjects / patients, include, without limitation, Diastat (manufactured by Axis-Shield Diagnostics, Scotland, UK), CCPoint (manufactured by Eurodiagnostica, Netherlands), CCPlus (manufactured by Eurodiagnostica, Netherlands), EDIA (manufactured by Eurodiagnostica, Netherlands), RA anti-CCP ELISA (manufactured by Eurodiagnostica, Netherlands), Euroimmun (manufactured by Euroimmun, Germany), Quanta Lite (manufactured by Inova, United States), ELIA CCP (manufactured by Phadia, Sweden, Germany), Quanta Lite CCP3 (manufactured by Inova, United States), Quanta Lite CCP3.1 (manufactured by Inova, United States), Org 548 anti-MCV (manufactured by Orgentec, Germany), Immunoscan-CCP Plus™ (manufactured by from Eurodiagnostica), and IMMUNOSCAN CCPlus (from SVAR). In a preferred embodiment, the ACPA level is determined using CCP2 assay.

[0136] In a preferred embodiment, the method disclosed herein comprises administering an anti- FcRn antibody to the subject with rheumatoid arthritis, wherein the subject has a baseline ACPA level higher than an ACPA reference level that is within the range of about 400-600 U / ml. In a yet preferred embodiment, the method disclosed herein comprises administering an anti-FcRn antibody to the subject with rheumatoid arthritis, wherein the subject has a baseline ACPA level higher than an ACPA reference level that is within the range of about 400-600 U / ml, and wherein the anti-FcRn antibody comprises a) a light chain comprising or consisting of the sequence of SEQ ID NO: 1 and b) a heavy chain comprising or consisting of the sequence of SEQ ID NO: 2. The term “baseline ACPA level” used herein refers to the ACPA level of a subject / patient that is or has been determined prior to receiving a first or initial administration of the anti-FcRn agent.

[0137] In some cases, the method disclosed herein for treating or reducing severity of rheumatoid arthritis in a subject in need thereof comprises administering an anti-neonatal Fc receptor (FcRn) agent to the subject, wherein, prior to the subject receiving an initial administration of the anti-FcRn agent, an anti-citrullinated protein antibody (ACPA) level in a blood sample from the subject is or has been found to be higher than an ACPA reference level. The anti-FcRn agent may be an anti-FcRn antibody. In some cases, the ACPA reference level is about 100 U / ml, and the anti-FcRn antibody comprises a) a light chain comprising or consisting of the sequence of SEQ ID NO: 1 and b) a heavy chain comprising or consisting of the sequence of SEQ ID NO: 2. The ACPA reference level may be about 125 U / ml and the anti-FcRn agent may comprise a) a light chain comprising or consisting of the sequence of SEQ ID NO: 1 and b) a heavy chain comprising or consisting of the sequence of SEQ ID NO: 2. The ACPA reference level may be about 150 U / ml and the anti-FcRn agent may comprise a) a light chain comprising or consisting of the sequence of SEQ ID NO: 1 and b) a heavy chain comprising or consisting of the sequence of SEQ ID NO: 2. The ACPA reference level may be about 175 U / ml and the anti- FcRn agent may comprise a) a light chain comprising or consisting of the sequence of SEQ ID NO: 1 and b) a heavy chain comprising or consisting of the sequence of SEQ ID NO: 2. The ACPA reference level may be about 200 U / ml and the anti-FcRn agent may comprise a) a light chain comprising or consisting of the sequence of SEQ ID NO: 1 and b) a heavy chain comprising or consisting of the sequence of SEQ ID NO: 2. The ACPA reference level may be about 225 U / ml and the anti-FcRn agent may comprise a) a light chain comprising or consisting of the sequence of SEQ ID NO: 1 and b) a heavy chain comprising or consisting of the sequence of SEQ ID NO: 2. The ACPA reference level may be about 250 U / ml and the anti-FcRn agent may comprise a) a light chain comprising or consisting of the sequence of SEQ ID NO: 1 and b) a heavy chain comprising or consisting of the sequence of SEQ ID NO: 2. The ACPA reference level may be about 275 U / ml and the anti-FcRn agent may comprise a) a light chain comprising or consisting of the sequence of SEQ ID NO: 1 and b) a heavy chain comprising or consisting of the sequence of SEQ ID NO: 2. The ACPA reference level may be about 300 U / ml and the anti- FcRn agent may comprise a) a light chain comprising or consisting of the sequence of SEQ ID NO: 1 and b) a heavy chain comprising or consisting of the sequence of SEQ ID NO: 2. The ACPA reference level may be about 325 U / ml and the anti-FcRn agent may comprise a) a light chain comprising or consisting of the sequence of SEQ ID NO: 1 and b) a heavy chain comprising or consisting of the sequence of SEQ ID NO: 2. The ACPA reference level may be about 350 U / ml and the anti-FcRn agent may comprise a) a light chain comprising or consisting of the sequence of SEQ ID NO: 1 and b) a heavy chain comprising or consisting of the sequence of SEQ ID NO: 2. The ACPA reference level may be about 375 U / ml and the anti-FcRn agent may comprise a) a light chain comprising or consisting of the sequence of SEQ ID NO: 1 and b) a heavy chain comprising or consisting of the sequence of SEQ ID NO: 2. The ACPA reference level may be about 400 U / ml and the anti-FcRn agent may comprise a) a light chain comprising or consisting of the sequence of SEQ ID NO: 1 and b) a heavy chain comprising or consisting of the sequence of SEQ ID NO: 2. The ACPA reference level may be about 425 U / ml and the anti- FcRn agent may comprise a) a light chain comprising or consisting of the sequence of SEQ ID NO: 1 and b) a heavy chain comprising or consisting of the sequence of SEQ ID NO: 2. The ACPA reference level may be about 450 U / ml and the anti-FcRn agent may comprise a) a light chain comprising or consisting of the sequence of SEQ ID NO: 1 and b) a heavy chain comprising or consisting of the sequence of SEQ ID NO: 2. The ACPA reference level may be about 475 U / ml and the anti-FcRn agent may comprise a) a light chain comprising or consisting of the sequence of SEQ ID NO: 1 and b) a heavy chain comprising or consisting of the sequence of SEQ ID NO: 2. The ACPA reference level may be about 500 U / ml and the anti-FcRn agent may comprise a) a light chain comprising or consisting of the sequence of SEQ ID NO: 1 and b) a heavy chain comprising or consisting of the sequence of SEQ ID NO: 2. The ACPA reference level may be about 525 U / ml and the anti-FcRn agent may comprise a) a light chain comprising or consisting of the sequence of SEQ ID NO: 1 and b) a heavy chain comprising or consisting of the sequence of SEQ ID NO: 2. The ACPA reference level may be about 550 U / ml and the anti- FcRn agent may comprise a) a light chain comprising or consisting of the sequence of SEQ ID NO: 1 and b) a heavy chain comprising or consisting of the sequence of SEQ ID NO: 2. The ACPA reference level may be about 575 U / ml and the anti-FcRn agent may comprise a) a light chain comprising or consisting of the sequence of SEQ ID NO: 1 and b) a heavy chain comprising or consisting of the sequence of SEQ ID NO: 2. The ACPA reference level may be about 600 U / ml and the anti-FcRn agent may comprise a) a light chain comprising or consisting of the sequence of SEQ ID NO: 1 and b) a heavy chain comprising or consisting of the sequence of SEQ ID NO: 2. The ACPA reference level may be about 625 U / ml and the anti-FcRn agent may comprise a) a light chain comprising or consisting of the sequence of SEQ ID NO: 1 and b) a heavy chain comprising or consisting of the sequence of SEQ ID NO: 2. The ACPA reference level may be about 650 U / ml and the anti-FcRn agent may comprise a) a light chain comprising or consisting of the sequence of SEQ ID NO: 1 and b) a heavy chain comprising or consisting of the sequence of SEQ ID NO: 2. The ACPA reference level may be about 675 U / ml and the anti- FcRn agent may comprise a) a light chain comprising or consisting of the sequence of SEQ ID NO: 1 and b) a heavy chain comprising or consisting of the sequence of SEQ ID NO: 2. The ACPA reference level may be about 700 U / ml and the anti-FcRn agent may comprise a) a light chain comprising or consisting of the sequence of SEQ ID NO: 1 and b) a heavy chain comprising or consisting of the sequence of SEQ ID NO: 2. The ACPA reference level may be about 725 U / ml and the anti-FcRn agent may comprise a) a light chain comprising or consisting of the sequence of SEQ ID NO: 1 and b) a heavy chain comprising or consisting of the sequence of SEQ ID NO: 2. The ACPA reference level may be about 750 U / ml and the anti-FcRn agent may comprise a) a light chain comprising or consisting of the sequence of SEQ ID NO: 1 and b) a heavy chain comprising or consisting of the sequence of SEQ ID NO: 2. The ACPA reference level may be about 775 U / ml and the anti-FcRn agent may comprise a) a light chain comprising or consisting of the sequence of SEQ ID NO: 1 and b) a heavy chain comprising or consisting of the sequence of SEQ ID NO: 2. The ACPA reference level may be about 800 U / ml and the anti- FcRn agent may comprise a) a light chain comprising or consisting of the sequence of SEQ ID NO: 1 and b) a heavy chain comprising or consisting of the sequence of SEQ ID NO: 2. The ACPA reference level may be about 825 U / ml and the anti-FcRn agent may comprise a) a light chain comprising or consisting of the sequence of SEQ ID NO: 1 and b) a heavy chain comprising or consisting of the sequence of SEQ ID NO: 2. The ACPA reference level may be about 850 U / ml and the anti-FcRn agent may comprise a) a light chain comprising or consisting of the sequence of SEQ ID NO: 1 and b) a heavy chain comprising or consisting of the sequence of SEQ ID NO: 2. The ACPA reference level may be about 875 U / ml and the anti-FcRn agent may comprise a) a light chain comprising or consisting of the sequence of SEQ ID NO: 1 and b) a heavy chain comprising or consisting of the sequence of SEQ ID NO: 2. The ACPA reference level may be about 900 U / ml and the anti-FcRn agent may comprise a) a light chain comprising or consisting of the sequence of SEQ ID NO: 1 and b) a heavy chain comprising or consisting of the sequence of SEQ ID NO: 2. The ACPA reference level may be about 925 U / ml and the anti- FcRn agent may comprise a) a light chain comprising or consisting of the sequence of SEQ ID NO: 1 and b) a heavy chain comprising or consisting of the sequence of SEQ ID NO: 2. The ACPA reference level may be about 950 U / ml and the anti-FcRn agent may comprise a) a light chain comprising or consisting of the sequence of SEQ ID NO: 1 and b) a heavy chain comprising or consisting of the sequence of SEQ ID NO: 2. The ACPA reference level may be about 975 U / ml and the anti-FcRn agent may comprise a) a light chain comprising or consisting of the sequence of SEQ ID NO: 1 and b) a heavy chain comprising or consisting of the sequence of SEQ ID NO: 2. The ACPA reference level may be about 1000 U / ml and the anti-FcRn agent may comprise a) a light chain comprising or consisting of the sequence of SEQ ID NO: 1 and b) a heavy chain comprising or consisting of the sequence of SEQ ID NO: 2.

[0138] In some cases, the ACPA reference level is about 100 U / ml, and the anti-FcRn agent is nipocalimab. The ACPA reference level may be about 125 U / ml and the anti-FcRn agent may be nipocalimab. The ACPA reference level may be about 150 U / ml and the anti-FcRn agent may be nipocalimab. The ACPA reference level may be about 175 U / ml and the anti-FcRn agent may be nipocalimab. The ACPA reference level may be about 200 U / ml and the anti-FcRn agent may be nipocalimab. The ACPA reference level may be about 225 U / ml and the anti-FcRn agent may be nipocalimab. The ACPA reference level may be about 250 U / ml and the anti-FcRn agent may be nipocalimab. The ACPA reference level may be about 275 U / ml and the anti- FcRn agent may be nipocalimab. The ACPA reference level may be about 300 U / ml and the anti-FcRn agent may be nipocalimab. The ACPA reference level may be about 325 U / ml and the anti-FcRn agent may be nipocalimab. The ACPA reference level may be about 350 U / ml and the anti-FcRn agent may be nipocalimab. The ACPA reference level may be about 375 U / ml and the anti-FcRn agent may be nipocalimab. The ACPA reference level may be about 400 U / ml and the anti-FcRn agent may be nipocalimab. The ACPA reference level may be about 425 U / ml and the anti-FcRn agent may be nipocalimab. The ACPA reference level may be about 450 U / ml and the anti-FcRn agent may be nipocalimab. The ACPA reference level may be about 475 U / ml and the anti-FcRn agent may be nipocalimab. The ACPA reference level may be about 500 U / ml and the anti-FcRn agent may be nipocalimab. The ACPA reference level may be about 525 U / ml and the anti-FcRn agent may be nipocalimab. The ACPA reference level may be about 550 U / ml and the anti-FcRn agent may be nipocalimab. The ACPA reference level may be about 575 U / ml and the anti-FcRn agent may be nipocalimab. The ACPA reference level may be about 600 U / ml and the anti-FcRn agent may be nipocalimab. The ACPA reference level may be about 625 U / ml and the anti-FcRn agent may be nipocalimab. The ACPA reference level may be about 650 U / ml and the anti-FcRn agent may be nipocalimab. The ACPA reference level may be about 675 U / ml and the anti-FcRn agent may be nipocalimab. The ACPA reference level may be about 700 U / ml and the anti-FcRn agent may be nipocalimab. The ACPA reference level may be about 725 U / ml and the anti-FcRn agent may be nipocalimab. The ACPA reference level may about be 750 U / ml and the anti-FcRn agent may be nipocalimab. The ACPA reference level may be about 800 U / ml and the anti-FcRn agent may be nipocalimab. The ACPA reference level may be about 825 U / ml and the anti-FcRn agent may be nipocalimab. The ACPA reference level may be about 850 U / ml and the anti-FcRn agent may be nipocalimab. The ACPA reference level may be about 875 U / ml and the anti-FcRn agent may be nipocalimab.

[0139] The ACPA reference level may be about 900 U / ml and the anti-FcRn agent may be nipocalimab.

[0140] The ACPA reference level may be about 925 U / ml and the anti-FcRn agent may be nipocalimab.

[0141] The ACPA reference level may be about 950 U / ml and the anti-FcRn agent may be nipocalimab.

[0142] The ACPA reference level may be about 975 U / ml and the anti-FcRn agent may be nipocalimab.

[0143] The ACPA reference level may be about 1000 U / ml and the anti-FcRn agent may be nipocalimab. In some embodiments, the subject being administered the anti-FcRn agent has demonstrated inadequate response to or is intolerant to at least one disease-modifying antirheumatic drug (DMARD).

[0144] As used herein, “inadequate response” or “IR” refers to a lack of sufficient response to a treatment of a disease as assessed by a treating physician. An inadequate response can be measured by clinical, laboratory or other measures of disease activity, including symptoms thereof. The lack of sufficient response to a treatment of a disease can be defined by specific clinical or other endpoints, including for example, where no discernable response to the treatment is observed after being treated for a sufficient period of time, or where a response to the treatment is observed, but considered insufficient to meaningfully alleviate symptoms of the disease. For example, the response or efficacy of a treatment to RA can be evaluated, for example, by Disease Activity Index Score 28 using C-reactive protein (CRP) (DAS28-CRP), DAS28-ESR, DAS28 LDA, DAS28-CRP remission, ACR responses, CD Al, SDAI, ACR / EULAR remission. The efficacy can also be measured by the Physician’s Global Assessment (PGA) of disease activity, joint assessment (tenderness and swelling), duration of morning stiffness. The efficacy can further be assessed by health-related quality of life outcomes, pain, and fatigue, e.g., PtGA of disease activity, pain VAS, FACIT-Fatigue, Joint Pain Severity NRS, HAQ-DI, SF-36 version 2 Standard survey.

[0145] In some embodiments of the application, a subject has demonstrated IR to >1 anti-TNF agent, as assessed by the treating physician: a) After at least 12 weeks dosage of etanercept, adalimumab, golimumab, and / or b. After at least 14 weeks dosage (i.e., at least 4 doses) of infliximab.

[0146] In some embodiments of the application, a subject has demonstrated IR to at least one biological disease-modifying antirheumatic drug (bDMARD) other than anti-TNF agents, as assessed by the treating physician, after at least 12 weeks of therapy including but not limited to abatacept, anakinra, tocilizumab, and sarilumab or at least 16 weeks of therapy with rituximab.

[0147] In some embodiments of the application, a subject has demonstrated IR to bDMARD other than anti-TNF agent, as assessed by the treating physician. In some embodiments of the application, a subject has demonstrated IR to at least one JAKi agent, as assessed by the treating physician, after at least 12 weeks of therapy with a JAKi which includes but is not limited to tofacitinib, baricitinib, upadacitinib.

[0148] As used herein, “intolerant to a therapy” refers to not being able to be treated with the therapy without inducing serious adverse event (SAE) or serious adverse effect. As used herein, the phrases “serious adverse event (SAE)” and “serious adverse effect” mean any adverse event that is serious, as defined by the Food and Drug Administration (FDA) Code of Federal Regulations (CFR), Chapter 21. A SAE can be any AE or suspected adverse reaction that in the view of an investigator or a medical doctor, results in any of the following outcomes: death, a life threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, or a congenital anomaly / birth defect. Important medical events that may not result in death, be life threatening, or require hospitalization may be considered serious when, based upon appropriate medical judgment, they may jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the outcomes listed in the above definition.

[0149] In some embodiments, the DMARD is an anti-tumor necrosis factor (TNF) agent. In some embodiments, the anti-TNF agent is adalimumab, certolizumab pegol, etanercept, golimumab, or infliximab. In some embodiments, the DMARD is a JAK inhibitor. In some embodiments, JAK inhibitor is tofacitinib, baricitinib, or upadacitinib. In some embodiments, the DMARD is an anti-interleukin-6 (IL-6) agent. In some embodiments, the anti-IL-6 agent is tocilizumab. In some embodiments, the DMARD is an anti-CD20 agent. In some embodiments, the anti-CD20 agent is rituximab. In some embodiments, the DMARD is a T-cell costimulation inhibitor. In some embodiments, the T-cell costimulation inhibitor is abatacept. In some embodiments, the DMARD is an anti- Inter leukin- 1 (IL-1) agent. In some embodiments, the anti- IL-1 agent is anakinra.

[0150] In some embodiments, the anti-TNF agent is adalimumab (also known as HUMIRA®), a human anti-TNF a monoclonal antibody. In some embodiments, adalimumab is described in U.S. Patent No. 6,090,382 as D2E7, which is incorporated herein by reference in its entirety. In some embodiments, adalimumab comprises or consists of a light chain comprising or consisting of the sequence:

[0151] DIQMTQSPSSLSASVGDRVTITCRASQGIRNYLAWYQQKPGKAPKLLIYAASTLQSGVPS RFSGSGSGTDFTLTISSLQPEDVATYYCQRYNRAPYTFGQGTKVEIKRTVAAPSVFIFPPS DEQLKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTL TLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 27); and a heavy chain comprising or consisting of the sequence:

[0152] EVQLVESGGGLVQPGRSLRLSCAASGFTFDDYAMHWVRQAPGKGLEWVSAITWNSGHI DYADSVEGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAKVSYLSTASSLDYWGQGTL VTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA VLQS S GLYSLS S WTVPS S SLGTQT YICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCP AP ELLGGPSVFLFPPI<PI<DTLMISRTPEVTCVVVDVSHEDPEVI<FNWYVDGVEVHNAI<TI<P REEQYNSTYRVVSVLTVLHQDWLNGI<EYI<CT<VSNI<ALPAPIEI<TISI<AI<GQPREPQVY

[0153] TLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSK LTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 28).

[0154] In some embodiments, the anti-TNF agent is certolizumab pegol (also known as CIMZIA®), a PEGylated Fab fragment. In some embodiments, certolizumab pegol is described in U.S. Patent No. 7,012,135, which is incorporated herein by reference in its entirety. In some embodiments, certolizumab pegol comprises or consists of a light chain comprising or consisting of the sequence:

[0155] DIQMTQSPSSLSASVGDRVTITCKASQNVGTNVAWYQQKPGKAPKALIYSASFLYSGVP YRFSGSGSGTDFTLTISSLQPEDFATYYCQQYNIYPLTFGQGTKVEIKRTVAAPSVFIFPPS DEQLKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTL TLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 29); and a heavy chain comprising or consisting of the sequence:

[0156] EVQLVESGGGLVQPGGSLRLSCAASGYVFTDYGMNWVRQAPGKGLEWMGWINTYIGE PIYADSVKGRFTFSLDTSKSTAYLQMNSLRAEDTAVYYCARGYRSYAMDYWGQGTLV TVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAV

[0157] LQSSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCAA (SEQ ID NO: 30).

[0158] In some embodiments, the anti-TNF agent is etanercept (also known as ENBREL™), a TNFR-Ig Fc fusion protein. In some embodiments, etanercept is described in U.S. Patent Nos. 5,395,760, and 5,605,690, which are incorporated herein by reference in their entireties. In some embodiments, etanercept comprises or consists of the sequence:

[0159] LPAQVAFTPYAPEPGSTCRLREYYDQTAQMCCSKCSPGQHAKVFCTKTSDTVCDSCEDS TYTQLWNWVPECLSCGSRCSSDQVETQACTREQNRICTCRPGWYCALSKQEGCRLCAP LRKCRPGFGVARPGTETSDWCKPCAPGTFSNTTSSTDICRPHQICNWAIPGNASMDAV CTSTSPTRSMAPGAVHLPQPVSTRSQHTQPTPEPSTAPSTSFLLPMGPSPPAEGSTGDEPK SCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWY VDGVEVHNAI<TI<PREEQYNSTYRVVSVLTVLHQDWLNGI<EYI<C I<VSNI<ALPAPIEI<TI SKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTP PVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 39).

[0160] In some embodiments, the anti-TNF agent is golimumab (also known as SIMPONI®), a human anti-TNF a monoclonal antibody. In some embodiments, golimumab is described in U.S. Patent No. 7,250,165, which is incorporated herein by reference in its entirety. In some embodiments, golimumab comprises or consists of a light chain comprising or consisting of the sequence:

[0161] EIVLTQSPATLSLSPGERATLSCRASQSVYSYLAWYQQKPGQAPRLLIYDASNRATGIPA RFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPPFTFGPGTKVDIKRTVAAPSVFIFPPS DEQLKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTL TLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 40); and a heavy chain comprising or consisting of the sequence:

[0162] QVQLVESGGGWQPGRSLRLSCAASGFIFSSYAMHWVRQAPGNGLEWVAFMSYDGSN KKYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDRGIAAGGNYYYYGMD VWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALT SGVHTFPAVLQSSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTH TCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVE VHNAI<TI<PREEQYNSTYRVVSVLTVLHQDWLNGI<EYI<CI<VSNI<ALPAPIEI<TISI<AI<G QPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDS DGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 41).

[0163] In some embodiments, the antibody has: (a) a light chain sequence that is at least 95%, 96%, 97% 98%, or 99% identical to SEQ ID NO: 40, wherein the CDR LI comprises the sequence RASQSVYSYLA (SEQ ID NO: 42), the CDR L2 comprises the sequence DASNRAT (SEQ ID NO: 43), the CDR L3 comprises the sequence QQRSNWPPFT (SEQ ID NO: 44); and (b) a heavy chain sequence that is at least 95%, 96%, 97% 98%, or 99% identical to SEQ ID NO: 41, wherein the CDR Hl comprises the sequence SYAMH (SEQ ID NO: 45), the CDR H2 comprises the sequence FMSYDGSNKKYADSVKG (SEQ ID NO: 46), and the CDR H3 comprises the sequence DRGIAAGGNYYYYGMDV (SEQ ID NO: 47).

[0164] In some embodiments, the antibody comprises a light chain variable region comprising an amino acid sequence that is at least 95%, 97%, 99%, or 100% identical to: EIVLTQSPAT LSLSPGERATLSCRASQSVYSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTD FTLTISSLEPEDFAVYYCQQRSNWPPFTFGPGTKVDIKRTV (SEQ ID NO: 48). In some embodiments, the light chain variable region contains a CDR LI having the sequence of SEQ ID NO: 42, a CDRL2 having the sequence of SEQ ID NO: 43, a CDRL3 having the sequence of SEQ ID NO: 44.

[0165] In some embodiments, the antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 95%, 97%, 99%, or 100% identical to: QVQLVESGGG WQPGRSLRLSCAASGFIFSSYAMHWVRQAPGNGLEWVAFMSYDGSNKKYADSVKGR FTISRDNSKNTLYLQMNSLRAEDTAVYYCARDRGIAAGGNYYYYGMDVWGQGTTVTV SS (SEQ ID NO: 49). In some embodiments, the heavy chain variable region contains a CDR Hl having the sequence of SEQ ID NO: 45, a CDR H2 having the sequence of SEQ ID NO: 46, and a CDRH3 having the sequence of SEQ ID NO: 47. In some embodiments, the anti-TNF agent is infliximab (also known as REMICADE™), a chimeric anti-TNFa monoclonal antibody. In some embodiments, infliximab is described in U.S. Patent No. 7,070,775, which is incorporated herein by reference in its entirety. In some embodiments, infliximab comprises or consists of a light chain comprising or consisting of the sequence:

[0166] DILLTQSPAILSVSPGERVSFSCRASQFVGSSIHWYQQRTNGSPRLLIKYASESMSGIPSRF SGSGSGTDFTLSINTVESEDIADYYCQQSHSWPFTFGSGTNLEVKRTVAAPSVFIFPPSDE QLKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLS KADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 50); and a heavy chain comprising or consisting of the sequence:

[0167] EVKLEESGGGLVQPGGSMKLSCVASGFIFSNHWMNWVRQSPEKGLEWVAEIRSKSINS ATHYAESVKGRFTISRDDSKSAVYLQMTDLRTEDTGVYYCSRNYYGSTYDYWGQGTTL TVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAV LQS SGLYSLS S WTVPS S SLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCP APE LLGGPSVFLFPPI<PI<DTLMISRTPEVTCVVVDVSHEDPEVI<FNWYVDGVEVHNAI<TI<PR EEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTL PPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLT VDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 51).

[0168] In a preferred embodiment, the DMARD is an anti-TNF agent. In another preferred embodiment, the method comprises administering an anti-FcRn antibody to a subject with rheumatoid arthritis, wherein the subject i) has a baseline ACPA level higher than an ACPA reference level that is within the range from about 400-600 U / ml and ii) has demonstrated inadequate response or is intolerant to the DMARD that is an anti-TNF agent, and wherein the anti-FcRn antibody comprising a) a light chain comprising or consisting of the sequence of SEQ ID NO: 1 and b) a heavy chain comprising or consisting of the sequence of SEQ ID NO: 2. In yet another preferred embodiment, the method comprises administering an anti-FcRn antibody to a subject with rheumatoid arthritis, wherein the subject i) has a baseline ACPA level higher than an ACPA reference level that is within the range from about 400-600 U / ml and ii) has demonstrated inadequate response or is intolerant to the DMARD that is an anti-TNF antibody, and wherein the anti-FcRn antibody comprising a) a light chain comprising or consisting of the sequence of SEQ ID NO: 1 and b) a heavy chain comprising or consisting of the sequence of SEQ ID NO: 2.

[0169] In some embodiments, the subject with rheumatoid arthritis is also treated with an anti- TNF agent, as described above. The anti-TNF agent that is administered to the subject may be different to the anti-TNF agent which the subject has demonstrated inadequate response to or is / was intolerant to. In some embodiments, the anti-TNF agent is an anti-TNF antibody, as described above. In some embodiments, the anti-FcRn agent and the anti-TNF agent are administered separately, simultaneously, or sequentially. In a preferred embodiment, an anti- FcRn antibody and an anti-TNF antibody are administered to a subject with rheumatoid arthritis separately, simultaneously, or sequentially.

[0170] In a preferred embodiment, the subject with rheumatoid arthritis i) has a baseline ACPA level higher than an ACPA reference level that is within the range from about 400-600 U / ml and ii) has demonstrated inadequate response or is intolerant to a DMARD, wherein the subject is being administered an anti-FcRn agent and an anti-TNF agent separately, simultaneously, or sequentially.

[0171] In another preferred embodiment, the subject with rheumatoid arthritis i) has a baseline ACPA level higher than an ACPA reference level that is within the range from about 400-600 U / ml and ii) has demonstrated inadequate response or is intolerant to a DMARD, wherein the subject is being administered an anti-FcRn antibody and an anti-TNF antibody separately, simultaneously, or sequentially.

[0172] In another preferred embodiment, the subject with rheumatoid arthritis i) has a baseline ACPA level higher than an ACPA reference level that is within the range from about 400-600 U / ml and ii) has demonstrated inadequate response or is intolerant to a DMARD, wherein the subject is being administered an anti-FcRn antibody and an anti-TNF antibody separately, simultaneously, or sequentially, and wherein the DMARD is the same as the anti-TNF antibody that is being administered. In another preferred embodiment, the subject with rheumatoid arthritis i) has a baseline ACPA level higher than an ACPA reference level that is within the range from about 400-600 U / ml and ii) has demonstrated inadequate response or is intolerant to a DMARD, wherein the subject is being administered an anti-FcRn antibody and an anti-TNF antibody separately, simultaneously, or sequentially, and wherein the DMARD is different from the anti-TNF antibody that is being administered.

[0173] In another preferred embodiment, the subject with rheumatoid arthritis i) has a baseline ACPA level higher than an ACPA reference level that is within the range from about 400-600 U / ml and ii) has demonstrated inadequate response or is intolerant to a DMARD, and the subject is being administered an anti-FcRn antibody and an anti-TNF antibody separately, simultaneously, or sequentially, wherein the anti-FcRn antibody comprises a) a light chain comprising or consisting of the sequence of SEQ ID NO: 1 and b) a heavy chain comprising or consisting of the sequence of SEQ ID NO: 2 and the anti-TNF antibody comprises a) a light chain comprising or consisting of the sequence of SEQ ID NO: 29 and b) a heavy chain comprising or consisting of the sequence of SEQ ID NO: 30.

[0174] In another preferred embodiment, the subject with rheumatoid arthritis i) has a baseline ACPA level higher than an ACPA reference level that is within the range from about 400-600 U / ml and ii) has demonstrated inadequate response or is intolerant to a DMARD, and the subject is being administered an anti-FcRn antibody and an anti-TNF antibody separately, simultaneously, or sequentially, wherein the anti-FcRn antibody comprises a) a light chain comprising or consisting of the sequence of SEQ ID NO: 1 and b) a heavy chain comprising or consisting of the sequence of SEQ ID NO: 2 and the anti-TNF antibody comprises a) a light chain comprising or consisting of the sequence of SEQ ID NO: 29 and b) a heavy chain comprising or consisting of the sequence of SEQ ID NO: 30, and wherein the DMARD is different from the anti-TNF antibody that is being administered.

[0175] In another preferred embodiment, the subject with rheumatoid arthritis i) has a baseline ACPA level higher than an ACPA reference level that is within the range from about 400-600 U / ml and ii) has demonstrated inadequate response or is intolerant to a DMARD, and the subject is being administered an anti-FcRn antibody and an anti-TNF antibody separately, simultaneously, or sequentially, wherein the anti-FcRn antibody comprises a) a light chain comprising or consisting of the sequence of SEQ ID NO: 1 and b) a heavy chain comprising or consisting of the sequence of SEQ ID NO: 2 and the anti-TNF antibody comprises a) a light chain comprising or consisting of the sequence of SEQ ID NO: 40 and b) a heavy chain comprising or consisting of the sequence of SEQ ID NO: 41.

[0176] In another preferred embodiment, the subject with rheumatoid arthritis i) has a baseline ACPA level higher than an ACPA reference level that is within the range from about 400-600 U / ml and ii) has demonstrated inadequate response or is intolerant to a DMARD, and the subject is being administered an anti-FcRn antibody and an anti-TNF antibody separately, simultaneously, or sequentially, wherein the anti-FcRn antibody comprises a) a light chain comprising or consisting of the sequence of SEQ ID NO: 1 and b) a heavy chain comprising or consisting of the sequence of SEQ ID NO: 2 and the anti-TNF antibody comprises a) a light chain comprising or consisting of the sequence of SEQ ID NO: 40 and b) a heavy chain comprising or consisting of the sequence of SEQ ID NO: 41, and wherein the DMARD is different from the anti-TNF antibody that is being administered.

[0177] As described herein, methods of the invention may comprise administering an anti-FcRn agent (such as an anti-FcRn antibody) to the subject, wherein, prior to the subject receiving an initial administration of the anti-FcRn agent, an anti-citrullinated protein antibody (APCA) level in a blood sample from the subject is or has been found to be higher than an ACPA reference level, and wherein the method further comprises administering an anti-tumor necrosis factor (TNF) agent to the subject. In some cases, the ACPA reference level is about 100 U / ml, and the anti-TNF agent is golimumab. The ACPA reference level may be about 125 U / ml and the anti- TNF agent may be golimumab. The ACPA reference level may be about 150 U / ml and the anti- TNF agent may be golimumab. The ACPA reference level may be about 175 U / ml and the anti- TNF agent may be golimumab. The ACPA reference level may be about 200 U / ml and the anti- TNF agent may be golimumab. The ACPA reference level may be about 225 U / ml and the anti- TNF agent may be golimumab. The ACPA reference level may be about 250 U / ml and the anti- TNF agent may be golimumab. The ACPA reference level may be about 275 U / ml and the anti- TNF agent may be golimumab. The ACPA reference level may be about 300 U / ml and the anti- TNF agent may be golimumab. The ACPA reference level may be about 325 U / ml and the anti- agent may be golimumab. The ACPA reference level may be about 350 U / ml and the antiagent may be golimumab. The ACPA reference level may be about 375 U / ml and the antiagent may be golimumab. The ACPA reference level may be about 400 U / ml and the antiagent may be golimumab. The ACPA reference level may be about 425 U / ml and the antiagent may be golimumab. The ACPA reference level may be about 450 U / ml and the antiagent may be golimumab. The ACPA reference level may be about 475 U / ml and the antiagent may be golimumab. The ACPA reference level may be about 500 U / ml and the antiagent may be golimumab. The ACPA reference level may be about 525 U / ml and the antiagent may be golimumab. The ACPA reference level may be about 550 U / ml and the antiagent may be golimumab. The ACPA reference level may be about 575 U / ml and the antiagent may be golimumab. The ACPA reference level may be about 600 U / ml and the antiagent may be golimumab. The ACPA reference level may be about 625 U / ml and the antiagent may be golimumab. The ACPA reference level may be about 650 U / ml and the antiagent may be golimumab. The ACPA reference level may be about 675 U / ml and the antiagent may be golimumab. The ACPA reference level may be about 700 U / ml and the antiagent may be golimumab. The ACPA reference level may be about 725 U / ml and the antiagent may be golimumab. The ACPA reference level may be about 750 U / ml and the antiagent may be golimumab. The ACPA reference level may be about 800 U / ml and the antiagent may be golimumab. The ACPA reference level may be about 825 U / ml and the antiagent may be golimumab. The ACPA reference level may be about 850 U / ml and the antiagent may be golimumab. The ACPA reference level may be about 875 U / ml and the antiagent may be golimumab. The ACPA reference level may be about 900 U / ml and the antiagent may be golimumab. The ACPA reference level may be about 925 U / ml and the antiagent may be golimumab. The ACPA reference level may be about 950 U / ml and the antiagent may be golimumab. The ACPA reference level may be about 975 U / ml and the antiagent may be golimumab. The ACPA reference level may be about 1000 U / ml and the anti¬ agent may be golimumab.

[0178] In some cases, the ACPA reference level is about 100 U / ml, the anti-FcRn agent is nipocalimab and the anti-TNF agent is golimumab. The ACPA reference level may be about 125 U / ml, the anti-FcRn agent may be nipocalimab and the anti-TNF agent may be golimumab. The ACPA reference level may be about 150 U / ml, the anti-FcRn agent may be nipocalimab and the anti-TNF agent may be golimumab. The ACPA reference level may be about 175 U / ml, the anti- FcRn agent may be nipocalimab and the anti-TNF agent may be golimumab. The ACPA reference level may be about 200 U / ml, the anti-FcRn agent may be nipocalimab and the anti- TNF agent may be golimumab. The ACPA reference level may be about 225 U / ml, the anti- FcRn agent may be nipocalimab and the anti-TNF agent may be golimumab. The ACPA reference level may be about 250 U / ml, the anti-FcRn agent may be nipocalimab and the anti- TNF agent may be golimumab. The ACPA reference level may be about 275 U / ml, the anti- FcRn agent may be nipocalimab and the anti-TNF agent may be golimumab. The ACPA reference level may be about 300 U / ml, the anti-FcRn agent may be nipocalimab and the anti- TNF agent may be golimumab. The ACPA reference level may be about 325 U / ml , the anti- FcRn agent may be nipocalimab and the anti-TNF agent may be golimumab. The ACPA reference level may be about 350 U / ml, the anti-FcRn agent may be nipocalimab and the anti- TNF agent may be golimumab. The ACPA reference level may be about 375 U / ml, the anti- FcRn agent may be nipocalimab and the anti-TNF agent may be golimumab. The ACPA reference level may be about 400 U / ml, the anti-FcRn agent may be nipocalimab and the anti- TNF agent may be golimumab. The ACPA reference level may be about 425 U / ml, the anti- FcRn agent may be nipocalimab and the anti-TNF agent may be golimumab. The ACPA reference level may be about 450 U / ml , the anti-FcRn agent may be nipocalimab and the anti- TNF agent may be golimumab. The ACPA reference level may be about 475 U / ml, the anti- FcRn agent may be nipocalimab and the anti-TNF agent may be golimumab. The ACPA reference level may be about 500 U / ml, the anti-FcRn agent may be nipocalimab and the anti- TNF agent may be golimumab. The ACPA reference level may be about 525 U / ml, the anti- FcRn agent may be nipocalimab and the anti-TNF agent may be golimumab. The ACPA reference level may be about 550 U / ml, the anti-FcRn agent may be nipocalimab and the anti- TNF agent may be golimumab. The ACPA reference level may be about 575 U / ml, the anti- FcRn agent may be nipocalimab and the anti-TNF agent may be golimumab. The ACPA reference level may be about 600 U / ml, the anti-FcRn agent may be nipocalimab and the anti- TNF agent may be golimumab. The ACPA reference level may be about 625 U / ml , the anti- FcRn agent may be nipocalimab and the anti-TNF agent may be golimumab. The ACPA reference level may be about 650 U / ml, the anti-FcRn agent may be nipocalimab and the anti- TNF agent may be golimumab. The ACPA reference level may be about 675 U / ml, the anti- FcRn agent may be nipocalimab and the anti-TNF agent may be golimumab. The ACPA reference level may be about 700 U / ml, the anti-FcRn agent may be nipocalimab and the anti- TNF agent may be golimumab. The ACPA reference level may be about 725 U / ml, the anti- FcRn agent may be nipocalimab and the anti-TNF agent may be golimumab. The ACPA reference level may be about 750 U / ml, the anti-FcRn agent may be nipocalimab and the anti- TNF agent may be golimumab. The ACPA reference level may be about 775 U / ml, the anti- FcRn agent may be nipocalimab and the anti-TNF agent may be golimumab. The ACPA reference level may be about 800 U / ml, the anti-FcRn agent may be nipocalimab and the anti- TNF agent may be golimumab. The ACPA reference level may be about 825 U / ml, the anti- FcRn agent may be nipocalimab and the anti-TNF agent may be golimumab. The ACPA reference level may be about 850 U / ml, the anti-FcRn agent may be nipocalimab and the anti- TNF agent may be golimumab. The ACPA reference level may be about 875 U / ml, the anti- FcRn agent may be nipocalimab and the anti-TNF agent may be golimumab. The ACPA reference level may be about 900 U / ml, the anti-FcRn agent may be nipocalimab and the anti- TNF agent may be golimumab. The ACPA reference level may be about 925 U / ml, the anti- FcRn agent may be nipocalimab and the anti-TNF agent may be golimumab. The ACPA reference level may be about 950 U / ml, the anti-FcRn agent may be nipocalimab and the anti- TNF agent may be golimumab. The ACPA reference level may be about 975 U / ml, the anti- FcRn agent may be nipocalimab and the anti-TNF agent may be golimumab. The ACPA reference level may be about 1000 U / ml, the anti-FcRn agent may be nipocalimab and the anti- TNF agent may be golimumab.

[0179] In some embodiments, the subject being administered the anti-FcRn agent also receives at least one conventional synthetic disease modifying anti-rheumatic drug (csDMARD) treatment. In some embodiments, the subject being administered the anti-FcRn agent and anti- TNF agent also receives at least one conventional synthetic disease modifying anti-rheumatic drug (csDMARD) treatment. In some embodiments, the csDMARD is methotrexate, hydroxychloroquine, leflunomide, or sulfasalazine.

[0180] In some embodiments, the methods described herein comprise administering the anti- FcRn agent, and optionally, separately, simultaneously, or sequentially with the anti-TNF agent to the subject or patient. The terms “subject” and “patient” can be used interchangeably. In some embodiments, the anti-FcRn agent and the anti-TNF agent are administered concurrently. In some embodiments, the anti-FcRn agent and the anti-TNF agent are administered sequentially. In some embodiments, the anti-FcRn agent is administered every week or every two weeks. In some embodiments, the anti-TNF agent is administered every week, every 2 weeks, every 3 weeks, every 4 weeks, every 6 weeks, or every 8 weeks. In some embodiments, the anti-FcRn agent is administered every week, and the anti-TNF agent is administered every week. In some embodiments, the anti-FcRn agent is administered every week, and the anti-TNF agent is administered every 2 weeks. In some embodiments, the anti-FcRn agent is administered every week, and the anti-TNF agent is administered every 3 weeks. In some embodiments, the anti- FcRn agent is administered every week, and the anti-TNF agent is administered every 4 weeks. In some embodiments, the anti-FcRn agent is administered every two weeks, and the anti-TNF agent is administered every week. In some embodiments, the anti-FcRn agent is administered every two weeks, and the anti-TNF agent is administered every two weeks. In some embodiments, the anti-FcRn agent is administered every two weeks, and the anti-TNF agent is administered every 3 weeks. In some embodiments, the anti-FcRn agent is administered every two weeks, and the anti-TNF agent is administered every 4 weeks.

[0181] In some embodiments, the anti-FcRn agent is nipocalimab and the anti-TNF agent is adalimumab. In some embodiments, the anti-FcRn agent is nipocalimab and the anti-TNF agent is certolizumab pegol. In some embodiments, the anti-FcRn agent is nipocalimab and the anti- TNF agent is etanercept. In some embodiments, the anti-FcRn agent is nipocalimab and the anti- TNF agent is golimumab. In some embodiments, the anti-FcRn agent is nipocalimab and the anti-TNF agent is infliximab.

[0182] In some embodiments, the anti-FcRn agent is rozanolixizumab and the anti-TNF agent is adalimumab. In some embodiments, the anti-FcRn agent is rozanolixizumab and the anti-TNF agent is certolizumab pegol. In some embodiments, the anti-FcRn agent is rozanolixizumab and the anti-TNF agent is etanercept. In some embodiments, the anti-FcRn agent is rozanolixizumab and the anti-TNF agent is golimumab. In some embodiments, the anti-FcRn agent is rozanolixizumab and the anti-TNF agent is infliximab.

[0183] In some embodiments, the anti-FcRn agent is batoclimab and the anti-TNF agent is adalimumab. In some embodiments, the anti-FcRn agent is batoclimab and the anti-TNF agent is certolizumab pegol. In some embodiments, the anti-FcRn agent is batoclimab and the anti-TNF agent is etanercept. In some embodiments, the anti-FcRn agent is batoclimab and the anti-TNF agent is golimumab. In some embodiments, the anti-FcRn agent is batoclimab and the anti-TNF agent is infliximab.

[0184] In some embodiments, the anti-FcRn agent is IMVT-1402 and the anti-TNF agent is adalimumab. In some embodiments, the anti-FcRn agent is IMVT-1402 and the anti-TNF agent is certolizumab pegol. In some embodiments, the anti-FcRn agent is IMVT-1402 and the anti- TNF agent is etanercept. In some embodiments, the anti-FcRn agent is IMVT-1402 and the anti- TNF agent is golimumab. In some embodiments, the anti-FcRn agent is IMVT-1402 and the anti-TNF agent is infliximab.

[0185] In some embodiments, the anti-FcRn agent is efgartigimod and the anti-TNF agent is adalimumab. In some embodiments, the anti-FcRn agent is efgartigimod and the anti-TNF agent is certolizumab pegol. In some embodiments, the anti-FcRn agent is efgartigimod and the anti- TNF agent is etanercept. In some embodiments, the anti-FcRn agent is efgartigimod and the anti- TNF agent is golimumab. In some embodiments, the anti-FcRn agent is efgartigimod and the anti-TNF agent is infliximab.

[0186] In some embodiments, the anti-FcRn agent is orilanolimab and the anti-TNF agent is adalimumab. In some embodiments, the anti-FcRn agent is orilanolimab and the anti-TNF agent is certolizumab pegol. In some embodiments, the anti-FcRn agent is orilanolimab and the anti- TNF agent is etanercept. In some embodiments, the anti-FcRn agent is orilanolimab and the anti- TNF agent is golimumab. In some embodiments, the anti-FcRn agent is orilanolimab and the anti-TNF agent is infliximab.

[0187] In some embodiments, the anti-FcRn agent is SYNT002 and the anti-TNF agent is adalimumab. In some embodiments, the anti-FcRn agent is SYNT002 and the anti-TNF agent is certolizumab pegol. In some embodiments, the anti-FcRn agent is SYNT002 and the anti-TNF agent is etanercept. In some embodiments, the anti-FcRn agent is SYNT002 and the anti-TNF agent is golimumab. In some embodiments, the anti-FcRn agent is SYNT002 and the anti-TNF agent is infliximab. In some embodiments, the anti-FcRn agent is ABY- 039 and the anti-TNF agent is adalimumab. In some embodiments, the anti-FcRn agent is ABY- 039 and the anti-TNF agent is certolizumab pegol. In some embodiments, the anti-FcRn agent is ABY- 039 and the anti-TNF agent is etanercept. In some embodiments, the anti-FcRn agent is ABY- 039 and the anti-TNF agent is golimumab. In some embodiments, the anti-FcRn agent is ABY- 039 and the anti-TNF agent is infliximab.

[0188] In some embodiments, the anti-FcRn agent is DX-2507 and the anti-TNF agent is adalimumab. In some embodiments, the anti-FcRn agent is DX-2507 and the anti-TNF agent is certolizumab pegol. In some embodiments, the anti-FcRn agent is DX-2507 and the anti-TNF agent is etanercept. In some embodiments, the anti-FcRn agent is DX-2507 and the anti-TNF agent is golimumab. In some embodiments, the anti-FcRn agent is DX-2507 and the anti-TNF agent is infliximab.

[0189] In some embodiments, the anti-FcRn agent is administered as part of a pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of the anti-FcRn agent.

[0190] In some embodiments, the anti-FcRn agent or pharmaceutical composition comprising the anti-FcRn agent is administered as a single dose. As used herein, “dose” refers to a single administration of the anti-FcRn agent or pharmaceutical composition comprising the anti-FcRn agent. In some embodiments, the anti-FcRn agent is dosed based on the weight of the subject. In some embodiments, the anti-FcRn agent is dosed at a fixed dose regardless the weight of the subject.

[0191] In some embodiments, the anti-FcRn agent or pharmaceutical composition comprising the anti-FcRn agent is administered at a dose from about 5 mg / kg to about 60 mg / kg. In some embodiments, the anti-FcRn agent or pharmaceutical composition comprising the anti-FcRn agent is administered at a dose from about 5 mg / kg to about 15 mg / kg. In some embodiments, the anti-FcRn agent or pharmaceutical composition comprising the anti-FcRn agent is administered at a dose from about 15 mg / kg to about 30 mg / kg. In some embodiments, the anti- FcRn agent or pharmaceutical composition comprising the anti-FcRn agent is administered at a dose from, about 15 mg / kg to about 60 mg / kg. In some embodiments, the anti-FcRn agent or pharmaceutical composition comprising the anti-FcRn agent is administered at a dose from about 30 mg / kg to about 60 mg / kg. In some embodiments, the anti-FcRn agent is administered every week or every two weeks at the dose ranges above. In some embodiments, the anti-FcRn agent or pharmaceutical composition comprising the anti-FcRn agent is administered intravenously or subcutaneously. In some embodiments, the anti-FcRn agent is nipocalimab.

[0192] In some embodiments, the anti-FcRn agent or pharmaceutical composition comprising the anti-FcRn agent is administered at a dose from about 100 - 1000 mg. In some embodiments, the anti-FcRn agent or pharmaceutical composition comprising the anti-FcRn agent is administered at a dose from about 200 - 8000 mg. In some embodiments, the anti-FcRn agent or pharmaceutical composition comprising the anti-FcRn agent is administered at a dose from about 300 - 700 mg. In some embodiments, the anti-FcRn agent is administered every week or every two weeks at the dose ranges above. In some embodiments, the anti-FcRn agent or pharmaceutical composition comprising the anti-FcRn agent is administered subcutaneously. In some embodiments, the anti-FcRn agent is nipocalimab.

[0193] In some embodiments, the anti-FcRn agent or pharmaceutical composition comprising the anti-FcRn agent is administered at a dose of about 60 mg / kg. In some embodiments, the anti- FcRn agent or pharmaceutical composition comprising the anti-FcRn agent is administered at a dose of about 55 mg / kg. In some embodiments, the anti-FcRn agent or pharmaceutical composition comprising the anti-FcRn agent is administered at a dose of about 50 mg / kg. In some embodiments, the anti-FcRn agent or pharmaceutical composition comprising the anti- FcRn agent is administered at a dose of about 45 mg / kg. In some embodiments, the anti-FcRn agent or pharmaceutical composition comprising the anti-FcRn agent is administered at a dose of about 40 mg / kg. In some embodiments, the anti-FcRn agent or pharmaceutical composition comprising the anti-FcRn agent is administered at a dose of about 35 mg / kg. In some embodiments, the anti-FcRn agent or pharmaceutical composition comprising the anti-FcRn agent is administered at a dose of about 30 mg / kg. In some embodiments, the anti-FcRn agent or pharmaceutical composition comprising the anti-FcRn agent is administered at a dose of about 25 mg / kg. In some embodiments, the anti-FcRn agent or pharmaceutical composition comprising the anti-FcRn agent is administered at a dose of about 20 mg / kg. In some embodiments, the anti- FcRn agent or pharmaceutical composition comprising the anti-FcRn agent is administered at a dose of about 15 mg / kg. In some embodiments, the anti-FcRn agent or pharmaceutical composition comprising the anti-FcRn agent is administered at a dose of about 10 mg / kg. In some embodiments, the anti-FcRn agent or pharmaceutical composition comprising the anti- FcRn agent is administered at a dose of about 5 mg / kg.

[0194] In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of the anti-FcRn agent. In some embodiments, the therapeutically effective amount is from about 5 mg / kg to about 60 mg / kg, about 5 mg / kg to about 15 mg / kg, about 15 mg / kg to about 30 mg / kg, about 15 mg / kg to about 45 mg / kg, about 30 mg / kg to about 45 mg / kg, or about 30 mg / kg to about 60 mg / kg of the anti-FcRn antibody (based on the weight of the subject). In some embodiments, the therapeutically effective amount is about 5 mg / kg, about 15 mg / kg, about 30 mg / kg, or about 45 mg / kg. In some embodiments, the therapeutically effective amount is about 5 mg / kg. In some embodiments, the therapeutically effective amount is about 15 mg / kg. In some embodiments, the therapeutically effective amount is about 30 mg / kg. In some embodiments, the therapeutically effective amount is about 45 mg / kg.

[0195] In some embodiments, pharmaceutical compositions comprising an anti-FcRn antibody are administered to a patient suffering from rheumatoid arthritis in a therapeutically effective amount from about 5 mg / kg to about 60 mg / kg (based on the weight of the subject) every 2 weeks. In some embodiments, pharmaceutical compositions comprising an anti-FcRn antibody are administered to a patient suffering from rheumatoid arthritis who previously received at least one DMARD in a therapeutically effective amount from about 5 mg / kg to about 60 mg / kg every 2 weeks. In some embodiments, the pharmaceutical composition is administered to the patient in a therapeutically effective amount from about 15 mg / kg to about 30 mg / kg every 2 weeks. In some embodiments, the pharmaceutical composition is administered to the patient in a therapeutically effective amount of about 15 mg / kg every 2 weeks. In some embodiments, the pharmaceutical composition is administered to the patient in a therapeutically effective amount of about 30 mg / kg every 2 weeks. In some embodiments, the pharmaceutical composition is administered to the patient in a therapeutically effective amount of about 45 mg / kg every 2 weeks. In some embodiments, the rheumatoid arthritis is moderate to severe active rheumatoid arthritis.

[0196] In some embodiments, the anti-FcRn agent, preferably an anti-FcRn antibody, is administered every week, every two weeks, or monthly. In some embodiments, the initial dose is different from every week or every two weeks dose. In some embodiments, the dose is the same every time it is administered. In some embodiments, the pharmaceutical composition is administered every week, every two weeks, or monthly. In some embodiments, the pharmaceutical composition is administered every week. In some embodiments, the pharmaceutical composition is administered every two weeks. In some embodiments, the pharmaceutical composition is administered monthly.

[0197] In some embodiments, the anti-TNF agent, preferably an anti-TNF antibody, is administered every week, every two weeks, or monthly. In some embodiments, the initial dose is different from every week or every two weeks dose. In some embodiments, the dose is the same every time it is administered. In some embodiments, the pharmaceutical composition is administered every week, every two weeks, or monthly. In some embodiments, the pharmaceutical composition is administered every week. In some embodiments, the pharmaceutical composition is administered every two weeks. In some embodiments, the pharmaceutical composition is administered every monthly.

[0198] In some embodiments, the anti-TNF agent or pharmaceutical composition comprising the anti-TNF agent is administered at a dose from about 50 - 500 mg. In some embodiments, the anti-TNF agent or pharmaceutical composition comprising the anti-TNF agent is administered at a dose from about 10 - 100 mg. In some embodiments, the anti-TNF agent or pharmaceutical composition comprising the anti-TNF agent is administered at a dose from about 20 - 200 mg. In some embodiments, the anti-TNF agent or pharmaceutical composition comprising the anti-TNF agent is administered at a dose from about 20 - 50 mg. In some embodiments, the anti-TNF agent or pharmaceutical composition comprising the anti-TNF agent is administered at a dose from about 30 - 150 mg. In some embodiments, the anti-TNF agent or pharmaceutical composition comprising the anti-TNF agent is administered at a dose from about 40 - 100 mg. In some embodiments, the anti-TNF agent is administered every week, every two weeks, every three weeks, or every four weeks at the dose ranges above. In some embodiments, the anti-TNF agent or pharmaceutical composition comprising the anti-TNF agent is administered intravenously or subcutaneously. In some embodiments, the anti-TNF agent is adalimumab, certolizumab pegol, etanercept, golimumab, or infliximab.

[0199] In some embodiments, the administration of the anti-FcRn agent or pharmaceutical composition comprising the anti-FcRn agent takes place over about 30-90 minutes. In some embodiments, the administration takes place over about 15-60 minutes. In some embodiments, the administration takes place in about 15 to about 30 minutes. In some embodiments, the administration takes place in about 15 to about 45 minutes. In some embodiments, the administration takes place in about 15 to about 90 minutes. In some embodiments, the administration takes place in about 15 to about 120 minutes. In some embodiments, the administration takes place in about 15 minutes, about 30 minutes, about 45 minutes, about 60 minutes, about 90 minutes, or about 120 minutes.

[0200] In some embodiments, the administration of the anti-TNF agent or pharmaceutical composition comprising the anti-TNF agent takes place over about 30-90 minutes. In some embodiments, the administration takes place over about 15-60 minutes. In some embodiments, the administration takes place in about 15 to about 30 minutes. In some embodiments, the administration takes place in about 15 to about 45 minutes. In some embodiments, the administration takes place in about 15 to about 90 minutes. In some embodiments, the administration takes place in about 15 to about 120 minutes. In some embodiments, the administration takes place in about 15 minutes, about 30 minutes, about 45 minutes, about 60 minutes, about 90 minutes, or about 120 minutes.

[0201] In some embodiments, the anti-FcRn agent or pharmaceutical composition comprising the anti-FcRn agent is administered parenterally. In some embodiments, the anti-FcRn agent or pharmaceutical composition comprising the anti-FcRn agent is administered intravenously or subcutaneously. In some embodiments, the anti-FcRn agent or pharmaceutical composition comprising the anti-FcRn agent is administered intraperitoneal, intradermally, or intramuscularly. In some embodiments, the anti-FcRn agent or pharmaceutical composition comprising the anti-FcRn agent is administered intravenously. In some embodiments, the anti- FcRn agent or pharmaceutical composition comprising the anti-FcRn agent is administered subcutaneously. In some embodiments, the anti-FcRn agent or pharmaceutical composition comprising the anti-FcRn agent is administered using an infusion pump. In some embodiments, the anti-FcRn agent or pharmaceutical composition comprising the anti-FcRn agent is administered using an autoinjector.

[0202] In some embodiments, the anti-TNF agent or pharmaceutical composition comprising the anti-TNF agent is administered parenterally. In some embodiments, the anti-TNF agent or pharmaceutical composition comprising the anti-TNF agent is administered intravenously or subcutaneously. In some embodiments, the anti-TNF agent or pharmaceutical composition comprising the anti-TNF agent is administered intraperitoneal, intradermally, or intramuscularly. In some embodiments, the anti-TNF agent or pharmaceutical composition comprising the anti- TNF agent is administered intravenously. In some embodiments, the anti-TNF agent or pharmaceutical composition comprising the anti-TNF agent is administered subcutaneously. In some embodiments, the anti-TNF agent or pharmaceutical composition comprising the anti-TNF agent is administered using an infusion pump. In some embodiments, the anti-TNF agent or pharmaceutical composition comprising the anti-TNF agent is administered using an auto injector.

[0203] In some embodiments, any pharmaceutical composition described herein comprises one or more of sodium phosphate, sodium chloride, trehalose, or polysorbate.

[0204] As used herein, the term “pharmaceutical composition” refers to a medicinal or pharmaceutical formulation that contains an active ingredient as well as one or more excipients and diluents to enable the active ingredient suitable for the method of administration. The pharmaceutical composition of the present disclosure includes pharmaceutically acceptable components that are compatible with the anti-FcRn agent, the anti-TNF agent, or both. The pharmaceutical composition may be in aqueous form for intravenous or subcutaneous administration or in tablet or capsule form for oral administration. In some embodiments, the composition is suitable for intravenous administration. In some embodiments, the composition is suitable for subcutaneous administration. In some embodiments, any pharmaceutical compositions that contain an anti-FcRn antibody may be formulated for intravenous administration, parenteral administration, subcutaneous administration, intramuscular administration, intra-arterial administration, intrathecal administration, or intraperitoneal administration. In some embodiments, the pharmaceutical composition may also be formulated for, or administered via, oral, nasal, spray, aerosol, rectal, or vaginal administration. For injectable formulations, various effective pharmaceutical carriers are known in the art.

[0205] In some embodiments, the pharmaceutical compositions that contain an anti-TNF agent may be formulated for intravenous administration, parenteral administration, subcutaneous administration, intramuscular administration, intra-arterial administration, intrathecal administration, or intraperitoneal administration. In some embodiments, the pharmaceutical composition may also be formulated for, or administered via, oral, nasal, spray, aerosol, rectal, or vaginal administration. For injectable formulations, various effective pharmaceutical carriers are known in the art.

[0206] As used herein, the term “pharmaceutically acceptable carrier” refers to an excipient or diluent in a pharmaceutical composition. The pharmaceutically acceptable carrier must be compatible with the other ingredients of the formulation and not deleterious to the recipient. In the present disclosure, the pharmaceutically acceptable carrier must provide adequate pharmaceutical stability to the Fc construct. The nature of the carrier differs with the mode of administration. For example, for intravenous administration, an aqueous solution carrier is generally used; for oral administration, a solid carrier may be preferred.

[0207] As used herein, the term “therapeutically effective amount” refers to an amount, e.g., pharmaceutical dose, effective in inducing a desired biological effect in a subject or patient or in treating a patient having a condition or disorder described herein. It is also to be understood that a “therapeutically effective amount” may be interpreted as an amount giving a desired therapeutic effect, either taken in one dose or in any dosage or route, taken alone or in combination with other therapeutic agents. As used herein, the term “no more than” refers to an amount that is less than or equal to. This may be an amount in integers. For example, no more than two substitutions can refer to 0, 1, or 2 substitutions.

[0208] As used herein, the terms “treatment” or “treating” refer to reducing, decreasing, decreasing the risk of, or decreasing the side effects of a particular disease or condition. Reducing, decreasing, decreasing the risk of, or decreasing the side effects of are relative to a subject who did not receive treatment, e.g., a control, a baseline, or a known control level or measurement.

[0209] Accordingly, in some embodiments, methods of treating rheumatoid arthritis in a subject are provided. In some embodiments, the rheumatoid arthritis is moderate to severe active rheumatoid arthritis. In some embodiments, the method comprises administering a pharmaceutical composition comprising administering an anti-FcRn antibody to the subject. In some embodiments, the anti-FcRn antibody is as provided for herein. In some embodiments, the subject being administered the anti-FcRn agent has demonstrated inadequate response to or is intolerant to at least one DMARD. In some embodiments, the subject being administered the anti-FcRn agent also receives at least one csDMARD treatment.

[0210] In some embodiments, the administration of the pharmaceutical composition to the patient to treat rheumatoid arthritis results in the patient showing improvement in DAS28-CRP score, ACR20 response, ACR50 response, ACR70 response, ACR90 response, HAQ-DI score, CD Al score, SDAI score, pain VAS score, FACIT-fatigue score, joint pain severity score, PtGA of disease activity score, and / or SF-36 score. In some embodiments, the subject treated for rheumatoid arthritis, or moderate to severe active rheumatoid arthritis, shows an improvement in one or more of the following assays, scores or criteria, which can be used to evaluate the improvement or condition of a subject with rheumatoid arthritis. In some embodiments, the subject shows improvement in one or more of the following: DAS28-CRP score, ACR20 response, ACR50 response, ACR70 response, ACR90 response, HAQ-DI score, CD Al score, SDAI score, pain VAS score, FACIT-fatigue score, joint pain severity score, PtGA of disease activity score, and SF-36 score. In some embodiments, the subject being treated for rheumatoid arthritis, or moderate to severe active rheumatoid arthritis has or shows a reduction in one or more immunoglobulin isotypes or total IgG. In some embodiments, the reduction is about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 1-20%, 5-20%, 5-25%, 10-30%, 15-35%, 20-40%, 40-60%, or, about, or at least, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, or 90% from the baseline level. In some embodiments, the isotype of immunoglobulins reduced is IgGl, IgG2, IgG3, IgG4, IgA, IgM or IgE, or any combination thereof. In some embodiments, the administration of the pharmaceutical composition to the patient shows a reduction in one or more immunoglobulin isotypes or total IgG in the patient. In some embodiments, the isotype is IgGl, IgG2, IgG3, IgG4, IgA, IgM or IgE. In some embodiments, the reduction is about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 1-20%, 5-20%, 5-25%, 10-30%, 15-35%, 20-40%, 40-60%, or, about, or at least, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, or 90% from the baseline level.

[0211] In some embodiments, the subject being treated for rheumatoid arthritis, or moderate to severe active rheumatoid arthritis has or shows a reduction in autoantibodies. In some embodiments, the reduction is about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 1-20%, 5- 20%, 5-25%, 10-30%, 15-35%, 20-40%, 40-60%, or, about, or at least, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, or 95% from the baseline level. In some embodiments, the autoantibodies reduced are selected from the group consisting of: rheumatoid factors (RF), anti-perinuclear factor (APF), anti-carbamylated protein antibodies (anti-CarP), anti-acetylated protein antibodies (AAPAs) anti-citrullinated protein antibodies (ACPA), anti-keratin antibodies (AKA), anti-filaggrin antibodies (AFA), and combinations thereof. In some embodiments, the administration of the pharmaceutical composition to the patient shows a reduction in autoantibodies. In some embodiments, the reduction is about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 1-20%, 5-20%, 5-25%, 10-30%, 15-35%, 20-40%, 40- 60%, or, about, or at least, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, or 95% from the baseline level. In some embodiments, the autoantibodies reduced are selected from the group consisting of: rheumatoid factors (RF), anti-perinuclear factor (APF), anti-carbamylated protein antibodies (anti-CarP), anti-acetylated protein antibodies (AAPAs) anti-citrullinated protein antibodies (ACPA), anti-keratin antibodies (AKA), anti-filaggrin antibodies (AFA), and combinations thereof. In some embodiments, the subject being treated for rheumatoid arthritis, or moderate to severe rheumatoid arthritis, shows an improvement as measured by the Disease Activity Index Score 28 using C-reactive protein (DAS28-CRP) score after being treated with the antibody. The DAS28-CRP is a statistically derived index combining tender joints (28 joints), swollen joints (28 joints), CRP, and PtGA of Disease Activity (van Riel et al., Van Zuiden Communications B.V.; 2000:40). The DAS28-CRP is a continuous parameter and is defined as follows:

[0212] DAS28-CRP = 0.56 x SQRT(TEN28) + 0.28 x SQRT(SW28) + 0.36 x In (CRP+1) + 0.014 x GH + 0.96

[0213] The set of 28 joint count is based on evaluation of the shoulder, elbow, wrist, metacarpophalangeal (MCP) 1, MCP2, MCP3, MCP4, MCP5, proximal interphalangeal (PIP) 1, PIP2, PIP3, PIP4, PIP5 joints of both the upper right extremity and the upper left extremity as well as the knee joints of lower right and lower left extremities. TEN28 is 28-joint count for tenderness. SQRT(TEN28) is square root of TEN28. SW28 is 28-joint count for swelling. SQRT(SW28) is square root of SW28. Ln (CRP+1) is natural logarithm of (CRP value [mg / L] + 1). GH is PtGA of Disease Activity on a VAS of 100 mm.

[0214] In some embodiments, the subject being treated for rheumatoid arthritis, or moderate to severe rheumatoid arthritis, shows an improvement as measured by the Disease Activity Index Score 28 using Erthrocyte Sedimentation Rate (DAS28-ESR) score after being treated with the antibody. The DAS28-ESR is a statistically derived index combining tender joints (28 joints), swollen joints (28 joints), ESR, and GH (Prevoo 1995). The DAS28-ESR is a continuous parameter and is defined as follows:

[0215] DAS28 (ESR) = 0.56 x SQRT(TEN28) + 0.28 x SQRT(SW28) + 0.70 x In (ESR) + 0.014 x GH

[0216] The set of 28 joint count is based on evaluation of the shoulder, elbow, wrist, metacarpophalangeal (MCP) 1, MCP2, MCP3, MCP4, MCP5, proximal interphalangeal (PIP) 1, PIP2, PIP3, PIP4, PIP5 joints of both the upper right extremity and the upper left extremity as well as the knee joints of lower right and lower left extremities. TEN28 is 28 joint count for tenderness. SQRT(TEN28) is square root of TEN28. SW28 is 28 joint count for swelling. SQRT(SW28) is square root of SW28. Ln (ESR) is natural logarithm of ESR. GH is PtGA of Disease Activity on a VAS of 100 mm.

[0217] DAS28 response is defined in Table A (van Riel 2000).

[0218] Table A: DAS 28 Response Criteria

[0219] Improvement from Baseline

[0220] DAS28 at the visit > 1.2 > 0.6 - 1.2 < 0.6

[0221] < 3.2 Good response Moderate response No response

[0222] > 3.2 - 5.1 Moderate response Moderate response No response

[0223] > 5.1 Moderate response No response No response

[0224] DAS28 low disease activity (LDA) is defined as a DAS28 value of <3.2 at a visit.

[0225] DAS28-CRP remission is defined as a DAS28 value of <2.6 at a visit. In some embodiments, the improvement is greater than or equal to 0.6 points from baseline. In some embodiments, the improvement is greater than 0.6 but no greater than 1.2 points from baseline. In some embodiments, the improvement is greater than 1.2 points from baseline. In some embodiments, the administration of the pharmaceutical composition to the patient results in an improvement in the patient as measured by the DAS28-CRP score over time or 12 weeks after administration of the first dose of the pharmaceutical composition to the patient. The baseline is the subject prior to be treated with the compositions or antibodies provided for herein.

[0226] In some embodiments, the improvement (i.e., a lower DAS28-CRP score) is greater than or equal to 0.6 points from baseline. In some embodiments, the improvement is greater than 0.6 but no greater than 1.2 points from baseline. In some embodiments, the improvement is greater than 1.2 points from baseline. In some embodiments, the administration of the pharmaceutical composition to the patient results in an improvement in the patient as measured by the DAS28- CRP score over time or 12 weeks after administration of the first dose of the pharmaceutical composition to the patient. The baseline is the subject prior to be treated with the compositions or antibodies provided for herein.

[0227] In some embodiments, the subject being treated for rheumatoid arthritis, or moderate to severe rheumatoid arthritis, shows an improvement as measured by the American College of Rheumatology Response (ACR) score after being treated with the antibody. ACR responses are presented as the numerical measurement of improvement in multiple disease assessment criteria.

[0228] In some embodiments, an ACR20 response (Felson et al., Arthritis Rheum. 1995;38(6):727-735) is defined as:

[0229] >20% improvement from baseline in both swollen joint count (66 joints) and tender joint count (68 joints); AND

[0230] >20% improvement from baseline in 3 of the following 5 assessments:

[0231] Patient’s Global Assessment of Disease Activity (VAS), Patient’s assessment of pain (VAS), Patient’s assessment of physical function as measured by HAQ-DI, Physician’s Global Assessment of Disease Activity (VAS), and CRP.

[0232] In some embodiments, an ACR50 response is defined as:

[0233] >50% improvement from baseline in both swollen joint count (66 joints) and tender joint count (68 joints); AND

[0234] >50% improvement from baseline in 3 of the following 5 assessments:

[0235] Patient’s Global Assessment of Disease Activity (VAS), Patient’s assessment of pain (VAS), Patient’s assessment of physical function as measured by HAQ-DI, Physician’s Global Assessment of Disease Activity (VAS), and CRP.

[0236] In some embodiments, an ACR70 response is defined as:

[0237] >70% improvement from baseline in both swollen joint count (66 joints) and tender joint count (68 joints); AND

[0238] >70% improvement from baseline in 3 of the following 5 assessments:

[0239] Patient’s Global Assessment of Disease Activity (VAS), Patient’s assessment of pain (VAS), Patient’s assessment of physical function as measured by HAQ-DI, Physician’s Global Assessment of Disease Activity (VAS), and CRP.

[0240] In some embodiments, an ACR90 response is defined as:

[0241] >90% improvement from baseline in both swollen joint count (66 joints) and tender joint count (68 joints); AND

[0242] >90% improvement from baseline in 3 of the following 5 assessments:

[0243] Patient’s Global Assessment of Disease Activity (VAS), Patient’s assessment of pain (VAS), Patient’s assessment of physical function as measured by HAQ-DI, Physician’s Global Assessment of Disease Activity (VAS), and CRP.

[0244] In some embodiments, the subject being treated for rheumatoid arthritis, or moderate to severe rheumatoid arthritis, shows an improvement as measured by the Health Assessment Questionnaire - Disability Index (HAQ-DI) score after being treated with the antibody. The functional status of the participant is assessed using the HAQ-DI (Fries 1980). This 20-question instrument assesses the degree of difficulty a person has in accomplishing tasks in 8 functional areas (dressing, arising, eating, walking, hygiene, reaching, gripping, and activities of daily living). Responses in each functional area are scored from 0, indicating no difficulty, to 3, indicating inability to perform a task in that area. A score decrease greater than or equal to 0.22 is considered the minimum threshold for a clinically important improvement (Kosinski 2000; Pope 2009; Wells 1993).

[0245] In some embodiments, the subject being treated for rheumatoid arthritis, or moderate to severe rheumatoid arthritis, shows an improvement as measured by the Clinical Disease Activity Index (CD Al) score after being treated with the antibody. The Clinical Disease Activity Index (CD Al) score is a derived score combining tender joints (28 joints), swollen joints (28 joints), PtGA of Disease Activity, and PGA of Disease Activity (Aletaha 2006). The CD Al score is defined as follows:

[0246] CD Al = TEN28 + SW28 + GH + PGH where:

[0247] TEN28 is 28 joint count for tenderness. SQRT(TEN28) is square root of TEN28. SW28 is 28 joint count for swelling. SQRT(SW28) is square root of SW28. GH is PtGA of Disease Activity (VAS). PGH is PGA of Disease Activity (VAS).

[0248] CD Al LDA is defined as a CD Al score of <10 at a visit. CD Al remission is defined as a CD Al score of <2.8 at a visit.

[0249] In some embodiments, the method comprises administering the anti-FcRn agent to the subject with rheumatoid arthritis and having a baseline ACPA level higher than the ACPA reference level, and the method provides a clinical benefit as measured by a decrease in DAS28- CRP by more than 0.7 from baseline within 12 weeks of initiation of treatment. In some embodiments, the subject achieved DAS28-CRP remission (i.e., a lower DAS28-CRP score) within 12 weeks of initiation of treatment. In some embodiments, the subject has at least a 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 110%, or 120% higher chance of achieving DAS28- CRP remission within 12 weeks of treatment compared to subjects having an ACPA level lower than the ACPA reference level prior to treatment. In some embodiments, the subject achieved DAS28-CRP LDA within 12 weeks of initiation of treatment. In some embodiments, the subject achieved a decrease in Clinical Disease Activity Index (CD Al) by more than 10 from baseline within 12 weeks of initiation of the treatment. In some embodiments, the subject achieved a decrease in Health Assessment Questionnaire-Disability Index (HAQ-DI) by more than 0.4 from baseline within 12 weeks of initiation of the treatment. In some embodiments, the subject achieved an ACR50 response within 12 weeks of initiation of the treatment. In some embodiments, the subject achieved an ACR70 response within 12 weeks of initiation of the treatment. In some embodiments, the subject achieved an ACR90 response within 12 weeks of initiation of the treatment. Throughout the present application, the terms “initiation of treatment” and “initiation of administering” are used interchangeably and refers to the start of the first dose of the composition comprising the anti-FcRn agent.

[0250] In some embodiments, where the subject being administered the anti-FcRn agent also receives at least one csDMARD treatment, the subject achieved a decrease in DAS28-CRP by more than 0.9 from baseline within 8 weeks, 9 weeks, 10 weeks, 11 weeks, or 12 weeks of initiation of the csDMARD treatment. In some embodiments, the subject achieved a decrease in DAS28-CRP by more than 1.2 from baseline within 10 weeks, 11 weeks, or 12 weeks of initiation of the csDMARD treatment. In some embodiments, the subject achieved a decrease in Clinical Disease Activity Index (CD Al) by more than 10 from baseline within 12 weeks of initiation of the csDMARD treatment.

[0251] In some embodiments, where the subject being administered the anti-FcRn agent and the anti-TNF agent and optionally the at least one csDMARD treatment, the method provides a clinical benefit as measured by a decrease in DAS28-CRP in the subject by more than 0.8 from baseline within 12 weeks of initiation of treatment. In some embodiments, the method provides a clinical benefit as measured by a decrease in DAS28-CRP by more than 1 from baseline within 12 weeks of initiation of treatment. In some embodiments, the method provides a clinical benefit as measured by a decrease in DAS28-CRP by more than 1.2 from baseline within 12 weeks of initiation of treatment. In some embodiments, the method provides a clinical benefit as measured by a decrease in DAS28-CRP by more than 1.4 from baseline within 12 weeks of initiation of treatment. In some embodiments, the method provides a clinical benefit as measured by a decrease in DAS28-CRP by more than 1.6 from baseline within 12 weeks of initiation of treatment. In some embodiments, the method provides a clinical benefit as measured by a decrease in DAS28-CRP by more than 1.8 from baseline within 12 weeks of initiation of treatment. In some embodiments, the method provides a clinical benefit as measured by a decrease in DAS28-CRP by more than 2 from baseline within 12 weeks of initiation of treatment. In some embodiments, the method provides a clinical benefit as measured by a decrease in DAS28-CRP by more than 2.2 from baseline within 12 weeks of initiation of treatment. In some embodiments, the method provides a clinical benefit as measured by a decrease in DAS28-CRP by more than 2.4 from baseline within 12 weeks of initiation of treatment. In some embodiments, the method provides a clinical benefit as measured by a decrease in DAS28-CRP by more than 2.6 from baseline within 12 weeks of initiation of treatment. In some embodiments, the method provides a clinical benefit as measured by a decrease in DAS28-CRP by more than 2.8 from baseline within 12 weeks of initiation of treatment. In some embodiments, the method provides a clinical benefit as measured by a decrease in DAS28-CRP by more than 3 from baseline within 12 weeks of initiation of treatment. In some embodiments, the method provides a clinical benefit as measured by a decrease in DAS28-CRP by more than 3.2 from baseline within 12 weeks of initiation of treatment. In some embodiments, the method provides a clinical benefit as measured by a decrease in DAS28-CRP by more than 3.4 from baseline within 12 weeks of initiation of treatment. In some embodiments, the method provides a clinical benefit as measured by a decrease in DAS28-CRP by more than 3.6 from baseline within 12 weeks of initiation of treatment. In some embodiments, the method provides a clinical benefit as measured by a decrease in DAS28-CRP by more than 3.8 from baseline within 12 weeks of initiation of treatment. In some embodiments, the method provides a clinical benefit as measured by a decrease in DAS28-CRP by more than 4 from baseline within 12 weeks of initiation of treatment. In some embodiments, the method provides a clinical benefit as measured by a decrease in DAS28-CRP by more than 4.2 from baseline within 12 weeks of initiation of treatment. In some embodiments, the method provides a clinical benefit as measured by a decrease in DAS28-CRP by more than 4.4 from baseline within 12 weeks of initiation of treatment. In some embodiments, the method provides a clinical benefit as measured by a decrease in DAS28-CRP by more than 4.6 from baseline within 12 weeks of initiation of treatment. In some embodiments, the method provides a clinical benefit as measured by a decrease in DAS28-CRP by more than 4.8 from baseline within 12 weeks of initiation of treatment. In some embodiments, the method provides a clinical benefit as measured by a decrease in DAS28-CRP by more than 5 from baseline within 12 weeks of initiation of treatment. In some embodiments, the method provides a clinical benefit as measured by a decrease in DAS28-CRP by more than 5.2 from baseline within 12 weeks of initiation of treatment. In some embodiments, the method provides a clinical benefit as measured by a decrease in DAS28-CRP by more than 5.4 from baseline within 12 weeks of initiation of treatment. In some embodiments, the method provides a clinical benefit as measured by a decrease in DAS28-CRP by more than 5.6 from baseline within 12 weeks of initiation of treatment. In some embodiments, the method provides a clinical benefit as measured by a decrease in DAS28-CRP by more than 5.8 from baseline within 12 weeks of initiation of treatment. In some embodiments, the method provides a clinical benefit as measured by a decrease in DAS28-CRP by more than 6 from baseline within 12 weeks of initiation of treatment.. In some embodiments, the subject achieved DAS28-CRP LDA within 12 weeks of initiation of the treatment. In some embodiment, the subject achieved a decrease in CD Al by more than 11 from baseline within 12 weeks of initiation of the treatment. In some embodiment, the subject achieved a decrease in CD Al by more than 13 from baseline within 12 weeks of initiation of the treatment. In some embodiment, the subject achieved a decrease in CD Al by more than 15 from baseline within 12 weeks of initiation of the treatment. In some embodiment, the subject achieved a decrease in CD Al by more than 17 from baseline within 12 weeks of initiation of the treatment. In some embodiment, the subject achieved a decrease in CD Al by more than 19 from baseline within 12 weeks of initiation of the treatment. In some embodiment, the subject achieved a decrease in CD Al by more than 21 from baseline within 12 weeks of initiation of the treatment. In some embodiment, the subject achieved a decrease in CD Al by more than 23 from baseline within 12 weeks of initiation of the treatment. In some embodiment, the subject achieved a decrease in CD Al by more than 25 from baseline within 12 weeks of initiation of the treatment. In some embodiment, the subject achieved a decrease in CD Al by more than 27 from baseline within 12 weeks of initiation of the treatment. In some embodiment, the subject achieved a decrease in CD Al by more than 29 from baseline within 12 weeks of initiation of the treatment. In some embodiment, the subject achieved a decrease in CD Al by more than 31 from baseline within 12 weeks of initiation of the treatment. In some embodiment, the subject achieved a decrease in CD Al by more than 33 from baseline within 12 weeks of initiation of the treatment. In some embodiment, the subject achieved a decrease in CD Al by more than 35 from baseline within 12 weeks of initiation of the treatment. In some embodiment, the subject achieved a decrease in CD Al by more than 37 from baseline within 12 weeks of initiation of the treatment. In some embodiment, the subject achieved a decrease in CD Al by more than 39 from baseline within 12 weeks of initiation of the treatment. In some embodiment, the subject achieved a decrease in CD Al by more than 41 from baseline within 12 weeks of initiation of the treatment. In some embodiment, the subject achieved a decrease in CD Al by more than 43 from baseline within 12 weeks of initiation of the treatment. In some embodiment, the subject achieved a decrease in CD Al by more than 45 from baseline within 12 weeks of initiation of the treatment. In some embodiment, the subject achieved a decrease in CD Al by more than 47 from baseline within 12 weeks of initiation of the treatment. In some embodiment, the subject achieved a decrease in CD Al by more than 49 from baseline within 12 weeks of initiation of the treatment. In some embodiment, the subject achieved a decrease in CD Al by more than 51 from baseline within 12 weeks of initiation of the treatment. In some embodiment, the subject achieved a decrease in CD Al by more than 53 from baseline within 12 weeks of initiation of the treatment. In some embodiment, the subject achieved a decrease in CD Al by more than 55 from baseline within 12 weeks of initiation of the treatment. In some embodiment, the subject achieved a decrease in CD Al by more than 57 from baseline within 12 weeks of initiation of the treatment. In some embodiment, the subject achieved a decrease in CD Al by more than 59 from baseline within 12 weeks of initiation of the treatment. In some embodiment, the subject achieved a decrease in CD Al by more than 61 from baseline within 12 weeks of initiation of the treatment. In some embodiment, the subject achieved a decrease in CD Al by more than 63 from baseline within 12 weeks of initiation of the treatment. In some embodiment, the subject achieved a decrease in CD Al by more than 65 from baseline within 12 weeks of initiation of the treatment. In some embodiment, the subject achieved a decrease in CD Al by more than 67 from baseline within 12 weeks of initiation of the treatment. In some embodiment, the subject achieved a decrease in CD Al by more than 69 from baseline within 12 weeks of initiation of the treatment. In some embodiment, the subject achieved a decrease in CD Al by more than 70 from baseline within 12 weeks of initiation of the treatment. In some embodiments, the subject achieved a decrease in HAQ-DI by more than 0.5 from baseline within 12 weeks of initiation of treatment. In some embodiments, the subject achieved a decrease in HAQ-DI by more than 0.6 from baseline within 12 weeks of initiation of treatment. In some embodiments, the subject achieved a decrease in HAQ-DI by more than 0.7 from baseline within 12 weeks of initiation of treatment. In some embodiments, the subject achieved a decrease in HAQ-DI by more than 0.8 from baseline within 12 weeks of initiation of treatment. In some embodiments, the subject achieved a decrease in HAQ-DI by more than 0.9 from baseline within 12 weeks of initiation of treatment. In some embodiments, the subject achieved a decrease in HAQ-DI by more than 1 from baseline within 12 weeks of initiation of treatment. In some embodiments, the subject achieved a decrease in HAQ-DI by more than 1.1 from baseline within 12 weeks of initiation of treatment. In some embodiments, the subject achieved a decrease in HAQ-DI by more than 1.2 from baseline within 12 weeks of initiation of treatment. In some embodiments, the subject achieved a decrease in HAQ-DI by more than 1.3 from baseline within 12 weeks of initiation of treatment. In some embodiments, the subject achieved a decrease in HAQ-DI by more than 1.4 from baseline within 12 weeks of initiation of treatment. In some embodiments, the subject achieved a decrease in HAQ-DI by more than 1.5 from baseline within 12 weeks of initiation of treatment. In some embodiments, the subject achieved a decrease in HAQ-DI by more than 1.6 from baseline within 12 weeks of initiation of treatment. In some embodiments, the subject achieved a decrease in HAQ-DI by more than 1.7 from baseline within 12 weeks of initiation of treatment. In some embodiments, the subject achieved a decrease in HAQ-DI by more than 1.8 from baseline within 12 weeks of initiation of treatment. In some embodiments, the subject achieved a decrease in HAQ-DI by more than 1.9 from baseline within 12 weeks of initiation of treatment. In some embodiments, the subject achieved a decrease in HAQ-DI by more than 2 from baseline within 12 weeks of initiation of treatment. In some embodiments, the patient achieves ACR20 after being treated with the antibody. In some embodiments, the patient achieves ACR50 after being treated with the anti-FcRn agent and the anti-TNF agent. In some embodiments, the patient achieves ACR70 after being treated with the anti-FcRn agent and the anti-TNF agent. In some embodiments, the patient achieves ACR90 after being treated with the anti-FcRn agent and the anti-TNF agent. In some embodiments, the administration of the pharmaceutical composition to the patient results in an improvement in the patient as measured by ACR score over time or 12 weeks after administration of the first dose of the anti-FcRn agent and the anti-TNF agent to the patient. In some embodiments, the subject achieves an ACR20 response within 12 weeks of initiation of treatment. In some embodiments, the subject achieves an ACR50 response within 12 weeks of initiation of treatment. In some embodiments, the subject achieves an ACR70 response within 12 weeks of initiation of treatment. In some embodiments, the subject achieves an ACR90 response within 12 weeks of initiation of treatment.

[0252] In some embodiments, the improvement (i.e., a score decrease) is greater than or equal to 0.22 points from baseline. In some embodiments, the improvement is greater than or equal to 0.4 points from baseline. In some embodiments, the administration of the pharmaceutical composition to the patient results in an improvement in HAQ-DI score over time or 12 weeks after administration of the first dose of the pharmaceutical composition to the patient. In some embodiments, the administration of the pharmaceutical composition to the patient results in an improvement of greater or equal to 0.22 on the HAQ-DI scale and indicates clinically important improvement. In some embodiments, the method provides a clinical benefit as measured by a decrease (i.e., an improvement) in HAQ-DI score by more than 0.4 from baseline within 12 weeks of initiation of treatment. In some embodiments, the method provides a clinical benefit as measured by a decrease in HAQ-DI score by more than 0.5 from baseline within 12 weeks of initiation of treatment. In some embodiments, the method provides a clinical benefit as measured by a decrease in HAQ-DI score by more than 0.6 from baseline within 12 weeks of initiation of treatment. In some embodiments, the method provides a clinical benefit as measured by a decrease in HAQ-DI score by more than 0.7 from baseline within 12 weeks of initiation of treatment. In some embodiments, the method provides a clinical benefit as measured by a decrease in HAQ-DI score by more than 0.8 from baseline within 12 weeks of initiation of treatment. In some embodiments, the method provides a clinical benefit as measured by a decrease in HAQ-DI score by more than 0.9 from baseline within 12 weeks of initiation of treatment. In some embodiments, the method provides a clinical benefit as measured by a decrease in HAQ-DI score by more than 1 from baseline within 12 weeks of initiation of treatment. The baseline is the subject prior to be treated with the anti-FcRn agent and the anti- TNF agent.

[0253] In some embodiments, the administration of the anti-FcRn agent and the anti-TNF agent to the patient results in a decreased in the CD Al baseline score over time or 12 weeks after initiation of the treatment. In some embodiments, the administration of the anti-FcRn agent and the anti-TNF agent to the patient results in a CD Al score that is less than 2.8 on the CD Al scale and indicates remission. In some embodiments, the administration of the anti-FcRn agent and the anti-TNF agent to the patient results a CD Al score that is less than or equal to 10 on the CD Al scale and indicates low disease activity. In some embodiments, the method provides a clinical benefit as measured by a decrease in CD Al score by more than 13 from baseline within 12 weeks of initiation of treatment. In some embodiments, the method provides a clinical benefit as measured by a decrease in CD Al score by more than 15 from baseline within 12 weeks of initiation of treatment. In some embodiments, the method provides a clinical benefit as measured by a decrease in Clinical Disease Activity Index (CD Al) by more than 17, more than 19, more than 21, more than 23, more than 25, more than 27, more than 29, more than 31, more than 33, or more than 35 from baseline within 12 weeks of initiation of treatment.

[0254] In some embodiments, wherein the subject being administered the anti-FcRn agent and the anti-TNF agent also receives at least one csDMARD treatment, the method provides a clinical benefit as measured by a decrease in a CD Al score by more than 17 from baseline within 12 weeks of initiation of treatment. In some embodiments, the method provides a clinical benefit as measured by a decrease in Clinical Disease Activity Index (CD Al) by more than 18, more than 19, more than 21, more than 23, more than 25, more than 27, more than 29, more than 31, more than 33, or more than 35, or more than 37, or more than 39 from baseline within 12 weeks of initiation of said administering. The baseline is the subject prior to be treated with the compositions or antibodies provided for herein.

[0255] In some embodiments, the subject being treated for rheumatoid arthritis, or moderate to severe rheumatoid arthritis, shows an improvement as measured by the Simplified Disease Activity Index (SDAI) score after being treated with the antibody. The Simplified Disease Activity Index (SDAI) for RA score is a derived score combining tender joints (28 joints), swollen joints (28 joints), PtGA of Disease Activity, PGA of Disease Activity, and CRP (Aletaha 2006). The SDAI score is defined as follows:

[0256] SDAI = TEN28 + SW28 + GH + PGH + CRP (mg / dL) where:

[0257] TEN28 is 28 joint count for tenderness. SQRT(TEN28) is square root of TEN28. SW28 is 28 joint count for swelling. SQRT(SW28) is square root of SW28. GH is Patient’s Global Assessment of Disease Activity (VAS). PGH is Physician’s Global Assessment of Disease Activity (VAS).

[0258] SDAI LDA is defined as a SDAI score of <5.5 at a visit. In some embodiments, the improvement is a SDAI score that is lesser than or equal to 5.5 points from baseline. In some embodiments, the improvement that is a SDAI score that is lesser than or equal to 5.5 points from baseline indicates SDAI LDA. SDAI-based ACR / EULAR remission is defined as a SDAI value of < 3.3 at a visit (Felson 2011). In some embodiments, the improvement is a SDAI score that is lesser than or equal to 3.3 points from baseline. In some embodiments, the improvement that is a SDAI score that is lesser than or equal to 3.3 points from baseline indicates ACR / EULAR remission. In some embodiments, the administration of the pharmaceutical composition to the patient results in an improvement in SDAI baseline score over time or 12 weeks after administration of the first dose of the pharmaceutical composition to the patient. In some embodiments, the administration of the pharmaceutical composition to the patient results in an improvement that is a SDAI score that is lesser than or equal to 3.3 on the SDAI scale and indicates remission. In some embodiments, the administration of the pharmaceutical composition to the patient results in an improvement that is a SDAI score that is lesser than or equal to 5.5 on the SDAI scale and indicates low disease activity. In some embodiments, the administration of the pharmaceutical composition to the patient results in an improvement in PtGA of disease activity baseline score over time or 12 weeks after administration of the first dose of the pharmaceutical composition to the patient. In some embodiments, the administration of the pharmaceutical composition to the patient results in an improvement on the PtGA of disease activity scale. In some embodiments, the improvement on the PtGA of disease activity scale is a PtGA score that is lesser than or equal to 2.0 on the PtGA of disease activity scale and indicates low disease activity. The baseline is the subject prior to be treated with the compositions or antibodies provided for herein.

[0259] In some embodiments, the subject being treated for rheumatoid arthritis, or moderate to severe rheumatoid arthritis, shows an improvement as measured by the pain assessment score after being treated with the antibody. Participants are asked to assess their average pain during the past week on a VAS. The scale ranges from “no pain” to “the worst possible pain”. This assessment is completed prior to the joint examination. The validity of this assessment has been evaluated and reviewed extensively as it is a component of the ACR response score (Felson 1993; Hawley 1992). In some embodiments, the improvement is improvement in pain intensity from baseline. In some embodiments, the administration of the pharmaceutical composition to the patient results in an improvement in pain intensity from baseline. The baseline is the subject prior to be treated with the compositions or antibodies provided for herein. In some embodiments, the improvement is at least 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, or 300% as compared to the baseline.

[0260] In some embodiments, the subject being treated for rheumatoid arthritis, or moderate to severe rheumatoid arthritis, shows an improvement as measured by the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) score after being treated with the antibody. The FACIT-Fatigue assessment (version 4.0) is a 13-item questionnaire formatted for participant self-administration that assesses patient-reported fatigue and its impact upon daily activities and function over the past 7 days. Participants are asked to answer each question using a 5-point Likert-type scale (0=Not at all; 1=A little bit; 2=Somewhat; 3=Quite a bit; and 4=Very Much). The interpretation of FACIT-Fatigue score is such that a higher score indicates less fatigue, with a range of possible scores of 0-52, with 0 being the worst possible score and 52 the best. The FACIT-Fatigue can generally be completed in 5 minutes (Celia 2002; Yellen 1997). In some embodiments, the administration of the pharmaceutical composition to the patient results in an improvement from baseline on FACIT-Fatigue scale. In some embodiments, the score increases at least 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, or 300% as compared to the baseline. In some embodiments, the subject being treated for rheumatoid arthritis, or moderate to severe rheumatoid arthritis, shows an improvement as measured by joint pain score after being treated with the antibody. Participants’ joint pain is assessed using a single item that asks the participant to report the worst severity of their joint pain over the past 7 days on a 0 to 10 numeric rating scale (NRS). In some embodiments, the administration of the pharmaceutical composition to the patient results in an improvement from baseline on NRS scale. Responses range from 'No joint pain' (0) to 'Severe joint pain' (10). In some embodiments, the improvement is at least 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, or 300% as compared to the baseline.

[0261] In some embodiments, the subject being treated for rheumatoid arthritis, or moderate to severe rheumatoid arthritis, shows an improvement as measured by joint pain score after being treated with the antibody. Participants' joint pain is assessed using a single item that asks the participant to report the worst severity of their joint pain over the past 7 days on a 0 to 10 numeric rating scale (NRS). In some embodiments, the administration of the pharmaceutical composition to the patient results in an improvement from baseline on NRS scale. Responses range from 'No joint pain' (0) to 'Severe joint pain' (10). In some embodiments, the improvement is at least 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, or 300% as compared to the baseline.

[0262] In some embodiments, the subject being treated for rheumatoid arthritis, or moderate to severe rheumatoid arthritis, shows an improvement as measured by joint assessments score after being treated with the antibody. Each of 68 joints is evaluated for tenderness, and each of 66 joints is evaluated for swelling (hips are excluded for swelling). All joints are examined at visits. It is recommended that the joint assessor should not be changed during the study. Joints should only be designated as “non-evaluable” by the joint assessor on the Joint Assessment Worksheet if it is physically impossible to assess the joint (i.e., joint inaccessible due to a cast, joint was replaced, joint not present due to an amputation, joint deformed so as to make it impossible to assess). In all other cases, the joint assessor should assess each joint for tenderness and swelling (hips are excluded for swelling) and complete the worksheet with their assessments. This should be completed regardless of any visual indications of prior surgeries (e.g., scars) or knowledge they may have of a participant’s prior joint procedures / inj ections (e.g., if the participant was the joint assessor’s patient prior to study participation). In some embodiments, the improvement is at least 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, or 300% as compared to the baseline.

[0263] In some embodiments, the subject being treated for rheumatoid arthritis, or moderate to severe rheumatoid arthritis, shows an improvement as measured by the 36-item Short Form Health Survey Questionnaire (SF-36) score after being treated with the antibody. The SF-36 version 2 Standard health survey is a self-administered, 36-item questionnaire measuring health related quality of life, with a recall period of the past 4 weeks. It includes 8 domains that measure physical functioning, role limitations due to physical health problems, bodily pain, general health, vitality, social functioning, role limitations due to emotional problems and mental health. The 8 domains can be aggregated into 2 summary scales that reflect physical and mental health: a physical component scale (PCS) and a mental component score (MCS). Responses to all items are rated on a 3-, 5- or 6 point Likert scale. The SF-36 version 2 Standard survey can generally be completed in 5 to 10 minutes (Quality Metric 2011). In some embodiments, the administration of the pharmaceutical composition to the patient results in an improvement from baseline on SF- 36 scale. In some embodiments, the administration of the pharmaceutical composition to the patient results in an improvement from baseline on PCS scale. In some embodiments, the administration of the pharmaceutical composition to the patient results in an improvement from baseline on MCS scale. In some embodiments, the improvement is an improvement on the physical health scale. In some embodiments, the improvement is an improvement on the mental health scale. In some embodiments, the improvement is an improvement on the physical and mental health scale. In some embodiments, the improvement is at least 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, or 300% as compared to the baseline.

[0264] As used herein, the term “change” in reference to a baseline refers to a subject having an improvement as compared to that subject’s conditions, scores, symptoms, and the like prior to being treated with the anti-FcRn antibodies as provided for herein.

[0265] “Baseline” refers to a subject prior to being treated with a therapeutic, such as the anti- FcRn agent, including those described herein. In some embodiments, the improvement in symptoms or conditions are referred to as occurring 12 weeks after initiation of treatment. Although reference is made to determining whether those improvements are measurable at 12 weeks after initiation of treatment, in some embodiments, the improvements or changes described herein will occur within 2, 4, 6, 8, 10, 12, 14, 16, or 18 weeks. In some embodiments, the changes or improvements will last at least 2, 4, 6, 8, 10, 12, 14, 16, 18 weeks, or longer.

[0266] In some embodiments, the subject being treated for rheumatoid arthritis, or moderate to severe active rheumatoid arthritis with an anti-FcRn agent has been previously treated with a different therapeutic to treat the rheumatoid arthritis, or moderate to severe active rheumatoid arthritis. In some embodiments, the subject has previously been treated with glucocorticoids, immunosuppressives, pharmacological gland stimulant, topical ophthalmologic medication (other than artificial tears), hydroxychloroquine (or other antimalarial); NSAIDs, Methotrexate, Leflunomide, rituximab, anti-BAFF monoclonal antibody, or other B cell depleting therapeutic, anti -tumor necrosis factor (TNF) therapeutic, or other biologic medication (e.g., tocilizumab, alefacept, efalizumab, natalizumab, abatacept, anakinra, brodalumab, secukinumab, ixekizumab, or agents whose mechanism of action targets interleukin (IL) 1, IL-2, IL-6, IL- 17, cytotoxic T- lymphocyte-associated protein (CTLA) 4, or interferon pathway drugs), cyclosporine A, tacrolimus, or pimecrolimus. In some embodiments, the subject has previously been treated with a first anti-FcRn agent and is then switched to a different anti-FcRn agent. In some embodiments, the subject has been previously treated with a therapeutic to treat the rheumatoid arthritis that is not an anti-FcRn agent described herein (e.g., the anti-FcRn antibody nipocalimab).

[0267] In some embodiments, the subject being treated for rheumatoid arthritis is a subject in need thereof.

[0268] In some embodiments, the subject being treated for rheumatoid arthritis with an anti- FcRn agent does not experience significantly increased levels of total cholesterol, high-density lipoprotein (HDL), calculated low-density lipoprotein (LDL), and triglycerides after being treated with the agent. In some embodiments, the anti-FcRn agent is an anti-FcRn antibody as provided herein. In some embodiments, the subject being treated for rheumatoid arthritis with an anti-FcRn antibody does not experience significantly increased levels of total cholesterol after being treated with the antibody. In some embodiments, the subject being treated for rheumatoid arthritis with an anti-FcRn antibody does not experience significantly increased levels of high- density lipoprotein (HDL) after being treated with the antibody. In some embodiments, the subject being treated for rheumatoid arthritis with an anti-FcRn antibody does not experience significantly increased levels of calculated low-density lipoprotein (LDL) after being treated with the antibody. In some embodiments, the subject being treated for rheumatoid arthritis with an anti-FcRn antibody does not experience significantly increased levels of triglycerides after being treated with the antibody. In some embodiments, the subject being treated for rheumatoid arthritis with an anti-FcRn antibody does not experience significantly increased levels of total cholesterol after being treated with the anti-FcRn antibody. In some embodiments, the subject being treated for rheumatoid arthritis with an anti-FcRn antibody does not experience significantly increased levels of high-density lipoprotein (HDL) after being treated with the anti- FcRn antibody. In some embodiments, the subject being treated for rheumatoid arthritis with an anti-FcRn antibody does not experience significantly increased levels of calculated low-density lipoprotein (LDL) after being treated with the anti-FcRn antibody. In some embodiments, the subject being treated for rheumatoid arthritis with an anti-FcRn antibody does not experience significantly increased levels of triglycerides after being treated with the anti-FcRn antibody.

[0269] In some embodiments, the administration of the pharmaceutical composition to the patient does not significantly increase levels of total cholesterol, high-density lipoprotein (HDL), calculated low-density lipoprotein (LDL), and triglycerides after administration of the pharmaceutical composition comprising the antibody. In some embodiments, the antibody is an anti-FcRn antibody. In some embodiments, the anti-FcRn antibody is as provided herein. In some embodiments, the administration of the pharmaceutical composition to the patient does not significantly increase levels of total cholesterol after administration of the pharmaceutical composition comprising the antibody. In some embodiments, the administration of the pharmaceutical composition to the patient does not significantly increase levels of high-density lipoprotein (HDL) after administration of the pharmaceutical composition comprising the antibody. In some embodiments, the administration of the pharmaceutical composition to the patient does not significantly increase levels of calculated low-density lipoprotein (LDL) after administration of the pharmaceutical composition comprising the antibody. In some embodiments, the administration of the pharmaceutical composition to the patient does not significantly increase levels of triglycerides after administration of the pharmaceutical composition comprising the antibody. In some embodiments, the administration of the pharmaceutical composition to the patient does not significantly increase levels of total cholesterol after administration of the pharmaceutical composition comprising the anti-FcRn antibody. In some embodiments, the administration of the pharmaceutical composition to the patient does not significantly increase levels of high-density lipoprotein (HDL) after administration of the pharmaceutical composition comprising the anti-FcRn antibody. In some embodiments, the administration of the pharmaceutical composition to the patient does not significantly increase levels of calculated low-density lipoprotein (LDL) after administration of the pharmaceutical composition comprising the anti-FcRn antibody. In some embodiments, the administration of the pharmaceutical composition to the patient does not significantly increase levels of triglycerides after administration of the pharmaceutical composition comprising the anti-FcRn antibody.

[0270] As used herein, the phrase “does not significantly increase” when used in reference to levels (measurements) of total cholesterol, high-density lipoprotein (HDL), calculated low- density lipoprotein (LDL), or triglycerides” means that any increase is at most 30% as compared to the level(s) prior (baseline) to the administration of the antibody or compositions provided for herein. In some embodiments, the increase is at most 25%, 20%, 15%, 10%, or 5%. In some embodiments, the increase is at most about 1% to about 30%, about 5% to about 25%, about 1% to about 20%, about 1% to about 15%, about 1% to about 10%, about 5% to about 15%, about 5% to about 20%, about 10% to about 20%, about 1%, about 5%, about 10%, about 15%, about 20%, about 25%, or about 30%.

[0271] As used herein and in the appended claims, the singular forms “a”, “an” and “the” include plural reference unless the context clearly dictates otherwise.

[0272] As used herein, the term “about” means that the numerical value is approximate and small variations would not significantly affect the practice of the disclosed embodiments. Where a numerical limitation is used, unless indicated otherwise by the context, “about” means the numerical value can vary by ±10% and remain within the scope of the disclosed embodiments. As used herein, the terms “comprising” (and any form of comprising, such as “comprise”, “comprises”, and “comprised”), “having” (and any form of having, such as “have” and “has”), “including” (and any form of including, such as “includes” and “include”), or “containing” (and any form of containing, such as “contains” and “contain”), are inclusive or open-ended and do not exclude additional, unrecited elements or method steps. Any composition or method that recites the term “comprising” should also be understood to also describe such compositions as consisting, consisting of, or consisting essentially of the recited components or elements.

[0273] As used herein, the term “individual,” “subject,” or “patient,” can be used interchangeably, means any animal, including mammals, such as mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, such as humans. As used herein, the term “mammal” means a rodent (i.e., a mouse, a rat, or a guinea pig), a monkey, a cat, a dog, a cow, a horse, a pig, or a human. In some embodiments, the mammal is a human.

[0274] As used herein, the phrase “in need thereof’ means that the subject has been identified as having a need for the method or treatment. In some embodiments, the identification can be by any means of diagnosis. In any of the methods and treatments described herein, the subject can be in need thereof. In some embodiments, the subject is in an environment or will be traveling to an environment in which a particular disease, disorder, or condition is prevalent.

[0275] Enumerated Embodiments

[0276] The following examples are illustrative, but not limiting, of the compounds, compositions and methods described herein. Other suitable modifications and adaptations known to those skilled in the art are within the scope of the following embodiments.

[0277] 1. A method of treating or reducing severity of rheumatoid arthritis in a subject in need thereof, the method comprising administering an anti-neonatal Fc receptor (FcRn) agent to the subject, wherein, prior to the subject receiving an initial administration of the anti-FcRn agent, an anti-citrullinated protein antibody (ACPA) level in a blood sample from the subject is or has been found to be higher than an ACPA reference level.

[0278] 2. A method of treating or reducing severity of rheumatoid arthritis in a subject in need thereof, the method comprising (a) determining an ACPA level in a blood sample from the subject; and

[0279] (b) administering an anti-neonatal Fc receptor (FcRn) agent to the subject if the ACPA level determined in step (a) is higher than an ACPA reference level.

[0280] 3. The method of claim 1 or 2, wherein the blood sample is serum sample.

[0281] 4. The method of any one of the preceding claims, wherein the ACPA reference level is within a range from about 100-1000 U / ml.

[0282] 5. The method of any one of the preceding claims, wherein the ACPA reference level is about 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 525, 550, 575, 600, 625, 650, 675, 700, 725, 750, 775, 800, 825, 850, 875, 900, 925, 950, 975, or 1000 U / ml.

[0283] 6. The method of any one of the preceding claims, wherein the ACPA reference level is within a range from about 400-600 U / ml.

[0284] 7. The method of any one of the preceding claims, wherein the ACPA level in the blood sample is determined using an ELISA assay.

[0285] 8. The method of any one of the preceding claims, wherein the ACPA level in the blood sample is determined using a cyclic citrullinated peptides (CCP) assay.

[0286] 9. The method of any one of the preceding claims, wherein the ACPA level in the blood sample is determined using a CCP2 assay.

[0287] 10. The method of any one of the preceding claims, wherein the ACPA level in the blood sample is determined using a CCP3 assay.

[0288] 11. The method of any one of the preceding claims, wherein the subject has not been previously treated with a disease-modifying antirheumatic drug (DMARD).

[0289] 12. The method of any one of the preceding claims, wherein the subject demonstrated inadequate response to or is intolerant to at least one disease-modifying antirheumatic drug (DMARD). 13. The method of claim 11 or 12, wherein the DMARD is an anti-tumor necrosis factor (TNF) agent.

[0290] 14. The method of claim 13, wherein the anti-TNF agent is adalimumab, certolizumab pegol, etanercept, golimumab, or infliximab.

[0291] 15. The method of claim 13, wherein the anti-TNF agent is adalimumab, etanercept, golimumab, or infliximab.

[0292] 16. The method of claim 11 or 12, wherein the DMARD is a JAK inhibitor.

[0293] 17. The method of claim 16, wherein the JAK inhibitor is tofacitinib, baricitinib, or upadacitinib.

[0294] 18. The method of claim 11 or 12, wherein the DMARD is an anti-interleukin-6 (IL-6) agent.

[0295] 19. The method of claim 18, wherein the anti -IL-6 agent is tocilizumab.

[0296] 20. The method of claim 11 or 12, wherein the DMARD is an anti-CD20 agent.

[0297] 21. The method of claim 20, wherein the anti-CD20 agent is rituximab.

[0298] 22. The method of claim 11 or 12, wherein the DMARD is a T-cell costimulation inhibitor.

[0299] 23. The method of claim 22, wherein the T-cell costimulation inhibitor is abatacept.

[0300] 24. The method of claim 11 or 12, wherein the DMARD is an anti-interleukin- 1 (IL-1) agent.

[0301] 25. The method of claim 24, wherein the anti -IL- 1 agent is anakinra.

[0302] 26. The method of any one of the preceding claims, wherein the subject has at least a 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 110%, or 120% higher chance of achieving DAS28- CRP remission within 12 weeks of initiation of said administering compared to subjects having an ACPA level lower than the ACPA reference level prior to receiving an initial administration of the anti-FcRn agent. 27. The method of any one of the preceding claims, wherein the method provides a clinical benefit as measured by a decrease in DAS28-CRP in the subject by more than 0.7 from baseline within 12 weeks of initiation of said administering.

[0303] 28. The method of any one of the preceding claims, wherein the subject achieves DAS28- CRP remission within 12 weeks of initiation of said administering.

[0304] 29. The method of any one of the preceding claims, wherein the method provides a clinical benefit as measured by a decrease in Clinical Disease Activity Index (CD Al) in the subject by more than 10 from baseline within 12 weeks of initiation of said administering.

[0305] 30. The method of any one of the preceding claims, wherein the method provides a clinical benefit as measured by a decrease in Health Assessment Questionnaire-Disability Index (HAQ- DI) in the subject by more than 0.4 from baseline within 12 weeks of initiation of said administering.

[0306] 31. The method of any one of the preceding claims further comprising administering at least one conventional synthetic disease modifying anti-rheumatic drug (csDMARD).

[0307] 32. The method of claim 31 , wherein the method provides a clinical benefit as measured by a decrease in DAS28-CRP in the subject by more than 0.9 from baseline within 8 weeks, 9 weeks, 10 weeks, 11 weeks, or 12 weeks of initiation of said administering the at least one csDMARD.

[0308] 33. The method of claim 32, wherein the method provides a clinical benefit as measured by a decrease in DAS28-CRP in the subject by more than 1.2 from baseline within 10 weeks, 11 weeks, or 12 weeks of initiation of said administering the at least one csDMARD.

[0309] 34. The method of any one of claims 31-33, wherein the method provides a clinical benefit as measured by a decrease in Clinical Disease Activity Index (CD Al) in the subject by more than 10 from baseline within 12 weeks of initiation of said administering the at least one csDMARD.

[0310] 35. The method of any one of claims 31-34, wherein the csDMARD is methotrexate, hydroxychloroquine, leflunomide, or sulfasalazine. 36. The method of any one of the preceding claims, wherein the subject achieves an ACR50 response within 12 weeks of initiation of said administering.

[0311] 37. The method of any one of the preceding claims, wherein the subject achieves an ACR70 response within 12 weeks of initiation of said administering.

[0312] 38. The method of any one of the preceding claims, wherein the subject achieves an ACR90 response within 12 weeks of initiation of said administering.

[0313] 39. The method of any one of the preceding claims, wherein the anti-FcRn agent is administered every week or every two weeks.

[0314] 40. The method of any one of the preceding claims, wherein the anti-FcRn agent is administered intravenously or subcutaneously.

[0315] 41. The method of any one of the preceding claims, wherein the anti-FcRn agent is administered at a therapeutically effective dose.

[0316] 42. The method of any one of the preceding claims, wherein the anti-FcRn agent is administered at a therapeutically effective dose for a period sufficient to treat or reduce severity of rheumatoid arthritis in the subject.

[0317] 43. The method of any one of the preceding claims, wherein the anti-FcRn agent is nipocalimab, rozanolixizumab, batoclimab, IMVT-1402, efgartigimod, orilanolimab, SYNT002, ABY- 039, or DX-2507.

[0318] 44. The method of any one of the preceding claims, wherein the anti-FcRn agent is an anti- FcRn antibody comprising:

[0319] (a) a light chain, which comprises a CDRL1 comprising an amino acid sequence of SEQ ID NO: 3, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 4, and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 5; and (b) a heavy chain, which comprises a CDRH1 comprising an amino acid sequence of SEQ ID NO: 6, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 7, and a CDR H3 comprising an amino acid sequence of SEQ ID NO: 8.

[0320] 45. The method of claim 44, wherein (a) the light chain of the anti-FcRn antibody comprises a light chain variable region comprising an amino acid sequence of SEQ ID NO: 9; and (b) the heavy chain of the anti-FcRn antibody comprises a heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 10.

[0321] 46. The method of claim 44 or claim 45, wherein (a) the light chain of the anti-FcRn antibody comprises an amino acid sequence of SEQ ID NO: 1; and (b) the heavy chain of the anti-FcRn antibody comprises an amino acid sequence of SEQ ID NO: 2.

[0322] 47. The method of any one of the preceding claims, wherein the anti-FcRn agent is Nipocalimab.

[0323] 48. The method of any one of the preceding claims, wherein the anti-FcRn agent is administered intravenously at about 15 mg / kg to about 30 mg / kg based on the weight of the subject.

[0324] 49. The method of any one of the preceding claims, wherein the method further comprises administering an anti-tumor necrosis factor (TNF) agent to the subject.

[0325] 50. The method of claim 49, wherein the subject demonstrated inadequate response to or is intolerant to a previous anti-TNF agent, which is different from the TNF agent administered to the subject.

[0326] 51. The method of claim 49 or 50, wherein the anti-FcRn agent is administered separately, simultaneously, or sequentially with the anti-TNF agent.

[0327] 52. The method of any one of claims 49-51, wherein the anti-FcRn agent is administered sequentially with the anti-TNF agent.

[0328] 53. The method of any one of claims 49-51, wherein the anti-FcRn agent is administered simultaneously with the anti-TNF agent. 54. The method of any one of claims 49-53, wherein the anti-TNF agent is administered intravenously or subcutaneously.

[0329] 55. The method of any one of claims 49-54, wherein the anti-TNF agent is administered every week, every 2 weeks, every 3 weeks, every 4 weeks, every 6 weeks, or every 8 weeks.

[0330] 56. The method of any one of claims 49-54, wherein the anti-TNF agent is adalimumab, certolizumab pegol, etanercept, golimumab, or infliximab.

[0331] 57. The method of any one of claims 49-55, wherein the anti-TNF agent is an anti-TNF antibody comprises:

[0332] (a) a light chain, which comprises a CDRL1 comprising an amino acid sequence of SEQ ID NO: 42, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 43, a CDR L3 comprising an amino acid sequence of SEQ ID NO: 44; and

[0333] (b) a heavy chain, which comprises a CDR Hl comprising an amino acid sequence of SEQ ID NO: 45, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 46, and a CDR H3 comprising an amino acid sequence of SEQ ID NO: 47.

[0334] 57. The method of claim 56, wherein (a) the light chain of the anti-TNF antibody comprises a light chain variable region comprising an amino acid sequence of SEQ ID NO: 48; and (b) the heavy chain of the anti-TNF antibody comprises a heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 49.

[0335] 58. The method of claim 56 or 57, wherein (a) the light chain of the anti-TNF antibody comprises an amin acid sequence of SEQ ID NO: 40; and (b) the heavy chain of the anti-TNF antibody comprises an amino acid sequence of SEQ ID NO: 41.

[0336] 59. The method of any one of claims 49-58, wherein the anti-TNF agent is golimumab.

[0337] 60. The method of any one of claims 49-55, wherein the anti-TNF agent is an anti-TNF antibody comprising (a) a light chain comprising an amino acid sequence of SEQ ID NO: 29; and (b) a heavy chain comprising an amino acid sequence of SEQ ID NO: 30. 61. The method of any one of claims 49-55 and 60, wherein the anti-TNF agent is certolizumab pegol.

[0338] 62. The method of any one of claims 49-61, wherein the method provides a clinical benefit as measured by a decrease in DAS28-CRP by more than 0.8, more than 1, more than 1.2, more than 1.4, more than 1.6, more than 1.8, more than 2, more than 2.2, more than 2.4, more than 2.6, more than 2.8, more than 3, more than 3.2, more than 3.4, more than 3.6, more than 3.8, more than 4, more than 4.2, more than 4.4, more than 4.6, more than 4.8, more than 5, more than 5.2, more than 5.4, more than 5.6, more than 5.8, or more than 6 from baseline within 12 weeks of initiation of said administering.

[0339] 63. The method of any one of claims 49-62, wherein the subject achieved DAS28-CRP LDA within 12 weeks of initiation of said administering.

[0340] 64. The method of any one of claims 49-63, wherein the method provides a clinical benefit as measured by a decrease in Clinical Disease Activity Index (CD Al) by more than 11, more than 13, more than 15, more than 17, more than 19, more than 21, more than 23, more than 25, more than 27, more than 29, more than 31, more than 33, more than 35, more than 37, more than 39, more than 41, more than 43, more than 45, more than 47, more than 49, more than 51, more than 53, more than 55, more than 57, more than 59, more than 61, more than 63, more than 65, more than 67, more than 69, or more than 70 from baseline within 12 weeks of initiation of said administering.

[0341] 65. The method of any one of claims 49-64, wherein the method provides a clinical benefit as measured by a decrease in Health Assessment Questionnaire-Disability Index (HAQ-DI) by more than 0.5, more than 0.6, more than 0.7, more than 0.8, more than 0.9 more than 1, more than 1.1, more than 1.2, more than 1.3, more than 1.4, more than 1.5, more than 1.6, more than 1.7, more than 1.8, more than 1.9, or more than 2 from baseline within 12 weeks of initiation of said administering.

[0342] 66. An anti-FcRn agent for use in a method of treating or reducing severity of rheumatoid arthritis in a subject in need thereof, the method comprising administering the anti-FcRn agent to the subject, wherein, prior to the subject receiving an initial administration of the anti-FcRn agent, an anti-cyclic citrullinated peptide autoantibody (ACPA) level in a blood sample from the subject is or has been found to be higher than an ACPA reference level.

[0343] 67. An anti-FcRn agent for use in a method of treating or reducing severity of rheumatoid arthritis in a subject in need thereof, the method comprising

[0344] (a) determining an ACPA level in a blood sample from the subject; and

[0345] (b) administering an anti-neonatal Fc receptor (FcRn) agent to the subject if the ACPA level determined in step (a) is higher than an ACPA reference level.

[0346] 68. The anti-FcRn agent for use according to claim 66 or 67, wherein the blood sample is serum sample.

[0347] 69. The anti-FcRn agent for use according to any one of claims 66-68, wherein the ACPA reference level is within a range from about 100-1000 U / ml.

[0348] 70. The anti-FcRn agent for use according to any one of claims 66-69, wherein the ACPA reference level is about 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 525, 550, 575, 600, 625, 650, 675, 700, 725, 750, 775, 800, 825, 850, 875, 900, 925, 950, 975, or 1000 U / ml.

[0349] 71. The anti-FcRn agent for use according to any one of claims 66-70, wherein the ACPA reference level is within a range from about 400-600 U / ml.

[0350] 72. The anti-FcRn agent for use according to any one of claims 66-71, wherein the ACPA level in the blood sample is determined using an ELISA assay.

[0351] 73. The anti-FcRn agent for use according to any one of claims 66-72, wherein the ACPA level in the blood sample is determined using a cyclic citrullinated peptides (CCP) assay.

[0352] 74. The anti-FcRn agent for use according to any one of claims 66-73, wherein the ACPA level in the blood sample is determined using a CCP2 assay.

[0353] 75. The anti-FcRn agent for use according to any one of claims 66-74, wherein the ACPA level in the blood sample is determined using a CCP3 assay. 76. The anti-FcRn agent for use according to any one of claims 66-75, wherein the subject has not been previously treated with a disease-modifying antirheumatic drug (DMARD).

[0354] 77. The anti-FcRn agent for use according to any one of claims 66-76, wherein the subject demonstrated inadequate response to or is intolerant to at least one disease-modifying antirheumatic drug (DMARD).

[0355] 78. The anti-FcRn agent for use according to any one of claims 66-77, wherein the DMARD is an anti-tumor necrosis factor (TNF) agent.

[0356] 79. The anti-FcRn agent for use according to claim 78, wherein the anti-TNF agent is adalimumab, certolizumab pegol, etanercept, golimumab, or infliximab.

[0357] 80. The anti-FcRn agent for use according to claim 78, wherein the anti-TNF agent is adalimumab, etanercept, golimumab, or infliximab.

[0358] 81. The anti-FcRn agent for use according to claim 76 or 77, wherein the DMARD is a JAK inhibitor.

[0359] 82. The anti-FcRn agent for use according to claim 81, wherein the JAK inhibitor is tofacitinib, baricitinib, or upadacitinib.

[0360] 83. The anti-FcRn agent for use according to claim 76 or 77, wherein the DMARD is an antiinterleukin-6 (IL-6) agent.

[0361] 84. The anti-FcRn agent for use according to claim 83, wherein the anti-IL-6 agent is tocilizumab.

[0362] 85. The anti-FcRn agent for use according to claim 76 or 77, wherein the DMARD is an anti- CD20 agent.

[0363] 86. The anti-FcRn agent for use according to claim 85, wherein the anti-CD20 agent is rituximab.

[0364] 87. The anti-FcRn agent for use according to claim 76 or 77, wherein the DMARD is a T-cell costimulation inhibitor. 88. The anti-FcRn agent for use according to claim 87, wherein the T-cell costimulation inhibitor is abatacept.

[0365] 89. The anti-FcRn agent for use according to claim 76 or 77, wherein the DMARD is an antiinterleukin-1 (IL-1) agent.

[0366] 90. The anti-FcRn agent for use according to claim 89, wherein the anti-IL-1 agent is anakinra.

[0367] 91. The anti-FcRn agent for use according to any one of claims 66-90, wherein the subject has at least a 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 110%, or 120% higher chance of achieving DAS28-CRP remission in the subject.

[0368] 92. The anti-FcRn agent for use according to any one of claims 66-91, wherein the method provides a clinical benefit as measured by a decrease in DAS28-CRP in the subject by more than 0.7 from baseline within 12 weeks of initiation of said administering.

[0369] 93. The anti-FcRn agent for use according to any one of claims 66-92, wherein the subject achieves DAS28-CRP remission within 12 weeks of initiation of said administering.

[0370] 94. The anti-FcRn agent for use according to any one of claims 66-93, wherein the method provides a clinical benefit as measured by a decrease in Clinical Disease Activity Index (CD Al) in the subject by more than 10 from baseline within 12 weeks of initiation of said administering.

[0371] 95. The anti-FcRn agent for use according to any one of claims 66-94, wherein the method provides a clinical benefit as measured by a decrease in Health Assessment Questionnaire- Disability Index (HAQ-DI) in the subject by more than 0.4 from baseline within 12 weeks of initiation of said administering.

[0372] 96. The anti-FcRn agent for use according to any one of claims 66-95, further comprising administering at least one conventional synthetic disease modifying anti-rheumatic drug (csDMARD).

[0373] 97. The anti-FcRn agent for use according to claim 96, wherein the method provides a clinical benefit as measured by a decrease in DAS28-CRP in the subject by more than 0.9 from baseline within 8 weeks, 9 weeks, 10 weeks, 11 weeks, or 12 weeks of initiation of said administering the at least one csDMARD.

[0374] 98. The anti-FcRn agent for use according to claim 96, wherein the method provides a clinical benefit as measured by a decrease in DAS28-CRP in the subject by more than 1.2 from baseline within 10 weeks, 11 weeks, or 12 weeks of initiation of said administering the at least one csDMARD.

[0375] 99. The anti-FcRn agent for use according to any one of claims 96-98, wherein the method provides a clinical benefit as measured by a decrease in Clinical Disease Activity Index (CD Al) in the subject by more than 10 from baseline within 12 weeks of initiation of said administering the at least one csDMARD.

[0376] 100. The anti-FcRn agent for use according to any one of claims 96-99, wherein the csDMARD is methotrexate, hydroxychloroquine, leflunomide, or sulfasalazine.

[0377] 101. The anti-FcRn agent for use according to any one of claims 66-100, wherein the subject achieves an ACR50 response within 12 weeks of initiation of said administering.

[0378] 102. The anti-FcRn agent for use according to any one of claims 66-101, wherein the subject achieves an ACR70 response within 12 weeks of initiation of said administering.

[0379] 103. The anti-FcRn agent for use according to any one of claims 66-102, wherein the subject achieves an ACR90 response within 12 weeks of initiation of said administering.

[0380] 104. The anti-FcRn agent for use according to any one of claims 66-103, wherein the anti- FcRn agent is administered every week or every two weeks.

[0381] 105. The anti-FcRn agent for use according to any one of claims 66-104, wherein the anti- FcRn agent is administered intravenously or subcutaneously.

[0382] 106. The anti-FcRn agent for use according to any one of claims 66-105, wherein the anti- FcRn agent is administered at a therapeutically effective dose. 107. The anti-FcRn agent for use according to any one of claims 66-106, wherein the anti- FcRn agent is administered at a therapeutically effective dose for a period sufficient to treat or reduce severity of rheumatoid arthritis in the subject.

[0383] 108. The anti-FcRn agent for use according to any one of claims 66-107, wherein the anti- FcRn agent is nipocalimab, rozanolixizumab, batoclimab, IMVT-1402, efgartigimod, onlanolimab, SYNT002, ABY- 039, or DX-2507.

[0384] 109. The anti-FcRn agent for use according to any one of claims 66-108, wherein the anti- FcRn agent is an anti-FcRn antibody comprising:

[0385] (a) a light chain, which comprises a CDRL1 comprising an amino acid sequence of SEQ ID NO: 3, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 4, and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 5; and

[0386] (b) a heavy chain, which comprises a CDR Hl comprising an amino acid sequence of SEQ ID NO: 6, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 7, and a CDR H3 comprising an amino acid sequence of SEQ ID NO: 8.

[0387] 110. The anti-FcRn agent for use according to claim 109, wherein (a) the light chain of the anti-FcRn antibody comprises a light chain variable region comprising an amino acid sequence of SEQ ID NO: 9; and (b) the heavy chain of the anti-FcRn antibody comprises a heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 10.

[0388] 111. The anti-FcRn agent for use according to claim 109 or claim 110, wherein (a) the light chain of the anti-FcRn antibody comprises an amino acid sequence of SEQ ID NO: 1; and (b) the heavy chain of the anti-FcRn antibody comprises an amino acid sequence of SEQ ID NO: 2.

[0389] 112. The anti-FcRn agent for use according to any one of claims 66-111 , wherein the anti- FcRn agent is nipocalimab.

[0390] 113. The anti-FcRn agent for use according to any one of claims 66-112, wherein the anti- FcRn agent is administered intravenously at about 15 mg / kg to about 30 mg / kg based on the weight of the subject. 114. The anti-FcRn agent for use according to any one of claims 66-113, wherein the method further comprises administering an anti -tumor necrosis factor (TNF) agent to the subject.

[0391] 115. The anti-FcRn agent for use according to claim 114, wherein the subject demonstrated inadequate response to or is intolerant to a previous anti-TNF agent, which is different from the TNF agent administered to the subject.

[0392] 116. The anti-FcRn agent for use according to claim 114 or claim 115, wherein the anti-FcRn agent is administered separately, simultaneously, or sequentially with the anti-TNF agent.

[0393] 117. The anti-FcRn agent for use according to any one of claims 114-116, wherein the anti- FcRn agent is administered sequentially with the anti-TNF agent.

[0394] 118. The anti-FcRn agent for use according to any one of claims 114-116, wherein the anti- FcRn agent is administered simultaneously with the anti-TNF agent.

[0395] 119. The anti-FcRn agent for use according to any one of claims 114-118, wherein the anti- TNF agent is administered intravenously or subcutaneously.

[0396] 120. The anti-FcRn agent for use according to any one of claims 114-119, wherein the anti- TNF agent is administered every week, every 2 weeks, every 3 weeks, every 4 weeks, every 6 weeks, or every 8 weeks.

[0397] 121. The anti-FcRn agent for use according to any one of claims 114-120, wherein the anti- TNF agent is adalimumab, certolizumab pegol, etanercept, golimumab, or infliximab.

[0398] 122. The anti-FcRn agent for use according to any one of claims 114-121, wherein the anti- TNF agent is an anti-TNF antibody comprises:

[0399] (a) a light chain, which comprises a CDRL1 comprising an amino acid sequence of SEQ ID NO: 42, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 43, a CDR L3 comprising an amino acid sequence of SEQ ID NO: 44; and

[0400] (b) a heavy chain, which comprises a CDR Hl comprising an amino acid sequence of SEQ ID NO: 45, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 46, and a CDR H3 comprising an amino acid sequence of SEQ ID NO: 47. 123. The anti-FcRn agent for use according to claim 122, wherein (a) the light chain of the anti-TNF antibody comprises a light chain variable region comprising an amino acid sequence of SEQ ID NO: 48; and (b) the heavy chain of the anti-TNF antibody comprises a heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 49.

[0401] 124. The anti-FcRn agent for use according to claim 122 or claim 123, wherein (a) the light chain of the anti-TNF antibody comprises an amin acid sequence of SEQ ID NO: 40; and (b) the heavy chain of the anti-TNF antibody comprises an amino acid sequence of SEQ ID NO: 41.

[0402] 125. The anti-FcRn agent for use according to any one of claims 114-124, wherein the anti- TNF agent is golimumab.

[0403] 126. The anti-FcRn agent for use according to any one of claims 114-125, wherein the anti- TNF agent is an anti-TNF antibody comprising (a) a light chain comprising an amino acid sequence of SEQ ID NO: 29; and (b) a heavy chain comprising an amino acid sequence of SEQ ID NO: 30.

[0404] 127. The anti-FcRn agent for use according to any one of claims 114-121 and 126, wherein the anti-TNF agent is certolizumab pegol.

[0405] 128. The anti-FcRn agent for use according to any one of claims 66-127, wherein the method provides a clinical benefit as measured by a decrease in DAS28-CRP by more than 0.8, more than 1, more than 1.2, more than 1.4, more than 1.6, more than 1.8, more than 2, more than 2.2, more than 2.4, more than 2.6, more than 2.8, more than 3, more than 3.2, more than 3.4, more than 3.6, more than 3.8, more than 4, more than 4.2, more than 4.4, more than 4.6, more than 4.8, more than 5, more than 5.2, more than 5.4, more than 5.6, more than 5.8, or more than 6 from baseline within 12 weeks of initiation of said administering.

[0406] 129. The anti-FcRn agent for use according to any one of claims 66-128, wherein the subject achieves DAS28-CRP LDA within 12 weeks of initiation of said administering.

[0407] 130. The anti-FcRn agent for use according to any one of claims 66-129, wherein the method provides a clinical benefit as measured by a decrease in Clinical Disease Activity Index (CD Al) by more than 11, by more than 13, more than 15, more than 17, more than 19, more than 21, more than 23, more than 25, more than 27, more than 29, more than 31, more than 33, more than 35, more than 37, more than 39, more than 41, more than 43, more than 45, more than 47, more than 49, more than 51, more than 53, more than 55, more than 57, more than 59, more than 61, more than 63, more than 65, more than 67, more than 69, or more than 70 from baseline within 12 weeks of initiation of said administering.

[0408] 131. The anti-FcRn agent for use according to any one of claims 66-130, wherein the method provides a clinical benefit as measured by a decrease in Health Assessment Questionnaire- Disability Index (HAQ-DI) by more than 0.4, more than 0.5, more than 0.6, more than 0.7, more than 0.8, more than 0.9 more than 1, more than 1.1, more than 1.2, more than 1.3, more than 1.4, more than 1.5, more than 1.6, more than 1.7, more than 1.8, more than 1.9, or more than 2 from baseline within 12 weeks of initiation of said administering.

[0409] 134. A combination of an anti-FcRn agent and an anti-TNF agent for use in a method as defined in any one of claims 49-65.

[0410] 135. A kit comprising an anti-neonatal Fc receptor (FcRn) agent and an anti-tumor necrosis factor (TNF) agent to the subject.

[0411] 136. The kit of claim 135, wherein the components of the kit are disposed separately.

[0412] 137. The kit of claim 135 or 136, wherein the anti-FcRn agent and the anti-TNF agent are for separate, simultaneous or sequential administration.

[0413] 138. The kit of any one of claims 135-137, wherein the anti-FcRn agent is an anti-FcRn agent as defined in any one of claims 43-47.

[0414] 139. The kit of any one of claims 135-138, wherein the anti-TNF agent is an anti-TNF agent as defined in any one of claims 56-61.

[0415] 140. The kit of any one of claims 135-139, further comprising instructions for use.

[0416] 141. The kit of any one of claims 135-140, further comprising instructions for a method of treating or reducing severity of rheumatoid arthritis in a subject. 142. The kit of claim 141, wherein the method is a method as defined in any one of claims 49- 65.

[0417] Examples

[0418] Example 1: Clinical Trial to Evaluate Efficacy and Safety of Anti-FcRn Antibodies for Treatment of Rheumatoid Arthritis

[0419] I. Study Design

[0420] This is a Phase 2a, randomized, double-blind, placebo-controlled, parallel-group, proof- of-concept, multicenter clinical study designed to evaluate the efficacy and safety of an anti- FcRn antibody for the treatment of rheumatoid arthritis (RA). The primary objective was to evaluate the efficacy and safety of the anti-FcRn agent, nipocalimab, versus a placebo in participants with moderate to severe active RA. Nipocalimab was administered at 15 mg / kg IV every 2 weeks (q2w). FIG. 1 depicts a schematic overview of the study.

[0421] This study’s target population was adults 18 to 75 years old with moderately to severely active RA despite standard therapy. Participants must have had an inadequate response (IR) or were intolerant to at least one anti-tumor necrosis factor (TNF) drug.

[0422] The total duration of the study was up to 24 weeks and involved 3 study periods: a < 6- week screening period (rescreening is permitted once per subject), a 12-week double-blind treatment period, and a 6-week safety follow-up period (8 weeks after the last study intervention administration).

[0423] At Week 0, eligible participants were randomized in a 2:3 ratio to one of the following two treatment groups using dynamic central randomization based on biased-coin algorithm to balance the distribution of subjects to achieve the randomization ratio of (2:3) at the study level and within the levels of each individual stratification factor: Baseline Methotrexate (MTX) use (not currently taking MTX, >0 to <12.5 mg / week, >12.5 mg / week), Baseline swollen and tender joint counts level categorized as four levels (<2.690 =1; >2.690 to <3.160 =2; >3.160 to <3.656 =3; >3.656 =4), and Anti-TNF IR / intolerance (Yes, No). The Baseline swollen and tender joint counts (28) are part of the components used to drive DAS28. Group 1 (n=20 participants) received a placebo IV q2w through Week 10. Group 2 (n=30 participants) received nipocalimab 15 mg / kg IV q2w through Week 10.

[0424] In general, permitted doses of concomitant therapies for RA (i.e., conventional synthetic disease modifying antirheumatic drugs (csDMARDs), oral corticosteroids, non-steroidal antiinflammatory drugs (NSAIDs), and other analgesics) were to remain stable through Week 12. Use of additional immunosuppressants or immunomodulators was not permitted in this study.

[0425] This example provides the analysis results for primary and key efficacy endpoints, safety, and biomarker data through Week 12. The primary endpoint was the mean change from baseline in Disease Activity Index Score 28 using C-reactive protein (CRP) [DAS28-CRP] at Week 12. The DAS28-CRP score is calculated based on the tender joints (28), swollen joints (28), patient’s global assessment of disease activity, and CRP. Change from baseline in DAS28-CRP measures the change in disease activity, where a negative change indicates an improvement, and a positive change indicates a worsening.

[0426] Key secondary efficacy endpoints included the following:

[0427] • Proportion of participants who achieved ACR20 responses at Week 12, defined as > 20% improvement from baseline in both swollen joint count (66 joints) and tender joint count (68 joints) AND > 20% improvement from baseline in 3 of the following 5 assessments: o Patient’s Global Assessment of Disease Activity (VAS) o Patient’s assessment of pain (VAS) o Patient’s assessment of physical function as measured by HAQ-DI o Physician’s Global Assessment of Disease Activity (VAS) o CRP

[0428] • Proportion of participants who achieved ACR50 responses at Week 12, defined similarly to ACR20 response, however, with an improvement threshold of 50%.

[0429] • Proportion of participants who achieved ACR70 responses at Week 12, defined similarly to ACR20 response, however, with an improvement threshold of 70%.

[0430] • Proportion of participants who achieved ACR90 responses at Week 12, defined similarly to ACR20 response, however, with an improvement threshold of 90%. • Proportion of participants achieving DAS28-CRP remission at Week 12, defined as a DAS28-CRP value of < 2.6 at Week 12.

[0431] • Proportion of participants achieving DAS28-CRP low disease activity (LDA) at Week 12, defined as a DAS28-CRP value > 2.6 and < 3.2 at Week 12.

[0432] • Change from baseline in Health Assessment Questionnaire Disability Index (HAQ- DI) score at Week 12, defined as change from baseline in the functional status, where a negative change reflects an improvement, and a positive change reflects a worsening.

[0433] Expected effect size and planned sample size: Assuming a difference of 1 in the change from baseline in DAS28-CRP between a nipocalimab group and placebo, a sample size of 20 and 30 participants in the placebo group and nipocalimab 15 mg / kg group, respectively, will provide a power of approximately 80% to detect a significant treatment difference at a 2-sided significance level of a=0.05 using a t-test. The difference of 1 was derived by a meta-analysis of effective treatments in RA.

[0434] IL Statistical Considerations

[0435] Treatment comparisons of the nipocalimab group versus placebo group were performed. The Least Square (LS) means (or LSMean) for each treatment group, and difference in LS means between nipocalimab group and placebo group and associated 95% confidence intervals (CI) are provided for change from baseline in DAS28-CRP and change from baseline in HAQ-DI. Proportion of participants who achieved (ACR20, ACR50, ACR70, ACR90, DAS28-CRP remission, and DAS28 (LDA) response and associated 95% Cis are provided for binary endpoints.

[0436] Analysis methods: Lor continuous endpoints (e.g., change from baseline in DAS28-CRP and change from baseline in HAQ-DI), an Analysis of Covariance (ANCOVA) model including treatment group, baseline score, and randomization stratification factor (baseline MTX use) was used. Lor binary endpoints (e.g., ACR20, ACR50, ACR70, ACR90, DAS28-CRP remission, and DAS28 (LDA) response), treatment groups were compared using a 2-sided Cochran-Mantel- Haenszel [CMH] chi-square test. If small number, the Lisher’s exact test was used instead of the CMH test. Multiplicity adjustment: There were no adjustments for multiple comparisons. All tests were performed at a 2-sided significance level of 0.05. All p-values presented are nominal.

[0437] HI. Results

[0438] A total of 53 participants were randomized (20 to placebo group and 33 to nipocalimab group) and dosed in 13 centers across five countries (Poland, Germany, Spain, Great Britain, and United States). The majority [44 (83.0%)] of participants were from Europe, with the remaining participants from USA [9 (17.0%)].

[0439] A. Disposition and baseline characteristic for the FAS (n=53)

[0440] At baseline, 37 (70%) of participants were receiving csDMARDs [21 (64%) in the nipocalimab group and 16 (80%) in the placebo group] and 35 (66%) participants were receiving oral corticosteroids [20 (61%) in the nipocalimab group and 15 (75%) in the placebo group] (Table 1). Majority of participants receiving csDMARDs were on MTX (89%). In addition, 52 out of the 53 participants had at least one prior anti-TNF agent, 40 (76%) of participants had only one prior anti-TNF agent [24 (73%) in the nipocalimab group and 16 (80%) in the placebo group] and 12 (23%) had two or more prior anti-TNF agents [8 (24%) in the nipocalimab group and 4 (20%) in the placebo group] (Table 2). One participant in the nipocalimab group was not recorded prior anti-TNF agent use.

[0441] B. Efficacy Endpoints

[0442] Nipocalimab 15 mg / kg IV q2w demonstrated numerically higher improvement in the primary endpoint (change from baseline at Week 12 in DAS28-CRP) compared to placebo. Similar results were obtained in participants who were receiving csDMARDs at baseline: nipocalimab 15 mg / kg IV q2w demonstrated numerically higher improvement from baseline in DAS28-CRP at Week 12 compared to placebo. Additionally, nipocalimab treated participants had numerically higher rates of ACR responses and DAS28-CRP remission at Week 12 compared to those treated with placebo. Change from baseline in all ACR components, except CRP, showed numerically bigger improvement for nipocalimab compared to placebo treated participants generally starting from Week 6 and through Week 12. Further, nipocalimab treated participants had numerically bigger improvement from baseline in Clinical Disease Activity Index (CD Al) over time compared to placebo treated.

[0443] Primary endpoint: the change from baseline in DAS28-CRP at Week 12. Participants treated with nipocalimab achieved a numerically greater mean change in DAS28-CRP at Week 12 based on the primary composite estimand: the LSMean was [-1.03 (95% CI: -1.66; -0.40)] compared to those treated with placebo [ -0.58 (95% CI: -1.24; 0.07)]; the LSMean difference between nipocalimab and placebo groups was [-0.45 (-1.17;0.28)] (p-value = 0.224) (Table 3).

[0444] Supplementary Analysis of the primary endpoint based on supplementary estimand was provided in Table 4. This analysis was based on the observed data, that is, no ICE rule was applied, and no missing data imputation was performed. Participants treated with nipocalimab achieved a numerically greater mean change in DAS28-CRP at Week 12: the LSMean (95% CI) was [-1.17 (-1.82; -0.52)] for the nipocalimab and [-0.89 (-1.57; -0.21)] for the placebo groups. In addition, the nipocalimab group also achieved a numerically greater mean improvement in DAS28-CRP than the placebo group over time starting from Week 8 (Table 5).

[0445] Secondary endpoint: subjects achieving an ACR response at Week 12. A numerically higher proportion of participants achieved an ACR20 response at Week 12, based on the main composite estimand. The proportion of nipocalimab group was [15 (45.5%)] compared to the placebo group [4 (20.0%)]. The treatment difference between the nipocalimab group and the placebo group based on the main composite estimand was [27.0% (3.2%; 50.9%)] (nominal p- value = 0.055). Similarly, ACR50, ACR70, and ACR90 all showed that approximately 6% - 15% of participants achieved a response at Week 12 (Table 6).

[0446] Secondary Endpoint: Subjects achieving DAS28-CRP Remission and LDA at Week 12. A numerically higher proportion of participants achieved DAS28-CRP remission at Week 12 based on the main composite estimand [7 (21.2%)] in the nipocalimab group than the placebo group [2 (10.0%)] (Table 7). There were no participants who achieved DAS28 (LDA) response at Week 12. Compared to the placebo group, a numerically higher proportion of participants in the nipocalimab group achieved DAS28-CRP remission over time. Secondary Endpoint: Change from Baseline in HAQ-DI Score at Week 12. Nipocalimab treated participants achieved a numerically higher mean improvement in HAQ-DI [-0.42 (-0.66; - 0.19)] compared to placebo [-0.21 (-0.45; 0.04)] at Week 12. The LSMean difference between the groups was [-0.22 (-0.49; 0.05)] (Table 8).

[0447] Tertiary Endpoint: Change from Baseline in CD Al Score at Week 12. Participants treated with nipocalimab achieved a numerically higher mean change in CD Al based on the main composite estimand [-13.53 (-19.94; -7.11)] compared to placebo [-6.01 (-12.80; 0.79)]; the LSMean difference between the nipocalimab and the placebo group at Week 12 was [-7.52 (- 14.98; -0.06)] (nominal p-value = 0.048) (Table 9).

[0448] Subgroup Analyses by Baseline csDMARDs Usage (Yes / No). The consistency of the treatment effect for the Week 12 primary, secondary, and tertiary endpoints through Week 12 was evaluated for baseline csDMARD usage subgroups.

[0449] For participants receiving csDMARDs at baseline (16 in placebo and 21 in nipocalimab):

[0450] • Those treated with nipocalimab achieved a numerically higher mean change from baseline in DAS28-CRP than those treated with placebo over time starting from Week 6 and through Week 12 (Table 10).

[0451] • At Week 12, the LSMean (95% CI) was [-1.27 (-2.16; -0.39)] in the nipocalimab and [-0.44 (-1.23; 0.36)] in the placebo groups; the LSMean difference (95% CI) between nipocalimab and placebo groups was [-0.83 (-1.74; 007)] (nominal p- value = 0.069) (Table 10).

[0452] • Those treated with nipocalimab had a numerically greater proportion of achieving an ACR20 response, ACR50 response, and DAS28-CRP remission compared to those treated with placebo over time starting from Week 6 or Week 8 and through Week 12 (Tables 11 and 12).

[0453] • Those treated with nipocalimab achieved a numerically higher mean change from baseline in CD Al than those treated with placebo over time through Week 12 (Table 13).

[0454] C. Safety Findings Summary Overall reported adverse events (AEs) were comparable between placebo (60.0%) and nipocalimab 15 mg / kg IV q2w (81.8%) through Week 18 (Table 14).

[0455] • Most frequently reported AEs in the placebo group: RA, infection, and nausea.

[0456] • Most common AEs in the nipocalimab group: infections, RA, headache.

[0457] • Two serious adverse events (SAEs) were reported, and both were from the nipocalimab group: infusion reaction and infected burn skin.

[0458] • Two or more nipocalimab treated participants experienced at least 1 AE in the following system organ class (preferred term): infections (covid- 19, nasopharyngitis); musculoskeletal (RA), general disorders (chills, fatigue); nervous system (headache); skin and subcutaneous (rash).

[0459] • AEs causing treatment discontinuation: 35.0% in placebo vs 21.2% in nipocalimab.

[0460] • No deaths reported.

[0461] • Infusion related reaction: 1 (5%) in placebo vs 4 (12%) in nipocalimab.

[0462] • About 10% increase from baseline in triglyceride observed at Week 12 in the nipocalimab group compared to the placebo group.

[0463] • No significant changes of LDL, HDL or total fasting cholesterol observed.

[0464] D. Pharmacodynamic / Biomarker Findings

[0465] Baseline biomarker levels were generally comparable between the nipocalimab and placebo groups. Relative to the baseline, no changes in complement activation markers or serum inflammatory markers were observed in either group.

[0466] Serum total IgG levels were reduced by nipocalimab from Weeks 4 through 12 and returned to baseline level at Week 18. At Week 12, there was a 58% reduction (geometric mean) in the total IgG levels observed in the nipocalimab group, compared to a 2.4% increase in the placebo group (FIG. 2A). The serum total IgG returned to baseline level at Week 18. Decreases from baseline in all IgG subclasses were consistent with those observed for total IgG levels. At Week 12, significant reductions of CIC (circulating immune complex) levels were observed in the nipocalimab group versus the placebo group and correlated with total IgG reduction (FIG. 2B). Similarly, significant reductions of anti-cyclic citrullinated protein autoantibodies (anti-CCP antibodies, also known as antibody to citrullinated protein antigens (ACPA)) were observed in the nipocalimab group versus the placebo group (FIG. 2C). Those who achieved DAS28-CRP remission at Week 12 had greater reduction in ACPA compared to non-responders (p=0.052).

[0467] Throughout this study, ACPA level was determined using a second generation anti-CCP test (CCP2) kit, IMMUNOSCAN CCPlus obtained from SVAR, which is based on an ELISA method. Briefly, the test utilized microtiter plate wells coated with citrullinated synthetic peptides (antigen). Diluted patient serum was applied to the wells and incubated. If specific antibodies were present, they would bind to the antigen in the wells. Unbound material was washed away and any bound antibody was detected by adding horse radish peroxidase (HRP) labelled anti-human IgG, followed by a second washing step and an incubation with substrate. The presence of reacting antibodies would result in the development of color, which was proportional to the quantity of bound antibody, and this was determined photometrically.

[0468] In a further analysis, DAS28-CRP % remission rate and ACR50 % response rate for patients with baseline ACPA levels at or higher than various ACPA reference levels (ACPA- high patients) within the nipocalimab group and placebo group were compared and tabulated in Table 15. For example, when the ACPA reference level was set at 200 U / ml, 67.9% of the total patients were ACPA-high patients (i.e., having an ACPA level at or above the ACPA reference level of 200 U / ml); the DAS28-CRP remission rate for ACPA-high patients in nipocalimab group and placebo group was 25% (6 / 24) and 16.7% (2 / 12), respectively; while the ACR50 response rate for ACPA-high patients in nipocalimab group and placebo group was 16.7% (4 / 24) and 0% (0 / 12), respectively. When the ACPA reference level was set at 400 U / ml, 49.1% of the total patients were ACPA patients (i.e., having an ACPA level at or above the ACPA reference level of 400 U / ml); the DAS28-CRP remission rate for ACPA-high patients in nipocalimab group and placebo group was 42.9% (6 / 14) and 16.7% (2 / 12), respectively; while the ACR50 response rate for ACPA-high patients in nipocalimab group and placebo group was 28.6% (4 / 14) and 0% (0 / 12), respectively. When the ACPA reference level was set at 600 U / ml, 37.7% of the total patients were ACPA-high patients (i.e., having an ACPA level at or above the ACPA reference level of 600 U / ml); the DAS28-CRP remission rate for ACPA-high patients in nipocalimab group and placebo group was 40% (4 / 10) and 20% (2 / 10), respectively; while the ACR50 response rate for ACPA-high patients in nipocalimab group and placebo group was 30% (3 / 10) and 0% (0 / 10), respectively. The bottom row of Table 15 listed the DAS28-CRP remission rate and ACR50 response rate of total patients within nipocalimab group and placebo group.

[0469] As shown here, among all patients, significantly higher % rate of patients in nipocalimab group achieved DAS28-CRP remission within 12 weeks of initiation of the administration of nipocalimab compared to that of patients in placebo group (21.2% v.s. 10%) and significantly higher % rate of patients in nipocalimab group achieved ACR50 response compared to that of patients in placebo group (15.2% v.s. 5%). In addition, within nipocalimab group, the % rate of patients in each ACPA-high subgroups achieving DAS28-CRP remission is higher compared to that of all patients in nipocalimab group, and the % rate of patients in each ACPA-high subgroups achieving ACR50 response is higher compared to that of all patients in nipocalimab group. For example, among patients in nipocalimab group and having baseline ACPA level above 396 U / ml (median ACPA at baseline), 40% achieved DAS28-CRP remission at week 12, compared to 21.2% among all patients in nipocalimab group (FIG. 4). While among patients in nipocalimab group and having baseline ACPA level above 396 U / ml (median ACPA at baseline), 26.7% achieved ACR50 response at Week 12, compared to 15.2% among all patients in nipocalimab group (FIG. 5).

[0470] TV. Conclusions

[0471] It has always been a challenge to provide a second line treatment for RA patients with inadequate response to or intolerant to DMARD, e.g., anti-TNF agent. For the first, the inventors herein discovered that Nipocalimab 15mg / kg IV q2w in RA participants with inadequate response to or intolerant to anti-TNF agent demonstrated numerically and clinically meaningful efficacy advantage over placebo with exception of no impact on inflammatory markers. Moreover, even more significant efficacy advantage was observed for patients with higher baseline ACPA level (e.g., baseline ACPA level higher than a ACPA reference level ranging with a range from about 400-600 U / ml). Nipocalimab 15mg / kg IV q2w was in general well tolerated, however, 2 SAEs reported in the study, and both occurred in the nipocalimab group. A higher proportion of nipocalimab treated participants experienced infusion reactions and infections compared to those treated with placebo.

[0472] Table 1: of Baseline Medication Usage for Rheumatoid Arthritis; All Randomized Set

[0473] Nipocalimab

[0474] _ Placebo _

[0475] Analysis set: Randomized participants 20 33 53

[0476] Subjects with one or more concomitant medications for RA 20 (100.0%) 33 (100.0%) 53 (100.0%) csDMARDs 16 (80.0%) 21 (63.6%) 37 (69.8%)

[0477] Methotrexate (MTX) 14 (70.0%) 19 (57.6%) 33 (62.3%)

[0478] Sulfasalazine (SSZ) 1 (5.0%) 0 1 (1.9%)

[0479] Hydroxychloroquine (HCQ) or CQ 1 (5.0%) 0 1 (1.9%)

[0480] Leflunomide (LEF) 1 (5.0%) 2 (6.1%) 3 (5.7%)

[0481] Oral corticosteroids 15 (75.0%) 20 (60.6%) 35 (66.0%)

[0482] Methylprednisolone 7 (35.0%) 10 (30.3%) 17 (32.1%)

[0483] Prednisolone 8 (40.0%) 5 (15.2%) 13 (24.5%)

[0484] Prednisone 0 5 (15.2%) 5 (9.4%)

[0485] NS AIDs 15 (75.0%) 21 (63.6%) 36 (67.9%)

[0486] Aceclofenac 0 1 (3.0%) 1 (1.9%)

[0487] Acetylsalicylic Acid 1 (5.0%) 2 (6.1%) 3 (5.7%)

[0488] Celecoxib 2 (10.0%) 0 2 (3.8%)

[0489] Diclofenac 2 (10.0%) 2 (6.1%) 4 (7.5%)

[0490] Diclofenac Potassium 0 1 (3.0%) 1 (1.9%)

[0491] Diclofenac Sodium 1 (5.0%) 8 (24.2%) 9 (17.0%)

[0492] Esomeprazole Magnesium, naproxen 1 (5.0%) 0 1 (1.9%)

[0493] Etoricoxib 1 (5.0%) 0 1 (1.9%)

[0494] Ibuprofen 0 2 (6.1%) 2 (3.8%)

[0495] Ketoprofen 3 (15.0%) 0 3 (5.7%)

[0496] Lomoxicam 1 (5.0%) 0 1 (1.9%)

[0497] Meloxicam 1 (5.0%) 2 (6.1%) 3 (5.7%)

[0498] Metamizole 0 2 (6.1%) 2 (3.8%)

[0499] Metamizole Sodium 2 (10.0%) 0 2 (3.8%)

[0500] Naproxen Sodium 0 1 (3.0%) 1 (1.9%)

[0501] Paracetamol 1 (5.0%) 1 (3.0%) 2 (3.8%)

[0502] Table 2: Overall Summary of Prior Anti TNF Therapy; All Randomized Analysis Set

[0503] Nipocalimab

[0504] _ Placebo _ 15 mg / kg IV q2w Total

[0505] Analysis Set: Randomized participants 20 33 53 Table 2: Overall Summary of Prior Anti TNF Therapy; All Randomized Analysis Set

[0506] Nipocalimab

[0507] Placebo 15 mg / kg IV q2w Total

[0508] Subjects who took only one prior anti-

[0509] TNF therapy 16 (80.0%) 24 (72.7%) 40 (75.5%)

[0510] Subjects who took two or more prior anti-

[0511] TNF therapy 4 (20.0%) 8 (24.2%) 12 (22.6%)

[0512] Table 3: Primary Endpoint Analysis (Primary Analysis, Primary Estimand): Summary of Change from Baseline in DAS28(CRP) Score at Week 12 Using an ANCOVA Model; Full Analysis Set

[0513] Nipocalimab

[0514] Placebo 15 mg / kg IV q2w

[0515] Analysis Set: Full Analysis Set 20 33

[0516] Subjects evaluable for change from baseline in

[0517] DAS28-CRP at Week 12 N 20 33

[0518] Mean (SD) -0.62 (0.964) -1.17 (1.344)

[0519] Median -0.23 -0.96

[0520] Range (-3.0; 1.1) (-3.7; 1.4)

[0521] IQ range (-1.28; 0.00) (-2.32; 0.00)

[0522] LSMean (95% CI) -0.58 (-1.24; 0.07) -1.03 (-1.66; -0.40)

[0523] LSMean Difference (95% CI) -0.45 (-1.17; 0.28) p-value 0.224

[0524] Definition: The DAS28-CRP score is calculated based on the tender joints (28), swollen joints (28), patient’s global assessment of disease activity, and CRP. Change from baseline in DAS28-CRP measures the change in disease activity, where a negative change indicates an improvement, and a positive change indicates a worsening. Key: IQ= interquartile; ICE= Intercurrent Event, ANCOVA= Analysis of Covariance; CI= Confidence Interval; CRP= C-reactive protein

[0525] Table 4: Primary Endpoint Analysis (Supplementary Analysis, Supplementary Estimand): Summary of Change from Baseline in DAS28-CRP Score at Week 12 Using an ANCOVA Model; Full _ Analysis Set _

[0526] Nipocalimab

[0527] Placebo 15 mg / kg IV q2w

[0528] Analysis Set: Full Analysis Set 20 33

[0529] Subjects evaluable for change from baseline in

[0530] DAS28-CRP at Week 12

[0531] N 20 32

[0532] Mean (SD) -0.99 (1.082) -1.31 (1.310)

[0533] Median -0.61 -1.25

[0534] Range (-3.0; 1.1) (-3.7; 1.4)

[0535] IQ range (-1.55; -0.28) (-2.32; -0.27)

[0536] LSMean (95% CI) -0.89 (-1.57; -0.21) -1.17 (-1.82; -0.52)

[0537] LSMean Difference (95% CI) -0.28 (-1.03; 0.48) Table 4: Primary Endpoint Analysis (Supplementary Analysis, Supplementary Estimand): Summary of Change from Baseline in DAS28-CRP Score at Week 12 Using an ANCOVA Model; Full

[0538] _ Analysis Set _

[0539] _ Nipocalimab _ Placebo 15 mg / kg IV q2w

[0540] _ p-value _ 0.463 _ Definition: The DAS28-CRP score is calculated based on the tender joints (28), swollen joints (28), patient’s global assessment of disease activity, and CRP. Change from baseline in DAS28-CRP measures the change in disease activity, where a negative change indicates an improvement, and a positive change indicates a worsening.

[0541] Key: IQ= interquartile; ICE= Intercurrent Event, ANCOVA= Analysis of Covariance; CI= Confidence Interval; CRP- C-reactive protein

[0542] Table 5: Tertiary Endpoint Analysis (Main Analysis, Main Estimand): Summary of Change from Baseline _ in DAS28(CRP) Score by Visit Through Week 12 Using an ANCOVA Model; Full Analysis Set

[0543] Nipocalimab

[0544] Placebo 15 mg / kg IV q2w

[0545] Analysis Set: Full Analysis Set 20 33

[0546] Change from baseline in D AS28-CRP

[0547] Week 2 N 20 29

[0548] Mean (SD) -0.64 (0.756) -0.42 (0.855)

[0549] Median -0.45 -0.30

[0550] Range (-2.1; 0.2) (-3.1; 0.6)

[0551] IQ range (-1.26; 0.00) (-0.76; 0.16)

[0552] LSMean (95% CI) -0.78 (-1.23; -0.34) -0.53 (-0.96; -0.09)

[0553] LSMean Difference (95% CI) 0.25 (-0.24; 0.75) p-value 0.307

[0554] Week 4 N 19 33

[0555] Mean (SD) -0.75 (0.867) -0.75 (1.039)

[0556] Median -0.62 -0.61

[0557] Range (-2.7; 0.4) (-3.2; 1.1)

[0558] IQ range (-1.27; 0.00) (-1.33; 0.00)

[0559] LSMean (95% CI) -0.78 (-1.33; -0.24) -0.73 (-1.25; -0.21)

[0560] LSMean Difference (95% CI) 0.05 (-0.55; 0.66) p-value 0.864

[0561] Week 6 N 20 32

[0562] Mean (SD) -0.61 (1.029) -0.75 (1.023)

[0563] Median -0.33 -0.46

[0564] Range (-3.7; 0.7) (-3.2; 0.8)

[0565] IQ range (-0.99; 0.07) (-1.19; 0.00)

[0566] LSMean (95% CI) -0.63 (-1.17; -0.09) -0.65 (-1.17; -0.13)

[0567] LSMean Difference (95% CI) -0.02 (-0.62; 0.58) p-value 0.953

[0568] Week 8 Table 5: Tertiary Endpoint Analysis (Main Analysis, Main Estimand): Summary of Change from Baseline in DAS28(CRP) Score by Visit Through Week 12 Using an ANCOVA Model; Full Analysis Set

[0569] Nipocalimab

[0570] Placebo 15 mg / kg IV q2w

[0571] Mean (SD) -0.72 (1.089) -1.11 (1.183)

[0572] Median -0.55 -1.15

[0573] Range (-2.8; 1.2) (-3.2; 1.2)

[0574] IQ range (-1.38; 0.00) (-2.01; 0.00)

[0575] LSMean (95% CI) -0.77 (-1.39; -0.15) -1.10 (-1.69; -0.51)

[0576] LSMean Difference (95% CI) -0.33 (-1.01; 0.36) p-value 0.339

[0577] Week 10 N 19 31

[0578] Mean (SD) -0.59 (0.840) -1.24 (1.339)

[0579] Median 0.00 -1.74

[0580] Range (-2.7; 0.3) (-3.1; 1.9)

[0581] IQ range (-1.21; 0.00) (-2.23; 0.00)

[0582] LSMean (95% CI) -0.51 (-1.14; 0.13) -1.07 (-1.67; -0.46)

[0583] LSMean Difference (95% CI) -0.56 (-1.27; 0.15) p-value 0.119

[0584] Week 12 N 20 33

[0585] Mean (SD) -0.62 (0.964) -1.17 (1.344)

[0586] Median -0.23 -0.96

[0587] Range (-3.0; 1.1) (-3.7; 1.4)

[0588] IQ range (-1.28; 0.00) (-2.32; 0.00)

[0589] LSMean (95% CI) -0.58 (-1.24; 0.07) -1.03 (-1.66; -0.40)

[0590] LSMean Difference (95% CI) -0.45 (-1.17; 0.28) p-value 0.224

[0591] Definition: The DAS28-CRP score is calculated based on the tender joints (28), swollen joints (28), patient’s global assessment of disease activity, and CRP. Change from baseline in DAS28-CRP measures the change in disease activity, where a negative change indicates an improvement, and a positive change indicates a worsening. Key: IQ= interquartile; ICE= Intercurrent Event, ANCOVA= Analysis of Covariance; CI= Confidence Interval; CRP= C-reactive protein

[0592] Table 6: Number of Subjects Who Achieved ACR20, ACR50, ACR70, or ACR90 Response at Week 12

[0593] Using CMH ' Table 7: Secondary Endpoint Analysis (Main Analysis, Main Estimand): Number of Subjects Who _ Achieved DAS28-CRP Remission at Week 12 Using CMH; Full Analysis Set _

[0594] _ Nipocalimab

[0595] Placebo 15 mg / kg IV q2w

[0596] Analysis Set: Full Analysis Set 20 33

[0597] Subjects evaluable for DAS28-CRP Remission at Week

[0598] 12 20 33

[0599] Subjects with DAS28-CRP remission 2 (10.0%) 7 (21.2%) Treatment difference (95% CI) 9.9% (-9.5%; 29.3%) p-value 0.456*

[0600] Definition: The DAS28-CRP remission is defined as DAS28-CRP value of <2.6 at Week 12

[0601] Key: ICE= Intercurrent Event; CI= Confidence Interval; CMH= Cochran-Mantel-Haenszel; DAS28= Disease ivity Score of 28 (Joint); CRP= C-reactive

[0602] Table 8: Secondary Endpoint Analysis (Main Analysis, Main Estimand): Summary of Change from _ Baseline in HAQ-DI Score at Week 12 Using an ANCOVA Model; Full Analysis Set _

[0603] _ Nipocalimab

[0604] Placebo 15 mg / kg IV q2w

[0605] Analysis Set: Full Analysis Set 20 33

[0606] Subjects evaluable for change from baseline in HAQ-DI

[0607] N 20 33

[0608] Mean (SD) -0.11 (0.363) -0.27 (0.550)

[0609] Median 0.00 0.00

[0610] Range (-0.9; 0.6) (-2.0; 1.0)

[0611] IQ range (-0.25; 0.00) (-0.50; 0.00)

[0612] LSMean (95% CI) -0.21 (-0.45; 0.04) -0.42 (-0.66; -0.19)

[0613] LSMean Difference (95% CI) -0.22 (-0.49; 0.05) p-value 0.108

[0614] Definition: HAQ-DI score ranges from 0-3, with lower scores indicative of better function in subjects

[0615] Key: IQ= interquartile; ICE= Intercurrent Event, ANCOVA= Analysis of Covariance; CI= Confidence Interval;

[0616] HAQ-DI- Health Assessment Questionnaire (HAQ) Disability Index (DI)

[0617] Table 9: Tertiary Endpoint Analysis (Main Analysis, Main Estimand) Change from Baseline in CDAI by Visit Through Week 12 Using an ANCOVA Model; Full Analysis Set

[0618] Change from baseline in CD Al

[0619] Week 12

[0620] N 20 33

[0621] Mean (SD) -7.44 (10.513) -14.48 (13.590)

[0622] Median -0.65 -11.10

[0623] Range (-30.8; 3.0) (-42.6; 5.7)

[0624] IQ range (-13.72; 0.00) (-27.30; 0.00)

[0625] LSMean (95% CI) ■6.01 (-12.80; 0.79) -13.53 (-19.94; -7.11)

[0626] LSMean Difference (95% CI) -7.52 (-14.98; -0.06) p-value 0.048 Table 9: Tertiary Endpoint Analysis (Main Analysis, Main Estimand) Change from Baseline in CDAI by Visit Through Week 12 Using an ANCOVA Model; Full Analysis Set

[0627] Nipocalimab _ Placebo _ 15 mg / kg IV q2w Definitions: The Clinical Disease Activity Index (CDAI) score is a derived score combining 4 disease assessments: tender joint counts (28 joints), swollen joint counts (28 joints), Patient’s Global Assessment of Disease Activity (PtGA), and Physician’s Global Assessment of Disease Activity (PGA)

[0628] Key: IQ = interquartile; ICE-lntercurrent Event, ANCOVA- Analysis of Covariance ; CI= Confidence Interval

[0629] Table 10: Tertiary Endpoint Analysis (Main Analysis, Main Estimand): Summary of Change from Baseline in DAS28-CRP Score by Visit Through Week 12 by Baseline csDMARDs Usage Using an ANCOVA Model; Full Analysis Set

[0630] Analysis Set: Full Analysis Set 20

[0631] Subjects with baseline usage of csDMARDs 16

[0632] Change from baseline in DAS28-CRP

[0633] Week 2

[0634] N 16 18

[0635] Mean (SD) -0.59 (0.785) -0.46 (0.695)

[0636] Median -0.40 -0.36

[0637] Range (-2.1; 0.2) (-2.1; 0.5)

[0638] IQ range (-1.19; 0.01) (-0.76; 0.00)

[0639] LSMean (95% CI) -0.69 (-1.18; -0.19) -0.58 (-1.15; 0.00)

[0640] LSMean Difference (95% CI) 0.11 (-0.45; 0.67) p-value 0.687

[0641] Week 4

[0642] N 15 21

[0643] Mean (SD) -0.71 (0.875) -0.78 (1.063)

[0644] Median -0.62 -0.84

[0645] Range (-2.7; 0.4) (-2.9; 1.1)

[0646] IQ range (-1.23; 0.07) (-1.41; 0.00)

[0647] LSMean (95% CI) -0.56 (-1.20; 0.09) -0.53 (-1.24; 0.17)

[0648] LSMean Difference (95% CI) 0.02 (-0.71; 0.75) p-value 0.950

[0649] Week 6

[0650] N 16 20

[0651] Mean (SD) -0.53 (1.107) -0.92 (0.980)

[0652] Median -0.23 -0.75

[0653] Range (-3.7; 0.7) (-3.0; 0.3)

[0654] IQ range (-0.84; 0.19) (-1.24; -0.31)

[0655] LSMean (95% CI) -0.33 (-0.95; 0.28) -0.46 (-1.15; 0.23)

[0656] LSMean Difference (95% CI) -0.12 (-0.82; 0.57) p-value 0.718

[0657] Week 8

[0658] N 16 21 Table 10: Tertiary Endpoint Analysis (Main Analysis, Main Estimand): Summary of Change from Baseline in DAS28-CRP Score by Visit Through Week 12 by Baseline csDMARDs Usage Using an ANCOVA Model; Full Analysis Set

[0659] Nipocalimab

[0660] Placebo

[0661] Mean (SD) -0.60 (1.073) -1.34 (1.041)

[0662] Median -0.46 -1.37

[0663] Range (-2.8; 1.2) (-3.2; 0.6)

[0664] IQ range (-1.27; 0.06) (-2.09; -0.61)

[0665] LSMean (95% CI) -0.40 (-1.06; 0.25) -0.99 (-1.72; -0.26)

[0666] LSMean Difference (95% CI) -0.59 (-1.33; 0.16) p-value 0.117

[0667] Week 10 N 15 19

[0668] Mean (SD) -0.55 (0.906) -1.53 (1.295)

[0669] Median 0.00 -2.01

[0670] Range (-2.7; 0.3) (-3.1; 1.9)

[0671] IQ range (-1.06; 0.00) (-2.27; -0.62)

[0672] LSMean (95% CI) -0.38 (-1.13; 0.38) -1.23 (-2.07; -0.40)

[0673] LSMean Difference (95% CI) -0.86 (-1.73; 0.02) p-value 0.055

[0674] Week 12 N 16 21

[0675] Mean (SD) -0.52 (1.011) -1.45 (1.347)

[0676] Median -0.11 -1.68

[0677] Range (-3.0; 1.1) (-3.7; 1.4)

[0678] IQ range (-0.89; 0.00) (-2.32; -0.37)

[0679] LSMean (95% CI) -0.44 (-1.23; 0.36) -1.27 (-2.16; -0.39)

[0680] LSMean Difference (95% CI) -0.83 (-1.74; 0.07) p-value 0.069

[0681] Subjects without baseline usage of csDMARDs 4 12

[0682] Change from baseline in DAS28-CRPa

[0683] Week 2 N 4 11

[0684] Mean (SD) -0.85 (0.683) -0.34 (1.102)

[0685] Median -0.95 0.08

[0686] Range (-1.5; 0.0) (-3.1; 0.6)

[0687] IQ range (-1.40; -0.30) (-1.03; 0.56)

[0688] LSMean (95% CI) -0.52 (-2.09; 1.05) 0.17 (-0.95; 1.30)

[0689] LSMean Difference (95% CI) 0.69 (-0.63; 2.02) p-value 0.276

[0690] Week 4 N 4 12

[0691] Mean (SD) -0.93 (0.939) -0.69 (1.037)

[0692] Median -0.82 -0.33

[0693] Range (-2.1; 0.0) (-3.2; 0.3)

[0694] IQ range (-1.68; -0.18) (-1.08; 0.04)

[0695] LSMean (95% CI) -0.64 (-2.28; 0.99) -0.23 (-1.38; 0.92)

[0696] LSMean Difference (95% CI) 0.41 (-0.95; 1.78) p-value 0.520 Table 10: Tertiary Endpoint Analysis (Main Analysis, Main Estimand): Summary of Change from Baseline in DAS28-CRP Score by Visit Through Week 12 by Baseline csDMARDs Usage Using an ANCOVA Model; Full Analysis Set

[0697] Nipocalimab

[0698] Week 6

[0699] N 4 12

[0700] Mean (SD) -0.90 (0.666) -0.46 (1.071)

[0701] Median -0.99 0.00

[0702] Range (-1.6; 0.0) (-3.2; 0.8)

[0703] IQ range (-1.32; -0.47) (-0.96; 0.04)

[0704] LSMean (95% CI) -0.79 (-2.46; 0.88) -0.20 (-1.37; 0.98)

[0705] LSMean Difference (95% CI) 0.59 (-0.80; 1.99) p-value 0.371

[0706] Week 8

[0707] N 4 12

[0708] Mean (SD) -1.22 (1.162) -0.71 (1.350)

[0709] Median -1.04 0.00

[0710] Range (-2.8; 0.0) (-3.1; 1.2)

[0711] IQ range (-1.97; -0.46) (-1.80; 0.00)

[0712] LSMean (95% CI) -1.21 (-3.35; 0.93) -0.39 (-1.90; 1.11)

[0713] LSMean Difference (95% CI) 0.82 (-0.97; 2.60) p-value 0.339

[0714] Week 10

[0715] N 4 12

[0716] Mean (SD) -0.73 (0.604) -0.79 (1.336)

[0717] Median -0.84 0.00

[0718] Range (-1.3; 0.0) (-3.0; 0.8)

[0719] IQ range (-1.23; -0.24) (-1.99; 0.09)

[0720] LSMean (95% CI) -1.28 (-3.26; 0.70) -0.95 (-2.34; 0.44)

[0721] LSMean Difference (95% CI) 0.32 (-1.33; 1.98) p-value 0.677

[0722] Week 12

[0723] N 4 12

[0724] Mean (SD) -1.03 (0.701) -0.69 (1.246)

[0725] Median -1.28 -0.06

[0726] Range (-1.6; 0.0) (-2.9; 0.7)

[0727] IQ range (-1.43; -0.63) (-1.65; 0.00)

[0728] LSMean (95% CI) -1.41 (-3.27; 0.45) -0.70 (-2.01; 0.61)

[0729] LSMean Difference (95% CI) 0.71 (-0.85; 2.26) p-value 0.343

[0730] Definition: The DAS28-CRP score is calculated based on the tender joints (28), swollen joints (28), patient’s global assessment of disease activity, and CRP. Change from baseline in DAS28-CRP measures the change in disease activity, where a negative change indicates an improvement, and a positive change indicates a worsening. Key: IQ= interquartile; ICE= Intercurrent Event, ANCOVA= Analysis of Covariance; CI= Confidence Interval; CRP= C-reactive protein Table 11: Number of Subjects Who Achieved an ACR20 Response by Visit Through Week 12 by Baseline csDMARDs Usage, Based on Main Estimand; Full Analysis Set

[0731] Nipocalimab

[0732] Placebo 15 mg / kg IV q2w

[0733] Analysis Set: Full Analysis Set 20 33

[0734] Subjects with baseline usage of csDMARDs 16 21

[0735] Week 2

[0736] Subjects evaluable for ACR 20 Response 16 21

[0737] Subjects with ACR 20 Response 3 (18.8%) 3 (14.3%)

[0738] Week 4

[0739] Subjects evaluable for ACR 20 Response 16 21

[0740] Subjects with ACR 20 Response 6 (37.5%) 4 (19.0%)

[0741] Week 6

[0742] Subjects evaluable for ACR 20 Response 16 21

[0743] Subjects with ACR 20 Response 3 (18.8%) 5 (23.8%)

[0744] Week 8

[0745] Subjects evaluable for ACR 20 Response 16 21

[0746] Subjects with ACR 20 Response 3 (18.8%) 9 (42.9%)

[0747] Week 10

[0748] Subjects evaluable for ACR 20 Response 16 21

[0749] Subjects with ACR 20 Response 2 (12.5%) 12 (57.1%)

[0750] Week 12

[0751] Subjects evaluable for ACR 20 Response 16 21

[0752] Subjects with ACR 20 Response 3 (18.8%) 12 (57.1%)

[0753] Subjects without baseline usage of csDMARDs 4 12

[0754] Week 2

[0755] Subjects evaluable for ACR 20 Response 4 12

[0756] Subjects with ACR 20 Response 1 (25.0%) 2 (16.7%)

[0757] Week 4

[0758] Subjects evaluable for ACR 20 Response 4 12

[0759] Subjects with ACR 20 Response 1 (25.0%) 4 (33.3%)

[0760] Week 6

[0761] Subjects evaluable for ACR 20 Response 4 12

[0762] Subjects with ACR 20 Response 1 (25.0%) 4 (33.3%)

[0763] Week 8

[0764] Subjects evaluable for ACR 20 Response 4 12

[0765] Subjects with ACR 20 Response 2 (50.0%) 4 (33.3%)

[0766] Week 10

[0767] Subjects evaluable for ACR 20 Response 4 12

[0768] Subjects with ACR 20 Response 1 (25.0%) 4 (33.3%)

[0769] Week 12

[0770] Subjects evaluable for ACR 20 Response 4 12 Table 11: Number of Subjects Who Achieved an ACR20 Response by Visit Through Week 12 by Baseline _ csDMARDs Usage, Based on Main Estimand; Full Analysis Set _

[0771] _ Nipocalimab _

[0772] Placebo 15 mg / kg IV q2w

[0773] Subjects with ACR 20 Response _ 1 (25,0%) _ 3 (25,0%) _

[0774] Definition: ACR20 response is defined as > 20% improvement from baseline in both tender joint count (68 joints) and swollen joint count (66 joints), and > 20% improvement from baseline in at least 3 of the 5 assessments: patient’s assessment of pain, patient’s global assessment of disease activity, physician’s global assessment of disease activity, HAQ -DI, and CRP

[0775] Key: ICE= Intercurrent Event; CRP= C-reactive protein; HAQ-DI= Health Assessment Questionnaire (HAQ) Disability Index (DI)

[0776] Table 12: Number of Subjects Who Achieved an ACR50 Response by Visit Through Week 12 by Baseline csDMARDs Usage, Based on Main Estimand; Full Analysis Set

[0777] _ Nipocalimab _

[0778] Placebo 15 mg / kg IV q2w

[0779] Analysis Set: Full Analysis Set 20 33

[0780] Subjects with baseline usage of csDMARDs 16 21

[0781] Week 2

[0782] Subjects evaluable for ACR 50 Response 16 21

[0783] Subjects with ACR 50 Response 2 (12.5%) 0

[0784] Week 4

[0785] Subjects evaluable for ACR 50 Response 16 21

[0786] Subjects with ACR 50 Response 2 (12.5%) 1 (4.8%)

[0787] Week 6

[0788] Subjects evaluable for ACR 50 Response 16 21

[0789] Subjects with ACR 50 Response 2 (12.5%) 2 (9.5%)

[0790] Week 8

[0791] Subjects evaluable for ACR 50 Response 16 21

[0792] Subjects with ACR 50 Response 2 (12.5%) 3 (14.3%)

[0793] Week 10

[0794] Subjects evaluable for ACR 50 Response 16 21

[0795] Subjects with ACR 50 Response 0 4 (19.0%)

[0796] Week 12

[0797] Subjects evaluable for ACR 50 Response 16 21

[0798] Subjects with ACR 50 Response 0 2 (9.5%)

[0799] Subjects without baseline usage of csDMARDs 4 12

[0800] Week 2

[0801] Subjects evaluable for ACR 50 Response 4 12

[0802] Subjects with ACR 50 Response 0 1 (8.3%)

[0803] Week 4

[0804] Subjects evaluable for ACR 50 Response 4 12

[0805] Subjects with ACR 50 Response 1 (25.0%) 1 (8.3%) Table 12: Number of Subjects Who Achieved an ACR50 Response by Visit Through Week 12 by Baseline _ csDMARDs Usage, Based on Main Estimand; Full Analysis Set _

[0806] _ Nipocalimab _

[0807] Placebo 15 mg / kg IV q2w

[0808] Week 6

[0809] Subjects evaluable for ACR 50 Response 4 12

[0810] Subjects with ACR 50 Response 0 2 (16.7%)

[0811] Week 8

[0812] Subjects evaluable for ACR 50 Response 4 12

[0813] Subjects with ACR 50 Response 1 (25.0%) 4 (33.3%)

[0814] Week 10

[0815] Subjects evaluable for ACR 50 Response 4 12

[0816] Subjects with ACR 50 Response 0 3 (25.0%)

[0817] Week 12

[0818] Subjects evaluable for ACR 50 Response 4 12

[0819] Subjects with ACR 50 Response 1 (25.0%) 3 (25.0%)

[0820] Definition: ACR50 response is defined as > 50% improvement from baseline in both tender joint count (68 joints) and swollen joint count (66 joints), and > 50% improvement from baseline in at least 3 of the 5 assessments: patient’s assessment of pain, patient’s global assessment of disease activity, physician’s global assessment of disease activity, HAQ -DI, and CRP

[0821] Key: ICE= Intercurrent Event; CRP= C-reactive protein; HAQ-DI= Health Assessment Questionnaire (HAQ) Disability Index (DI)

[0822] Table 13: Tertiary Endpoint Analysis (Main Analysis, Main Estimand) Change from Baseline in CDAI by Visit Through Week 12 by Baseline csDMARDs Usage Using an ANCOVA Model; Full Analysis _ Set _ _ Nipocalimab _ Placebo 15 mg / kg IV q2w

[0823] Analysis Set: Full Analysis Set 20 33

[0824] Subjects with baseline usage of csDMARDs 16 21

[0825] Change from baseline in DAS28-CRP

[0826] Week 2

[0827] N 16 19

[0828] Mean (SD) -7.56 (9.000) -7.61 (7.882)

[0829] Median -6.64 -4.60

[0830] Range (-22.2; 5.0) (-26.2; 8.1)

[0831] IQ range (-15.10; -0.64) (-12.12; -3.50)

[0832] LSMean (95% CI) -9.11 (-14.66; -3.56) -9.96 (-16.25; -3.66)

[0833] LSMean Difference (95% CI) -0.85 (-7.29; 5.59) p-value 0.790

[0834] Week 4

[0835] N 15 21

[0836] Mean (SD) -8.33 (8.856) -10.21 (10.459)

[0837] Median -9.50 -10.00

[0838] Range (-20.6; 5.6) (-27.6; 13.0) Table 13: Tertiary Endpoint Analysis (Main Analysis, Main Estimand) Change from Baseline in CDAI by Visit Through Week 12 by Baseline csDMARDs Usage Using an ANCOVA Model; Full Analysis Set

[0839] Nipocalimab

[0840] Placebo

[0841] IQ range (-16.20; 0.00) (-20.20; -4.79)

[0842] LSMean (95% CI) -7.58 (-14.06; -1.09) -9.32 (-16.21; -2.44)

[0843] LSMean Difference (95% CI) -1.75 (-9.33; 5.83) p-value 0.642

[0844] Week 6 N 16 20

[0845] Mean (SD) -5.47 (11.604) -11.72 (9.156)

[0846] Median -1.50 -11.29

[0847] Range (-28.3; 12.9) (-30.9; 1.0)

[0848] IQ range (-14.25; 1.75) (-18.70; -3.85)

[0849] LSMean (95% CI) -5.54 (-11.96; 0.87) -9.69 (-16.67; -2.71)

[0850] LSMean Difference (95% CI) -4.15 (-11.71; 3.42) p-value 0.272

[0851] Week 8 N 16 21

[0852] Mean (SD) -8.76 (11.692) -16.59 (10.611)

[0853] Median -5.45 -18.90

[0854] Range (-34.1; 9.9) (-36.8; 0.0)

[0855] IQ range (-16.65; 0.00) (-24.60; -11.10)

[0856] LSMean (95% CI) -6.76 (-13.55; 0.03) -15.80 (-23.13; -8.46)

[0857] LSMean Difference (95% CI) -9.04 (-16.99; -1.08) p-value 0.027

[0858] Week 10 N 16 20

[0859] Mean (SD) -6.56 (10.180) -18.40 (14.241)

[0860] Median -0.20 -22.93

[0861] Range (-26.3; 2.4) (-40.5; 16.0)

[0862] IQ range (-11.93; 0.00) (-26.96; -9.73)

[0863] LSMean (95% CI) -4.26 (-12.38; 3.86) -17.08 (-25.91; -8.25)

[0864] LSMean Difference (95% CI) -12.82 (-22.45; -3.19) p-value 0.011

[0865] Week 12 N 16 21

[0866] Mean (SD) -6.64 (11.168) -17.56 (14.003)

[0867] Median 0.00 -15.90

[0868] Range (-30.8; 3.0) (-42.6; 5.7)

[0869] IQ range (-11.77; 0.00) (-28.00; -6.60)

[0870] LSMean (95% CI) -4.38 (-12.31; 3.54) -18.12 (-26.68; -9.56)

[0871] LSMean Difference (95% CI) -13.74 (-23.02; -4.46) p-value 0.005

[0872] Subjects without baseline usage of csDMARDs 4 12

[0873] Change from baseline in DAS28-CRP

[0874] Week 2 N 4 12 Table 13: Tertiary Endpoint Analysis (Main Analysis, Main Estimand) Change from Baseline in CDAI by Visit Through Week 12 by Baseline csDMARDs Usage Using an ANCOVA Model; Full Analysis Set

[0875] Nipocalimab

[0876] Placebo

[0877] Mean (SD) -8.96 (6.792) -5.15 (8.719)

[0878] Median -10.03 -2.45

[0879] Range (-15.8; 0.0) (-25.7; 3.8)

[0880] IQ range (-13.98; -3.95) (-9.30; 0.10)

[0881] LSMean (95% CI) -7.20 (-19.67; 5.27) -2.75 (-11.72; 6.22)

[0882] LSMean Difference (95% CI) 4.45 (-5.66; 14.57) p-value 0.356

[0883] Week 4 N 4 12

[0884] Mean (SD) -9.71 (9.403) -10.15 (9.815)

[0885] Median -8.78 -7.45

[0886] Range (-21.3; 0.0) (-30.2; 0.0)

[0887] IQ range (-17.13; -2.30) (-12.30; -4.15)

[0888] LSMean (95% CI) -9.50 (-24.54; 5.53) -8.96 (-19.78; 1.86)

[0889] LSMean Difference (95% CI) 0.54 (-11.65; 12.74) p-value 0.925

[0890] Week 6 N 4 12

[0891] Mean (SD) -10.61 (7.883) -6.71 (10.633)

[0892] Median -12.76 -3.50

[0893] Range (-16.9; 0.0) (-29.9; 6.5)

[0894] IQ range (-16.60; -4.61) (-13.20; 0.00)

[0895] LSMean (95% CI) -13.54 (-29.63; 2.55) -8.29 (-19.87; 3.28)

[0896] LSMean Difference (95% CI) 5.25 (-7.81; 18.30) p-value 0.398

[0897] Week 8 N 4 12

[0898] Mean (SD) -11.05 (10.550) -10.13 (13.270)

[0899] Median -10.05 -4.75

[0900] Range (-24.1; 0.0) (-34.9; 6.8)

[0901] IQ range (-19.30; -2.80) (-19.60; 0.00)

[0902] LSMean (95% CI) -15.67 (-34.91; 3.57) -12.57 (-26.41; 1.28)

[0903] LSMean Difference (95% CI) 3.10 (-12.51; 18.71) p-value 0.673

[0904] Week 10 N 4 12

[0905] Mean (SD) -8.09 (8.765) -9.58 (13.108)

[0906] Median -6.83 -1.25

[0907] Range (-18.7; 0.0) (-28.6; 6.4)

[0908] IQ range (-15.25; -0.93) (-23.10; 0.00)

[0909] LSMean (95% CI) -15.95 (-34.23; 2.33) -14.89 (-28.04; -1.74)

[0910] LSMean Difference (95% CI) 1.06 (-13.77; 15.89) p-value 0.879

[0911] Week 12 N 4 12

[0912] Mean (SD) -10.63 (7.711) -9.10 (11.447) Table 13: Tertiary Endpoint Analysis (Main Analysis, Main Estimand) Change from Baseline in CDAI by Visit Through Week 12 by Baseline csDMARDs Usage Using an ANCOVA Model; Full Analysis _ Set _ Nipocalimab

[0913] Median -12.65 -3.65

[0914] Range (-17.2; 0.0) (-30.1; 4.6)

[0915] IQ range (-16.25; -5.00) (-20.35; 0.00)

[0916] LSMean (95% CI) -17.77 (-33.52; -2.01) -13.92 (-25.25; -2.58)

[0917] LSMean Difference (95% CI) 3.85 (-8.93; 16.63) p-value 0.524

[0918] Definitions: The Clinical Disease Activity Index (CDAI) score is a derived score combining 4 disease assessments: tender joint counts (28 joints), swollen joint counts (28 joints), Patient’s Global Assessment of Disease Activity (PtGA), and Physician’s Global Assessment of Disease Activity (PGA)

[0919] Key: IQ = interquartile; ICE-lntercurrent Event, ANCOVA- Analysis of Covariance ; CI= Confidence Interval

[0920] Example 2: Clinical Trial to Evaluate Efficacy and Safety of a Combination of Anti-FcRn Antibodies and Anti-TNF Antibodies for Treatment of Rheumatoid Arthritis.

[0921] I. Protocol Summary This study is a Phase 2a multicenter, randomized, double blind, parallel, proof of concept study evaluating the efficacy and safety of nipocalimab and certolizumab combination therapy in participants with active rheumatoid arthritis (RA) despite prior treatment with advanced therapies (bDMARD or tsDMARD). Nipocalimab (also referred to M281) is a fully human aglycosylated IgGl monoclonal antibody designed to selectively bind, saturate, and block the IgG binding site on the endogenous neonatal Fc receptor. Certolizumab (Cimzia®) is an approved anti-TNFa agent indicated for active Crohn’s disease, RA, PsA, AS, nr-axSpA, and PsO.

[0922] The study population with moderately to severely active RA has already had inadequate initial response, loss of response, or intolerance to >1 advanced therapy (bDMARDs or tsDMARDs), therefore combination therapy may provide a higher chance of lower disease activity and remission. Multiple risk mitigation measures are in place to manage a potential increase in infections risk with certolizumab and nipocalimab combination therapy. Based on the well characterized safety profile of certolizumab and the available safety data of nipocalimab to date, the overall anticipated benefits outweigh the risks of participation in this clinical study.

[0923] The primary objective will be to evaluate the efficacy of combination therapy with nipocalimab and certolizumab compared to certolizumab monotherapy in participants with moderately to severely active RA despite >1 advanced therapy (bDMARDs or tsDMARDs). The endpoint of the primary objective will be a change from baseline in DAS28-CRP at Week 12. The primary hypothesis is that treatment with nipocalimab in combination with certolizumab is superior to certolizumab monotherapy in participants with moderately to severely active RA despite treatment with >1 advanced therapy (bDMARDs or tsDMARDs) as assessed by the mean change from baseline in DAS28-CRP at Week 12.

[0924] The secondary objectives are 1) to evaluate the efficacy of combination therapy with nipocalimab and certolizumab compared to certolizumab monotherapy in participants with moderately to severely active RA; and 2) to evaluate the safety and tolerability of combination therapy with nipocalimab and certolizumab. The endpoints of the first secondary objective are ACR20, ACR50, ACR70, and ACR90 responses at Week 12, DAS28-CRP remission at Week 12, DAS28-CRP LDA at Week 12, change from baseline in HAQ-DI score at Week 12, and change from baseline in CD Al at Week 12. The endpoints for the second secondary objective are measures of treatment- emergent adverse events (AEs), treatment-emergent severe AEs, treatment-emergent AEs leading to discontinuation of study intervention, and treatment- emergent AESIs.

[0925] Tertiary and / or exploratory objectives are 1) to evaluate the safety and tolerability of combination therapy with nipocalimab and certolizumab; 2) to evaluate the PK and immunogenicity of combination therapy with nipocalimab and certolizumab; 3) to evaluate the efficacy of combination therapy with nipocalimab and certolizumab in participants with ACPA high and baseline csDMARD use; and 4) to evaluate the efficacy of combination therapy with nipocalimab and certolizumab; 5) to evaluate the impact of combination therapy with nipocalimab and certolizumab on PD and disease biomarkers The total duration of the study is up to 36 weeks, consisting of 3 study periods, a 6- week screening period, a 24-week double-blind study period (22 weeks of treatment), and 6 weeks of safety follow-up (8 weeks after last dose). Participants who have had an IR to at least one advanced therapy (bDMARDs or tsDMARDs) but are certolizumab naive, will be enrolled. Participants will be randomized into 1 of 2 arms. The experimental arm will receive nipocalimab and certolizumab combination therapy. A placebo and certolizumab control arm will be used to allow for blinded evaluation of the efficacy and safety of certolizumab and nipocalimab combination therapy in participants with moderately to severely active RA.

[0926] Efficacy, safety, PK, immunogenicity, and biomarkers will be assessed. Pharmacogenomic blood samples will be collected from participants who consent to the collection (and where local regulations permit). The primary endpoint (change from baseline in DAS28-CRP at Week 12) will be evaluated after all participants have completed the Week 12 visit or have discontinued. An IA may be conducted when 50% of the planned number of participants have completed the Week 12 assessment.

[0927] A total of approximately 85 participants are planned to be enrolled. Participants will be randomly assigned to 1 of 2 treatment groups using a 2:3 randomization ratio. Control arm: placebo matching nipocalimab and certolizumab (certolizumab monotherapy). Experimental arm: Nipocalimab and certolizumab (combination therapy). Nipocalimab will be administered at 30 mg / kg Q2W. Certolizumab will be administered at 400 mg as a loading dose at Week 0,2,4 and then reduced to 200 mg Q2W as a maintenance dose. Both groups will receive their assigned treatment for 22 weeks. A schematic overview of the study is depicted in FIG. 3.

[0928] IL Study Design

[0929] This is a randomized, double blind, parallel, multicenter, PoC interventional study to evaluate the efficacy and safety of a combination therapy with nipocalimab and certolizumab in participants between 18 and 75 years old, with moderately to severely active RA despite >1 advanced therapy (bDMARDs or tsDMARDs) but are certolizumab naive. The total study duration is up to 36 weeks, consisting of a 6- week screening period, a 24- week double-blind period (22 weeks of treatment), and a 6-week safety follow-up period (8 weeks after last dose).

[0930] A target of approximately 85 participants will be randomly assigned in this study with 34 participants in the certolizumab monotherapy and 51 participants in the nipocalimab in combination with certolizumab group.

[0931] An IV administered placebo will be used in the certolizumab monotherapy group to allow for double blinded evaluation of efficacy and safety. Efficacy, safety, PK, PD, immunogenicity, and biomarkers will be assessed.

[0932] The primary endpoint (change from baseline in DAS28-CRP at Week 12 in participants receiving nipocalimab with certolizumab combination therapy compared to participants receiving certolizumab monotherapy) will be evaluated after all participants have completed the Week 12 visit (or have discontinued study participation). An IA may be conducted when approximately 43 participants (approximately 50% of the planned number of participants) complete the Week 12 assessment.

[0933] Every reasonable effort will be made to keep concomitant therapy stable. All concomitant therapies, as well as changes to concomitant therapy will be recorded throughout the study including screening. Key safety assessments include AEs, SAEs, AESIs, clinical laboratory parameters (eg, hematology, chemistry, lipid panel), physical examinations, and vital signs.

[0934] In this study, all participants will receive certolizumab. Participants in the experimental arm will receive both nipocalimab and certolizumab, while participants in the control arm will receive certolizumab and placebo. The placebo in the control arm will be used to establish the frequency and magnitude of changes in clinical endpoints that may occur in the absence of nipocalimab intervention.

[0935] III. Study Population

[0936] Screening for eligible participants will be performed within 6 weeks before administration of the study intervention. The inclusion and exclusion criteria for enrolling participants in this study are described below. If there is a question about these criteria, the investigator must consult with the appropriate sponsor representative and resolve any issues before enrolling a participant in the study. Waivers are not allowed.

[0937] Inclusion Criteria

[0938] Each potential participant must satisfy all of the following criteria to be enrolled in the study:

[0939] 1. 18 to 75 years of age, inclusive (in regions where the legal age of consent is above 18 years of age and the participant is under the legal age, signed informed consent must be obtained from both the participant and his or her legally acceptable representative).

[0940] 2. Medically stable on the basis of physical examination, medical history, vital signs, and 12-lead ECG performed at screening. Any abnormalities must be consistent with the underlying illness in the study population and this determination must be recorded in the participant's source documents and initialed by the investigator.

[0941] 3. Medically stable on the basis of clinical laboratory tests performed at screening. If the results of the serum chemistry panel, hematology, or urinalysis are outside the normal reference ranges, the participant may be included only if the investigator judges the abnormalities or deviations from normal to be not clinically significant or to be appropriate and reasonable for the population under study. This determination must be recorded in the participant's source documents and initialed by the investigator.

[0942] 4. Diagnosis of RA and meeting the 2010 ACR / EULAR Criteria for RA for at least 12 weeks before screening.

[0943] 5. Has moderate to severe active RA as defined by persistent disease activity with at least 6 of 66 swollen joints and 6 of 68 tender joints at the time of screening and at baseline.

[0944] 6. Is positive for ACPA or RF by the central laboratory at the time of screening.

[0945] 7. Has CRP >0.3 mg / dL by the central laboratory at the time of screening. 8. If has received prior anti-TNF agent, has demonstrated IR to >1 anti-TNF agent, as assessed by the treating physician: a. After at least 12 weeks dosage of etanercept, adalimumab, golimumab, and / or b. After at least 14 weeks dosage (i.e., at least 4 doses) of infliximab. Documented IR may include inadequate improvement or loss in response after initial improvement in joint counts or other parameters of disease activity.

[0946] 9. If has received prior bDMARDs other than anti-TNF agent in RA, has demonstrated IR or intolerance to the therapy based on one of the following: a. IR to at least IbDMARD other than anti-TNF agents, as assessed by the treating physician, after at least 12 weeks of therapy including but not limited to abatacept, anakinra, tocilizumab, and sarilumab or at least 16 weeks of therapy with rituximab; or b. Intolerance to bDMARD other than anti-TNF agent, as assessed by the treating physician. Documented intolerance includes side effects and injection / infusion reactions.

[0947] 10. If has received prior JAKi therapy for RA, has demonstrated IR or intolerance to the therapy based on 1 of the following: a. IR to at least 1 JAKi agent, as assessed by the treating physician, after at least 12 weeks of therapy with a JAKi which includes but is not limited to tofacitinib, baricitinib, upadacitinib; or b. Intolerance to JAKi agent as assessed by the treating physician.

[0948] 11. If using csDMARDs (e.g., MTX, SSZ, HCQ, CQ, or leflunomide), has started treatment at least 12 weeks prior to the first administration of study intervention, is on a stable dosage for at least 8 weeks prior to the first administration of study intervention, and has no serious toxic side effects attributable to the csDMARDs: a. If using MTX: on stable dosage of no more than 25 mg / week IM, SC or PO; b. If using SSZ: on stable dosage of 1000-2000 mg / day; c. If using HCQ or CQ: on a stable dosage of 200-400 mg / day; d. If using leflunomide: on stable dosage of 10-20 mg / day.

[0949] 12. If currently not using csDMARDs (ie, MTX, SSZ, HCQ, CQ, or leflunomide), has not received these DMARDs for at least 4 weeks prior to the first administration of the study intervention. 13. If using MTX, is on a stable dosage of oral folic / folinic acid (>5 mg / week) for at least 4 weeks prior to the first administration of study intervention.

[0950] 14. If using oral corticosteroids, is on a stable dosage equivalent to <10 mg / day of prednisone for at least 2 weeks prior to the first administration of study intervention. If not currently using corticosteroids, the participant must not have received oral corticosteroids for at least 2 weeks prior to the first administration of study intervention.

[0951] 15. If using nonsteroidal anti-inflammatory drugs (NSAIDs) or other analgesics for RA, is on a stable dosage for at least 2 weeks prior to the first administration of study intervention.

[0952] 16. A female participant of childbearing potential must have a negative urine pregnancy test at screening and Week 0 prior to administration of study intervention.

[0953] 17. Is not currently breastfeeding, pregnant, intends to become pregnant during the study, or within 70 days after the last administration of study intervention.

[0954] 18. A female participant must be a. Not of childbearing potential OR b. Of childbearing potential and o Practicing a highly effective method of contraception (failure rate of <1% per year when used consistently and correctly) and agrees to remain on a highly effective method while receiving study intervention and until 70 days after last dose - the end of relevant systemic exposure. The investigator must evaluate the potential for contraceptive method failure (e.g., noncompliance, recently initiated) in relationship to the first dose of study intervention.

[0955] 19. A female participant must agree not to donate eggs (ova, oocytes) or freeze for future use for the purposes of assisted reproduction during the study and for a period of 70 days after the last administration of study intervention.

[0956] 20. A male participant who has not had a vasectomy, must agree not to plan to father a child while enrolled in this study or within 90 days after the last dose of study intervention.

[0957] 21. A male participant must wear a condom when engaging in any activity that allows for passage of ejaculate to another person; male participants must also be advised of the benefit for a female partner of childbearing potential to use a highly effective method of contraception as condom may break or leak. 22. A male participant must agree not to donate sperm for the purpose of reproduction during the study and for a minimum of 90 days after receiving the last dose of study intervention.

[0958] 23. Must sign an ICF (or their legally acceptable representative must sign) indicating that participant understands the purpose of, and procedures required for, the study and is willing to participate in the study.

[0959] 24. Must sign a separate informed consent form (or their legally acceptable representative must sign) if the participant agrees to provide optional DNA samples for research (where local regulations permit). Refusal to give consent for the optional DNA research samples does not exclude a participant from participation in the study.

[0960] 25. Must be willing and able to adhere to the lifestyle restrictions specified in this protocol.

[0961] 26. Must be able to read and write. Visually impaired subjects may participate with the support of a legally acceptable representative.

[0962] 27. It is recommended to be up to date on all age-appropriate vaccinations prior to screening per routine local medical guidelines. It is strongly recommended that participants will have completed a locally approved, (or emergency use authorized), COVID- 19 vaccination regimen at least 2 weeks prior to the study-related visits or procedures. Study participants should follow applicable local vaccine labeling, guidelines, and standard of care for patients receiving immune targeted therapy when determining an appropriate interval between vaccination and study enrollment).

[0963] Exclusion Criteria

[0964] Any potential participant who meets any of the following criteria will be excluded from participating in the study:

[0965] 1. Has a diagnosed or reported history or current signs or symptoms indicating severe, progressive, or uncontrolled hepatic, renal, cardiac, vascular, pulmonary, gastrointestinal, endocrine, neurologic, hematologic, rheumatologic (except RA), psychiatric, or metabolic disturbances, which are detected at screening assessments (i.e., laboratory testing, physical examination, vital signs) or reported by the participant.

[0966] 2. Has a confirmed or suspected clinical immunodeficiency syndrome not related to treatment of RA or has a family history of congenital or hereditary immunodeficiency unless confirmed absent.

[0967] 3. Has other inflammatory diseases that might confound the evaluation of benefit in this study, including but not limited to Crohn’s disease, ulcerative colitis, interstitial lung disease, ankylosing spondylitis, psoriatic arthritis, primary Sjogren’s syndrome, SLE, and Lyme disease.

[0968] 4. Has a history of any clinically significant adverse reaction to therapeutic proteins (e.g., mABs), including, but not limited to, allergic reactions or severe immediate hypersensitivity reactions, such as anaphylaxis.

[0969] 5. Allergies, hypersensitivity, or intolerance to nipocalimab or certolizumab or their excipients (refer to the nipocalimab IB or the Cimzia SmPC).

[0970] 6. Is (anatomically or functionally) asplenic

[0971] 7. Has experienced MI, unstable ischemic heart disease, or stroke <12 weeks of screening.

[0972] 8. Has a diagnosis of congestive heart failure including medically controlled, asymptomatic congestive heart failure.

[0973] 9. Has a history of known demyelinating disease such as multiple sclerosis or optic neuritis.

[0974] 10. Had an organ transplant (with exception of corneal transplant >12 weeks prior to screening)

[0975] 11. Had major surgery, (e.g., requiring general anesthesia) within 8 weeks before screening, or has undergone surgical treatment for RA, including synovectomy and arthroplasty <12 weeks prior to first dose of study intervention, or will not have fully recovered from surgery, or has surgery planned during the time the participant is expected to participate in the study or <14 weeks after the last dose of study intervention administration. Note: Participants with planned surgical procedures to be conducted under local anesthesia may participate.

[0976] 12. Poor tolerability of venipuncture or lacks adequate venous access for required blood sample collections during the study period.

[0977] 13. Has any of the following screening laboratory test result: a. Hemoglobin <8.0 g / dL (International system of Units [SI]: <80 g / L); b. WBCs <3.0x103 cells / pL (SI:<3.0x109 cells / L); c. Neutrophils <1.0x103 cells / pL (SI: <1.0x109 cells / L); d. Platelet count <75x103 cells / pL (SI: <75xlO9 / L); e. Estimated glomerular filtration rate <30 mL / min per 1.73 m2 using the CKDEPI formula; f. Liver function test (aspartate aminotransferase [AST] OR alanine aminotransferase [ALT]) results that are >2 x the upper limit of normal (ULN); g. Serum total IgG <6 g / L (<600 mg / dL).

[0978] 14. Currently has or history of malignancy within 5 years before screening (exceptions are squamous and basal cell carcinomas of the skin and carcinoma in situ of the cervix, or malignancy, which is considered cured with minimal risk of recurrence).

[0979] 15. Has a history of lymphoproliferative disease, including lymphoma, or signs suggestive of possible lymphoproliferative disease such as lymphadenopathy of unusual size or location, or splenomegaly.

[0980] 16. History of HIV positive tests, or tests positive for HIV at screening.

[0981] 17. Tests positive for HBV infection.

[0982] 18. Is seropositive for antibodies to HCV, unless they satisfy 1 of the following conditions: a. Has a history of successful treatment, defined as being negative for HCV RNA at least 24 weeks after completing antiviral treatment, and has a negative HCV RNA test result at screening, OR b. While seropositive, has a negative HCV RNA test result at least 24 weeks prior to screening and a negative HCV RNA test at the screening. 19. Has a chronic or recurring infection (e.g., bronchiectasis, chronic osteomyelitis, chronic pyelonephritis) or requires chronic treatment with anti-infectives (e.g., antibiotics, antivirals).

[0983] 20. Has a severe infection including opportunistic infections (e.g., pneumonia, biliary tract infection, diverticulitis, clostridioides difficile infection, cytomegalovirus, pneumocystosis, and aspergillosis) requiring parenteral anti-infectives and / or hospitalization, and / or is assessed as serious / clinically significant by the investigator, within 8 weeks prior to screening. The patient may be rescreened after the 8 weeks exclusionary period has passed.

[0984] 21. Has a history of an infected joint prosthesis or has ever received antibiotics for a suspected infection of a joint prosthesis if that prosthesis has not been removed or replaced.

[0985] 22. Has a history of latent or active granulomatous infection, including but not limited to tuberculosis (see exclusion #24 on the detailed TB screening criteria below), cryptococcosis, histoplasmosis or coccidioidomycosis, prior to screening.

[0986] 23. Has a herpes zoster infection within 8 weeks before the first dose of study intervention.

[0987] 24. Meet ANY of the following TB screening criteria: a. Have a history of active TB or show signs or symptoms suggestive of active TB upon medical history and / or physical examination at screening. b. Have a history of untreated latent TB prior to screening. An exception is made for participants who are currently receiving treatment or will initiate treatment for latent TB prior to first administration of study intervention. c. Have had recent close contact with a person with active TB. An exception is made if such participants are referred to a physician specializing in TB to determine if treatment is warranted or not. This evaluation must be adequately documented and, if treatment is recommended, the participant must be receiving appropriate treatment prior to the first administration of study intervention. d. Have a positive IGRA test result within 60 days prior to the first administration of study intervention. An exception is made for participants who: i. have a history of adequately treated latent TB described above; ii. have a newly identified positive IGRA test result in which active TB has been ruled out and for which appropriate treatment for latent TB has been initiated prior to the first administration of study intervention; iii. have a false-positive IGRA test as determined by the following: a suspected false-positive initial IGRA test must be repeated. If repeat testing is NOT positive, the participant must be referred to a physician specializing in TB to determine if the initial test can be considered a false-positive. e. Have a chest radiograph or chest computed tomography within 90 days prior to the first administration of study intervention that shows abnormalities suggestive of active or inactive TB

[0988] 25. COVID- 19 infection. During the 6 weeks prior to baseline, has had any of the following (regardless of vaccination status): (a) confirmed SARS-CoV-2 infection (test positive) OR (b) suspected SARS-CoV-2 infection (clinical features of COVID-19 without documented test results) OR (c) close contact with a person with known or suspected SARS-CoV-2 infection. Exception: may be included with a documented negative result for a validated SARS-CoV-2 test i. obtained at least 2 weeks after conditions (a), (b), (c) above (timed from resolution of key clinical features if present, [e.g., fever, cough, dyspnea]) AND ii. with absence of all conditions (a), (b), (c) above during the period between the negative test result and the baseline study visit

[0989] 26. Is naive to bDMARDs and tsDMARDs.

[0990] 27. Has taken any disallowed therapies (within the period of time detailed in Section 6.8.5) prior to the planned first administration of study intervention.

[0991] 28. Currently taking IgGFc- related therapies.

[0992] 29. Has received certolizumab or nipocalimab previously.

[0993] 30. Has received plasmapheresis, immunoadsorption therapy, or IVIg within 6 weeks prior to screening. 31. Has received BCG vaccine within 1 year or any other live vaccine within 4 weeks before first dose of study intervention. Non-live vaccines approved or authorized for emergency use (eg, COVID-19) by local health authorities are allowed. Has a known need to receive a live vaccine during the study or within 8 weeks of the last study intervention administration.

[0994] 32. Has received anti-TNF agent within 30 days or 5 half-lives (whichever is longer), prior to the first administration of study intervention.

[0995] 33. Has received biologic therapy or targeted synthetic DMARDs including but not limited to the below within 30 days or 5 half-lives, whichever is longer, prior to the first administration of study intervention: a. anti-interleukin (IL)-6 receptor mAb (e.g., tocilizumab or sarilumab); b. anti-IL-1 blockers (e.g., anakinra); c. Co-stimulatory inhibitors (e.g., abatacept); d. Janus kinase inhibitors (JAKi, e.g., tofacitinib, baricitinib, upadacitinib).

[0996] 34. Has received rituximab within 26 weeks prior to first administration of study intervention.

[0997] 35. Currently using MTX and leflunomide combination therapy.

[0998] 36. Has used oral cyclophosphamide within 12 weeks or IV cyclophosphamide within 24 weeks prior to first administration of study intervention.

[0999] 37. Has received cyclosporine A, azathioprine, tacrolimus, my cophenolate mofetil, oral or parenteral gold, or D-pencillamine within 4 weeks prior to first administration of study intervention.

[1000] 38. Has received intraarticular, intramuscular, intra-bursal, intra-lesional, intra- vertebral, epidural, or IV glucocorticoids, including intramuscular adrenocorticotropic hormone within 4 weeks prior to first study intervention.

[1001] 39. Use of complementary therapies, including traditional / Chinese medicines, herbs, ointments, or procedures (e.g., acupuncture), that have the potential to activate (e.g., echinacea) or inhibit (e.g., Tripterygium wilfordii Hook F) the immune system is prohibited within 6 weeks of first administration of study intervention. In addition, use of complementary therapies, including traditional / Chinese medicines and herbs, that have the potential to interact with antithrombotic agents (e.g., St. John’s Wort) is prohibited within 6 weeks of first administration of study intervention in those taking antithrombotic agents. Any questions or concerns with the use of these therapies should be discussed with the study sponsor and / or Medical Monitor.

[1002] 40. Received an investigational intervention or used an invasive investigational medical device <12 weeks or 5 half-lives (whichever is longer) before the planned first dose of study intervention or received an investigational biological product within 12 weeks or 5 half-lives, whichever is longer, before the planned study intervention, or is currently enrolled in an investigational study.

[1003] 41. Employee of the investigator or study site, with direct involvement in the proposed study or other studies under the direction of that investigator or study site, as well as family members of the employees or the investigator.

[1004] 42. Any condition for which, in the opinion of the investigator, participation would not be in the best interest of the participant (e.g., compromise the well-being) or that could prevent, limit, or confound the protocol-specified assessments.

[1005] 43. History of drug or alcohol abuse according to Diagnostic and Statistical Manual of Mental Disorders (5th edition; DSM-V) criteria within 1 year before screening or positive test result(s) for alcohol or drugs of abuse (including barbiturates, opiates, cocaine, cannabinoids, amphetamines, and benzodiazepines) at screening.

[1006] 44. Currently participating or intends to participate in any other study using an investigational agent or procedure during the conduct of this study.

[1007] 45. Lives in an institution on court or authority order.

[1008] IV. Evaluations

[1009] The Patient’s and Physician’s Global Assessments of Disease Activity will be recorded on a VAS. The scale for the participant’s assessment ranges from “very well” to “very poor.” The scale for the physician’s assessment ranges from “no arthritis activity” to “extremely active arthritis.” The evaluating physician and participant must complete the global assessment independently of each other. The physician should preferably be the same person at every study visit for a given participant.

[1010] Participants will be asked to assess their average pain during the past week on a VAS. The scale ranges from “no pain” to “the worst possible pain.” This assessment should be completed prior to the joint examination. The validity of this assessment has been evaluated and reviewed extensively as it is a component of the ACR response score.

[1011] Participants' joint pain will be assessed using a single item that asks the participant to report the worst severity of their joint pain over the past 7 days on a 0 to 10 NRS. Responses range from “No joint pain” (0) to “'Severe joint pain” (10).

[1012] The functional status of the participant will be assessed using the Health Assessment Questionnaire -Disability Index (HAQ-DI). This 20-question instrument assesses the degree of difficulty a person has in accomplishing tasks in 8 functional areas (dressing, arising, eating, walking, hygiene, reaching, gripping, and activities of daily living). Responses in each functional area are scored from 0, indicating no difficulty, to 3, indicating inability to perform a task in that area. A score change of (-0.22) is considered the minimum threshold for a clinically important improvement.

[1013] Each of 68 joints will be evaluated for tenderness, and each of 66 joints will be evaluated for swelling (hips are excluded for swelling). The joint assessment should be performed by adequately trained joint assessor. Training on how the joint count will be performed will be provided by the sponsor. The joint assessor should be a rheumatologist or a health care provider with at least 1 year of experience in performing joint assessments. A health care provider with less than 1 year of experience may serve as a joint assessor based on the approval of the sponsor. The same assessor should perform joint assessments at every visit. It is recommended that the designated joint assessor identify an appropriate backup joint assessor in case the designated joint assessor is unavailable.

[1014] Joints should only be designated as “nonevaluable” by the joint assessor on the Joint Assessment Worksheet if it is physically impossible to assess the joint (i.e., joint inaccessible due to a cast, joint was replaced, joint not present due to an amputation, joint deformed so as to make it impossible to assess). In all other cases, the joint assessor should assess each joint for tenderness and swelling (hips are excluded for swelling) and complete the worksheet with their assessments. This should be completed regardless of any visual indications of prior surgical procedures (e.g., scars) or knowledge they may have of a participant’s prior joint procedures / inj ections (e.g., if the participant was the joint assessor’s patient prior to study participation).

[1015] V. Statistical Considerations

[1016] The primary hypothesis is that treatment with nipocalimab in combination with certolizumab is superior to certolizumab monotherapy in participants with moderately to severely active RA despite treatment with >1 advanced therapy (bDMARDs or tsDMARDs) as assessed by the mean change from baseline in DAS28-CRP at Week 12.

[1017] Approximately 85 participants are planned to be randomized in a 2:3 ratio to the control arm and experimental arm into the study. The sample size selection was determined based on the primary endpoint of the change from baseline in DAS28-CRP at Week 12.

[1018] • Treatment by Week 12: o Control arm: Certolizumab 400 mg at Week 0, 2, 4; then 200mg Q2W; Placebo IV q2w o Experimental arm: Certolizumab 400 mg at Week 0, 2, 4; then 200 mg Q2W; Nipocalimab 30 mg / kg IV q2w

[1019] • Population: Participants between the ages 18 and 75, inclusive, with moderately to severely active RA despite >1 advanced therapy (bDMARD or tsDMARD).

[1020] • Variable (Endpoint): Change from baseline in DAS28-CRP at Week 12. A participant who initiates or adjusts medication or discontinues or experiences an ICE in categories 1, 2, 3, or 4 (categories defined below) during treatment prior to the Week 12 visit will be considered a treatment failure and will be assigned a zero change from baseline in the DAS28-CRP score, regardless of the observed change. For a participant who experiences an ICE in category 5, the observed change from baseline in the DAS28-CRP score will not be used and will be assumed to follow a MAR assumption. • ICE and Corresponding Strategies: o 1. Initiated protocol prohibited medications / therapies for RA o 2. Initiation or dose increase of csDMARDs (such as MTX, SSZ, HCQ, CQ, or leflunomide) or oral corticosteroid therapy above the baseline dose for RA o 3. Discontinuation of study intervention due to lack of efficacy or an AE of RA worsening o 4. Discontinuation of study intervention due to COVID-19 infection or for reasons other than those in ICE 3 and 5 o 5. Discontinuation of study intervention due to study conduct affected by

[1021] COVID-19 reasons i.e., site closure / restricted access

[1022] • Population- level summary: Differences in the mean change in DAS28-CRP score at Week 12 as defined in the Variable attribute above between the combination therapy (certolizumab + nipocalimab) group and the monotherapy (certolizumab + placebo) group.

Claims

1. A method for treating or reducing the severity of rheumatoid arthritis in a subject in need thereof, comprising administering to the subject an anti-neonatal Fc receptor (FcRn) agent, wherein prior to the subject receiving the initial administration of the anti-FcRn agent, the level of anti-citrullinated protein antibodies (ACPA) in a blood sample of the subject is or has been found to be above a reference ACPA level.

2. A method for treating or reducing the severity of rheumatoid arthritis in a subject in need thereof, comprising (a) determining the level of ACPA in a blood sample of the subject; and (b) administering to the subject an anti-neonatal Fc receptor (FcRn) agent if the ACPA level determined in step (a) is above the reference ACPA level.

3. The method according to claim 1 or 2, wherein the blood sample is a serum sample.

4. The method of any one of the preceding claims, wherein the reference ACPA level is in the range of about 100-1000 U / mL.

5. The method of any one of the preceding claims, wherein the reference ACPA level is about 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 525, 550, 575, 600, 625, 650, 675, 700, 725, 750, 775, 800, 825, 850, 875, 900, 925, 950, 975, or 1000 U / mL.

6. The method of any one of the preceding claims, wherein the reference ACPA level is in the range of about 400-600 U / mL.

7. The method according to any one of the preceding claims, wherein the level of ACPA in the blood sample is determined using an ELISA assay.

8. The method according to any one of the preceding claims, wherein the level of ACPA in the blood sample is determined using a cyclic citrullinated peptide (CCP) assay.

9. The method according to any one of the preceding claims, wherein the level of ACPA in the blood sample is determined using the CCP2 assay.

10. The method according to any one of the preceding claims, wherein the level of ACPA in the blood sample is determined using the CCP3 assay.

11. The method of any one of the preceding claims, wherein the subject has not previously received treatment with a disease-modifying antirheumatic drug (DMARD).

12. The method of any one of the preceding claims, wherein the subject has demonstrated an inadequate response to or intolerance to at least one disease-modifying antirheumatic drug (DMARD).

13. The method of claim 11 or 12, wherein the DMARD is an anti-tumor necrosis factor (TNF) agent.

14. The method of claim 13, wherein the anti-TNF agent is adalimumab, certolizumab pegol, etanercept, golimumab, or infliximab.

15. The method of claim 13, wherein the anti-TNF agent is adalimumab, etanercept, golimumab, or infliximab.

16. The method of claim 11 or 12, wherein the DMARD is a JAK inhibitor.

17. The method of claim 16, wherein the JAK inhibitor is tofacitinib, baricitinib, or upadacitinib.

18. The method of claim 11 or 12, wherein the DMARD is an anti-interleukin-6 (IL-6) agent.

19. The method of claim 18, wherein the anti-IL-6 agent is tocilizumab.

20. The method of claim 11 or 12, wherein the DMARD is an anti-CD20 agent.

21. The method of claim 20, wherein the anti-CD20 agent is rituximab.

22. The method of claim 11 or 12, wherein the DMARD is a T cell costimulation inhibitor.

23. The method of claim 22, wherein the T cell costimulation inhibitor is abatacept.

24. The method of claim 11 or 12, wherein the DMARD is an anti-interleukin-1 (IL-1) agent.

25. The method of claim 24, wherein the anti-IL-1 agent is anakinra.

26. The method of any one of the preceding claims, wherein the subject has at least a 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 110%, or 120% higher likelihood of achieving DAS28-CRP remission 12 weeks after starting said administration compared to subjects who have an ACPA level below a reference ACPA level before receiving the initial administration of the anti-FcRn agent.

27. The method of any one of the preceding claims, which provides a beneficial clinical effect measured by a reduction in DAS28-CRP in the subject of greater than 0.7 points relative to baseline at 12 weeks after the start of said administration.

28. The method of any one of the preceding claims, wherein the subject achieves DAS28-CRP remission 12 weeks after starting said administration.

29. The method of any one of the preceding claims, which provides a beneficial clinical effect, measured by a reduction in the Clinical Disease Activity Index (CDAI) in the subject by more than 10 points relative to baseline, 12 weeks after the start of said administration.

30. The method of any one of the preceding claims, which provides a beneficial clinical effect, measured by a reduction in the Health Assessment Questionnaire - Disability Index (HAQ-DI) score in the subject by more than 0.4 points relative to baseline, 12 weeks after the start of said administration.

31. The method according to any one of the preceding claims, further comprising administering at least one conventional synthetic disease-modifying antirheumatic drug (csDMARD).

32. The method of claim 31, providing a beneficial clinical effect measured by a decrease in DAS28-CRP in the subject by more than 0.9 points relative to baseline at 8 weeks, 9 weeks, 10 weeks, 11 weeks, or 12 weeks after starting said administration of at least one csDMARD.

33. The method of claim 32, which provides a beneficial clinical effect measured by a reduction in DAS28-CRP in the subject of more than 1.2 points relative to baseline at 10 weeks, 11 weeks, or 12 weeks after starting said administration of at least one csDMARD.

34. The method of any one of claims 31-33, providing a beneficial clinical effect measured by a reduction in the Clinical Disease Activity Index (CDAI) in the subject by more than 10 points relative to baseline 12 weeks after starting said administration of at least one csDMARD.

35. The method according to any one of paragraphs 31-34, wherein the csDMARD is methotrexate, hydroxychloroquine, leflunomide, or sulfasalazine.

36. The method of any one of the preceding claims, wherein the subject achieves an ACR50 response 12 weeks after starting said administration.

37. The method of any one of the preceding claims, wherein the subject achieves an ACR70 response 12 weeks after starting said administration.

38. The method of any one of the preceding claims, wherein the subject achieves an ACR90 response 12 weeks after starting said administration.

39. The method of any one of the preceding claims, wherein the anti-FcRn agent is administered every week or every two weeks.

40. The method according to any of the preceding claims, wherein the anti-FcRn agent is administered intravenously or subcutaneously.

41. The method according to any one of the preceding claims, wherein the anti-FcRn agent is administered in a therapeutically effective dose.

42. The method of any one of the preceding claims, wherein the anti-FcRn agent is administered at a therapeutically effective dose for a period sufficient to treat or reduce the severity of rheumatoid arthritis in the subject.

43. The method according to any one of the preceding claims, wherein the anti-FcRn agent is nipocalimab, rosanolixizumab, batoclimab, IMVT-1402, efgartigimod, orilanolimab, SYNT002, ABY-039, or DX-2507.

44. The method according to any one of the preceding claims, wherein the anti-FcRn agent is an antibody to FcRn comprising: (a) a light chain that comprises a light chain complementarity determining region 1 (CDR L1) comprising the amino acid sequence of SEQ ID NO: 3, a CDR L2 comprising the amino acid sequence of SEQ ID NO: 4, and a CDR L3 comprising the amino acid sequence of SEQ ID NO: 5; and (b) a heavy chain that comprises a heavy chain complementarity determining region 1 (CDR H1) comprising the amino acid sequence of SEQ ID NO: 6, a CDR H2 comprising the amino acid sequence of SEQ ID NO: 7, and a CDR H3 comprising the amino acid sequence of SEQ ID NO:

8.

45. The method of claim 44, wherein (a) the light chain of the anti-FcRn antibody comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO: 9; and (b) the heavy chain of the anti-FcRn antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:

10.

46. ​​The method according to claim 44 or 45, wherein (a) the light chain of the anti-FcRn antibody comprises the amino acid sequence of SEQ ID NO: 1; and (b) the heavy chain of the anti-FcRn antibody comprises the amino acid sequence of SEQ ID NO:

2.

47. The method according to any one of the preceding claims, wherein the anti-FcRn agent is nipocalimab.

48. The method of any one of the preceding claims, wherein the anti-FcRn agent is administered intravenously at a dose of from about 15 mg / kg to about 30 mg / kg based on the body weight of the subject.

49. The method of any one of the preceding claims, further comprising administering to the subject an anti-tumor necrosis factor (TNF) agent.

50. The method of claim 49, wherein the subject has demonstrated an inadequate response to, or intolerance to, a prior anti-TNF agent other than the TNF agent administered to the subject.

51. The method of claim 49 or 50, wherein the anti-FcRn agent is administered separately, simultaneously, or sequentially with the anti-TNF agent.

52. The method according to any one of claims 49-51, wherein the anti-FcRn agent is administered sequentially with the anti-TNF agent.

53. The method according to any one of claims 49-51, wherein the anti-FcRn agent is administered simultaneously with the anti-TNF agent.

54. The method according to any one of claims 49-53, wherein the anti-TNF agent is administered intravenously or subcutaneously.

55. The method of any one of claims 49-54, wherein the anti-TNF agent is administered every week, every 2 weeks, every 3 weeks, every 4 weeks, every 6 weeks, or every 8 weeks.

56. The method according to any one of claims 49-54, wherein the anti-TNF agent is adalimumab, certolizumab pegol, etanercept, golimumab, or infliximab.

57. The method according to any one of paragraphs 49-55, wherein the anti-TNF agent is an antibody to TNF comprising: (a) a light chain that comprises a CDR L1 comprising the amino acid sequence of SEQ ID NO: 42, a CDR L2 comprising the amino acid sequence of SEQ ID NO: 43, a CDR L3 comprising the amino acid sequence of SEQ ID NO: 44; and (b) a heavy chain that comprises a CDR H1 comprising the amino acid sequence of SEQ ID NO: 45, a CDR H2 comprising the amino acid sequence of SEQ ID NO: 46, and a CDR H3 comprising the amino acid sequence of SEQ ID NO:

47.

58. The method of claim 57, wherein (a) the light chain of the TNF antibody comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO: 48; and (b) the heavy chain of the TNF antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:

49.

59. The method according to claim 57 or 58, wherein (a) the light chain of the TNF antibody comprises the amino acid sequence of SEQ ID NO: 40; and (b) the heavy chain of the TNF antibody comprises the amino acid sequence of SEQ ID NO:

41.

60. The method according to any one of claims 49-59, wherein the anti-TNF agent is golimumab.

61. The method according to any one of claims 49-55, wherein the anti-TNF agent is an antibody to TNF comprising (a) a light chain comprising the amino acid sequence of SEQ ID NO: 29; and (b) a heavy chain comprising the amino acid sequence of SEQ ID NO:

30.

62. The method according to any one of claims 49-55 and 61, wherein the anti-TNF agent is certolizumab pegol.

63. The method of any one of claims 49-62, providing a beneficial clinical effect measured by a reduction in DAS28-CRP of greater than 0.8, greater than 1, greater than 1.2, greater than 1.4, greater than 1.6, greater than 1.8, greater than 2, greater than 2.2, greater than 2.4, greater than 2.6, greater than 2.8, greater than 3, greater than 3.2, greater than 3.4, greater than 3.6, greater than 3.8, greater than 4, greater than 4.2, greater than 4.4, greater than 4.6, greater than 4.8, greater than 5, greater than 5.2, greater than 5.4, greater than 5.6, greater than 5.8, or greater than 6 points relative to baseline 12 weeks after the start of said administration.

64. The method of any one of claims 49-63, wherein the subject achieves low disease activity (LDA) as measured by DAS28-CRP 12 weeks after the start of said administration.

65. The method according to any of paragraphs. 49-64, providing a favorable clinical effect measured by a reduction in the Clinical Disease Activity Index (CDAI) by more than 11, more than 13, more than 15, more than 17, more than 19, more than 21, more than 23, more than 25, more than 27, more than 29, more than 31, more than 33, more than 35, more than 37, more than 39, more than 41, more than 43, more than 45, more than 47, more than 49, more than 51, more than 53, more than 55, more than 57, more than 59, more than 61, more than 63, more than 65, more than 67, more than 69, or more than 70 points relative to baseline after 12 weeks from the start of said administration.

66. The method of any one of claims 49-65, providing a beneficial clinical effect measured by a reduction in the Health Assessment Questionnaire - Disability Index (HAQ-DI) score by more than 0.5, more than 0.6, more than 0.7, more than 0.8, more than 0.9, more than 1, more than 1.1, more than 1.2, more than 1.3, more than 1.4, more than 1.5, more than 1.6, more than 1.7, more than 1.8, more than 1.9, or more than 2 points relative to baseline 12 weeks after the start of said administration.

67. An anti-FcRn agent for use in a method of treating or reducing the severity of rheumatoid arthritis in a subject in need thereof, wherein the method comprises administering to the subject an anti-FcRn agent, wherein prior to the subject receiving the initial administration of the anti-FcRn agent, the level of cyclic citrullinated peptide autoantibodies (ACPA) in a blood sample of the subject is or has been found to be above a reference level of ACPA.

68. An anti-FcRn agent for use in a method of treating or reducing the severity of rheumatoid arthritis in a subject in need thereof, the method comprising (a) determining the level of ACPA in a blood sample of the subject; and (b) administering to the subject an anti-neonatal Fc receptor (FcRn) agent if the ACPA level determined in step (a) is above the reference ACPA level.

69. An anti-FcRn agent for use according to claim 67 or 68, wherein the blood sample is a serum sample.

70. An anti-FcRn agent for use according to any one of claims 67-69, wherein the reference ACPA level is in the range of about 100-1000 U / mL.

71. An anti-FcRn agent for use according to any one of claims 67-70, wherein the reference ACPA level is about 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 525, 550, 575, 600, 625, 650, 675, 700, 725, 750, 775, 800, 825, 850, 875, 900, 925, 950, 975, or 1000 U / mL.

72. An anti-FcRn agent for use according to any one of claims 67-71, wherein the reference ACPA level is in the range of about 400-600 U / mL.

73. An anti-FcRn agent for use according to any one of claims 67-72, wherein the level of ACPA in the blood sample is determined using an ELISA assay.

74. An anti-FcRn agent for use according to any one of claims 67-73, wherein the level of ACPA in the blood sample is determined using a cyclic citrullinated peptide (CCP) assay.

75. An anti-FcRn agent for use according to any one of claims 67-74, wherein the level of ACPA in the blood sample is determined using the CCP2 assay.

76. An anti-FcRn agent for use according to any one of claims 67-75, wherein the level of ACPA in the blood sample is determined using a CCP3 assay.

77. An anti-FcRn agent for use according to any one of claims 67-76, wherein the subject has not previously received treatment with a disease-modifying antirheumatic drug (DMARD).

78. An anti-FcRn agent for use according to any one of claims 67-77, wherein the subject has demonstrated an inadequate response to or intolerance to at least one disease-modifying antirheumatic drug (DMARD).

79. An anti-FcRn agent for use according to any one of claims 67-78, wherein the DMARD is an anti-tumor necrosis factor (TNF) agent.

80. An anti-FcRn agent for use according to claim 79, wherein the anti-TNF agent is adalimumab, certolizumab pegol, etanercept, golimumab, or infliximab.

81. An anti-FcRn agent for use according to claim 79, wherein the anti-TNF agent is adalimumab, etanercept, golimumab, or infliximab.

82. An anti-FcRn agent for use according to claim 77 or 78, wherein the DMARD is a JAK inhibitor.

83. An anti-FcRn agent for use according to claim 82, wherein the JAK inhibitor is tofacitinib, baricitinib, or upadacitinib.

84. An anti-FcRn agent for use according to claim 77 or 78, wherein the DMARD is an anti-interleukin-6 (IL-6) agent.

85. An anti-FcRn agent for use according to claim 84, wherein the anti-IL-6 agent is tocilizumab.

86. An anti-FcRn agent for use according to claim 77 or 78, wherein the DMARD is an anti-CD20 agent.

87. An anti-FcRn agent for use according to claim 86, wherein the anti-CD20 agent is rituximab.

88. An anti-FcRn agent for use according to claim 77 or 78, wherein the DMARD is a T cell costimulation inhibitor.

89. An anti-FcRn agent for use according to claim 88, wherein the T cell costimulation inhibitor is abatacept.

90. An anti-FcRn agent for use according to claim 77 or 78, wherein the DMARD is an anti-interleukin-1 (IL-1) agent.

91. An anti-FcRn agent for use according to claim 90, wherein the anti-IL-1 agent is anakinra.

92. An anti-FcRn agent for use according to any one of claims 67-91, wherein the subject has at least a 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 110%, or 120% higher likelihood of achieving DAS28-CRP remission in the subject.

93. An anti-FcRn agent for use according to any one of claims 67-92, wherein the method provides a beneficial clinical effect measured by a reduction in DAS28-CRP in the subject by more than 0.7 points relative to baseline 12 weeks after the start of said administration.

94. An anti-FcRn agent for use according to any one of claims 67-93, wherein the subject achieves DAS28-CRP remission 12 weeks after starting said administration.

95. An anti-FcRn agent for use according to any one of claims 67-94, wherein the method provides a beneficial clinical effect measured by a reduction in the clinical disease activity index (CDAI) in the subject by more than 10 points relative to baseline 12 weeks after the start of said administration.

96. An anti-FcRn agent for use according to any one of claims 67-95, wherein the method provides a beneficial clinical effect measured by a reduction in the subject's Health Assessment Questionnaire - Disability Index (HAQ-DI) score by more than 0.4 points relative to baseline 12 weeks after the start of said administration.

97. An anti-FcRn agent for use according to any one of claims 67-96, further comprising administering at least one conventional synthetic disease-modifying antirheumatic drug (csDMARD).

98. An anti-FcRn agent for use according to claim 97, wherein the method provides a beneficial clinical effect measured by a reduction in DAS28-CRP in the subject of greater than 0.9 points relative to baseline at 8 weeks, 9 weeks, 10 weeks, 11 weeks, or 12 weeks after starting said administration of at least one csDMARD.

99. An anti-FcRn agent for use according to claim 97, wherein the method provides a beneficial clinical effect measured by a reduction in DAS28-CRP in the subject of greater than 1.2 points relative to baseline at 10 weeks, 11 weeks, or 12 weeks after starting said administration of at least one csDMARD.

100. An anti-FcRn agent for use according to any one of claims 97-99, wherein the method provides a beneficial clinical effect measured by a reduction in the clinical disease activity index (CDAI) in the subject by more than 10 points relative to baseline 12 weeks after starting said administration of at least one csDMARD.

101. An anti-FcRn agent for use according to any one of claims 97-100, wherein the csDMARD is methotrexate, hydroxychloroquine, leflunomide, or sulfasalazine.

102. An anti-FcRn agent for use according to any one of claims 67-101, wherein the subject achieves an ACR50 response 12 weeks after starting said administration.

103. An anti-FcRn agent for use according to any one of claims 67-102, wherein the subject achieves an ACR70 response 12 weeks after starting said administration.

104. An anti-FcRn agent for use according to any one of claims 67-103, wherein the subject achieves an ACR90 response 12 weeks after starting said administration.

105. An anti-FcRn agent for use according to any one of claims 67-104, which is administered every week or every two weeks.

106. An anti-FcRn agent for use according to any one of claims 67-105 that is administered intravenously or subcutaneously.

107. An anti-FcRn agent for use according to any one of claims 67-106, which is administered at a therapeutically effective dose.

108. An anti-FcRn agent for use according to any one of claims 67-107, which is administered at a therapeutically effective dose for a period sufficient to treat or reduce the severity of rheumatoid arthritis in a subject.

109. An anti-FcRn agent for use according to any one of claims 67-108, which is nipocalimab, rosanolixizumab, batoclimab, IMVT-1402, efgartigimod, orilanolimab, SYNT002, ABY-039, or DX-2507.

110. An anti-FcRn agent for use according to any one of claims 67-109, which is an anti-FcRn antibody comprising: (a) a light chain that comprises a CDR L1 comprising the amino acid sequence of SEQ ID NO: 3, a CDR L2 comprising the amino acid sequence of SEQ ID NO: 4, and a CDR L3 comprising the amino acid sequence of SEQ ID NO: 5; and (b) a heavy chain that comprises a CDR H1 comprising the amino acid sequence of SEQ ID NO: 6, a CDR H2 comprising the amino acid sequence of SEQ ID NO: 7, and a CDR H3 comprising the amino acid sequence of SEQ ID NO:

8.

111. An anti-FcRn agent for use according to claim 110, wherein (a) the light chain of the anti-FcRn antibody comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO: 9; and (b) the heavy chain of the anti-FcRn antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:

10.

112. An anti-FcRn agent for use according to claim 110 or claim 111, wherein (a) the light chain of the anti-FcRn antibody comprises the amino acid sequence of SEQ ID NO: 1; and (b) the heavy chain of the antibody to FcRn comprises the amino acid sequence of SEQ ID NO:

2.

113. An anti-FcRn agent for use according to any one of claims 67-112, which is nipocalimab.

114. An anti-FcRn agent for use according to any one of claims 67-113, which is administered intravenously at a dose of about 15 mg / kg to about 30 mg / kg based on the body weight of the subject.

115. An anti-FcRn agent for use according to any one of claims 67-114, wherein the method further comprises administering to the subject an anti-tumor necrosis factor (TNF) agent.

116. An anti-FcRn agent for use according to claim 115, wherein the subject has demonstrated an inadequate response to, or intolerance to, a previous anti-TNF agent other than the TNF agent administered to the subject.

117. An anti-FcRn agent for use according to claim 115 or 116 that is administered separately, simultaneously, or sequentially with the anti-TNF agent.

118. An anti-FcRn agent for use according to any one of claims 115-117 that is administered sequentially with an anti-TNF agent.

119. An anti-FcRn agent for use according to any one of claims 115-117, which is administered concurrently with an anti-TNF agent.

120. An anti-FcRn agent for use according to any one of claims 115-119, wherein the anti-TNF agent is administered intravenously or subcutaneously.

121. An anti-FcRn agent for use according to any one of claims 115-120, wherein the anti-TNF agent is administered every week, every 2 weeks, every 3 weeks, every 4 weeks, every 6 weeks, or every 8 weeks.

122. An anti-FcRn agent for use according to any one of claims 115-121, wherein the anti-TNF agent is adalimumab, certolizumab pegol, etanercept, golimumab, or infliximab.

123. An anti-FcRn agent for use according to any one of claims 115-122, wherein the anti-TNF agent is an antibody to TNF comprising: (a) a light chain that comprises a CDR L1 comprising the amino acid sequence of SEQ ID NO: 42, a CDR L2 comprising the amino acid sequence of SEQ ID NO: 43, a CDR L3 comprising the amino acid sequence of SEQ ID NO: 44; and (b) a heavy chain that comprises a CDR H1 comprising the amino acid sequence of SEQ ID NO: 45, a CDR H2 comprising the amino acid sequence of SEQ ID NO: 46, and a CDR H3 comprising the amino acid sequence of SEQ ID NO:

47.

124. An anti-FcRn agent for use according to claim 123, wherein (a) the light chain of the TNF antibody comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO: 48; and (b) the heavy chain of the TNF antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:

49.

125. An anti-FcRn agent for use according to claim 123 or 124, wherein (a) the light chain of the anti-TNF antibody comprises the amino acid sequence of SEQ ID NO: 40; and (b) the heavy chain of the TNF antibody comprises the amino acid sequence of SEQ ID NO:

41.

126. An anti-FcRn agent for use according to any one of claims 115-125, wherein the anti-TNF agent is golimumab.

127. An anti-FcRn agent for use according to any one of claims 115-126, wherein the anti-TNF agent is an antibody to TNF comprising (a) a light chain comprising the amino acid sequence of SEQ ID NO: 29; and (b) a heavy chain comprising the amino acid sequence of SEQ ID NO:

30.

128. An anti-FcRn agent for use according to any one of claims 115-122 and 127, wherein the anti-TNF agent is certolizumab pegol.

129. An anti-FcRn agent for use according to any one of claims 67-128, wherein the method provides a beneficial clinical effect measured by a reduction in DAS28-CRP of greater than 0.8, greater than 1, greater than 1.2, greater than 1.4, greater than 1.6, greater than 1.8, greater than 2, greater than 2.2, greater than 2.4, greater than 2.6, greater than 2.8, greater than 3, greater than 3.2, greater than 3.4, greater than 3.6, greater than 3.8, greater than 4, greater than 4.2, greater than 4.4, greater than 4.6, greater than 4.8, greater than 5, greater than 5.2, greater than 5.4, greater than 5.6, greater than 5.8, or greater than 6 points relative to baseline at 12 weeks after the start of said administration.

130. An anti-FcRn agent for use according to any one of claims 67-129, wherein the subject achieves an LDA for DAS28-CRP 12 weeks after the start of said administration.

131. An anti-FcRn agent for use according to any one of claims 67-130, wherein the method provides a beneficial clinical effect measured by a reduction in the Clinical Disease Activity Index (CDAI) by more than 11, more than 13, more than 15, more than 17, more than 19, more than 21, more than 23, more than 25, more than 27, more than 29, more than 31, more than 33, more than 35, more than 37, more than 39, more than 41, more than 43, more than 45, more than 47, more than 49, more than 51, more than 53, more than 55, more than 57, more than 59, more than 61, more than 63, more than 65, more than 67, more than 69, or more than 70 points relative to the baseline at 12 weeks after the start of said administration.

132. An anti-FcRn agent for use according to any one of claims 67-131, wherein the method provides a beneficial clinical effect measured by a reduction in the Health Assessment Questionnaire - Disability Index (HAQ-DI) score by more than 0.4, more than 0.5, more than 0.6, more than 0.7, more than 0.8, more than 0.9, more than 1, more than 1.1, more than 1.2, more than 1.3, more than 1.4, more than 1.5, more than 1.6, more than 1.7, more than 1.8, more than 1.9, or more than 2 points relative to baseline at 12 weeks after starting said administration.

133. A combination of an anti-FcRn agent and an anti-TNF agent for use in the method of any one of claims 49-66.

134. A kit comprising an anti-neonatal Fc receptor (FcRn) agent and an anti-tumor necrosis factor (TNF) agent for a subject.

135. The set according to item 134, wherein the components of the set are located separately.

136. The kit of claim 134 or 135, wherein the anti-FcRn agent and the anti-TNF agent are intended for separate, simultaneous, or sequential administration.

137. The kit of any one of claims 134-136, wherein the anti-FcRn agent is the anti-FcRn agent of any one of claims 43-47.

138. The kit according to any one of paragraphs 134-137, wherein the anti-TNF agent is the anti-TNF agent according to any one of paragraphs 56-62.

139. A kit according to any one of paragraphs 134-138, additionally containing instructions for use.

140. The kit of any one of claims 134-139, further comprising instructions for a method of treating or reducing the severity of rheumatoid arthritis in a subject.

141. The kit of claim 140, wherein the method is the method of any one of claims 49-66.