Treatment of autoimmune diseases

Abstract

This disclosure provides a method for treating rheumatic diseases that are difficult to treat in human patients who are seronegative for rheumatoid factor, using a biological disease-modifying antirheumatic drug lacking an Fc fragment. In some embodiments, the method includes treating a patient with rheumatoid arthritis who is seronegative for rheumatoid factor using certolizumab pegol.

Description

Technical Field

[0001] Cross - reference to Related Applications This application claims priority based on European Patent Application No. 23173178.7 filed on May 12, 2023, European Patent Application No. 23176822.7 filed on June 1, 2023, European Patent Application No. 24164645.4 filed on March 19, 2024, and European Patent Application No. 24170908.8 filed on April 17, 2024, which are hereby incorporated by reference in their entirety.

[0002] The present invention is in the field of the treatment of autoimmune diseases, particularly rheumatoid arthritis, juvenile idiopathic arthritis, systemic lupus erythematosus, vasculitis and Sjögren's syndrome. The present invention provides methods and compounds for treating patients suffering from inflammatory autoimmune diseases, particularly rheumatoid arthritis.

Background Art

[0003] Autoimmune diseases are a group of different disorders that share similar clinical, laboratory findings and immunological symptoms. Their basic pathophysiological finding is the expression of an excessive autoreactive antigen - driven immune response characterized by inflammation and subsequent progressive tissue damage.

[0004] Rheumatic autoimmune diseases include conditions such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), juvenile idiopathic arthritis, vasculitis and primary Sjögren's syndrome (pSS).

[0005] Rheumatoid arthritis (RA) is a chronic, symmetrical, inflammatory autoimmune disease that initially affects small joints and progresses to larger joints, eventually affecting the skin, eyes, heart, kidneys, and lungs. Often, the bones and cartilage of the joints are destroyed, and the tendons and ligaments weaken. All of this damage to the joints leads to deformities and bone erosions, which are usually very painful for the patient. Common symptoms of RA include morning stiffness in the affected joints lasting more than 30 minutes, fatigue, fever, weight loss, tenderness, swelling, and warmth of the joints, as well as subcutaneous rheumatic nodules. The disease typically develops between the ages of 35 and 60 and is accompanied by remissions and exacerbations.

[0006] There are three common classes of drugs commonly used to treat rheumatoid arthritis: nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, and disease-modifying antirheumatic drugs (DMARDs). NSAIDs and corticosteroids have a short onset of action, while DMARDs may take weeks or months to demonstrate their clinical effect. DMARDs include methotrexate, sulfasalazine, leflunomide, antimalarial drugs, and biological drugs such as etanercept, infliximab, adalimumab, certolizumab pegol, golimumab, abatacept, rituximab, tocilizumab, and anakinra. Other immunomodulatory drugs, including azathioprine and cyclosporine, are used occasionally. Because cartilage damage and bone erosion frequently occur within the first two years of the disease, rheumatologists now actively transition to DMARDs early in the course of the disease, usually as soon as the diagnosis is confirmed.

[0007] The current treatment paradigm for rheumatoid arthritis (RA) is based on a "targeted therapy" approach, meaning that treatment is added until the patient reaches a therapeutic target, such as low disease activity (LDA). The "targeted therapy" approach is associated with better long-term outcomes and reduced injury incidence. Biological disease-modifying anti-inflammatory drugs (DMARDs) are effective in rapidly slowing the progression of joint damage caused by RA. They are considered a more "direct, defined, and targeted" treatment method. Nevertheless, biologics raise serious side effect issues, such as an increased risk of infection.

[0008] Among bDMARDs, etanercept, infliximab, adalimumab, golimumab, and certolizumab pegol are all TNFα inhibitors that prevent the recruitment of inflammatory cells. Tumor necrosis factor alpha (TNFα) is a messenger protein that promotes inflammation in the joints. Biological TNFα inhibitors are recommended when other second-line drugs are ineffective. Tumor necrosis factor alpha (TNFα) inhibitors have become central to the treatment of rheumatoid arthritis (RA) patients after failure to respond to conventional DMARDs. Despite the clinical efficacy of TNFα inhibitors (TNFi), many RA patients experience TNFi treatment failure (secondary failure) due to the development of anti-drug antibodies (ADAs) that can reduce drug levels and lead to RA disease relapse. Furthermore, approximately 20-30% of RA patients treated with TNFα inhibitors show primary failure (no efficacy response to at least 12-18 weeks of treatment).

[0009] 60%–90% of RA patients possess detectable levels of rheumatoid factor (RF), specifically native antibodies targeting the fragment crystallizable (Fc) region of immunoglobulin (Ig) G and exhibiting high reactivity to the IgG1 isotype. Rheumatoid factors have been identified as IgA, IgD, IgE, IgG, and IgM isotypes in presymptomatic individuals (Ingegnoli et al., Rheumatoid Factors: Clinical Applications, Dis Markers. 2013). While IgM antibodies typically have lower affinity for their antigens, little is known about the functional differences between these three isotypes. In its physiological role, the most common RF subtype, pentameric IgM RF, increases immune complex clearance by binding to up to 10 IgG1-Fc regions per RF molecule (Figure 21). These large immune complexes are then eliminated by endocytosis via binding to congeneral Fc receptors. There is evidence supporting the pathogenic role of rheumatoid factor (RF), which makes a significant contribution to the pathophysiology of rheumatoid arthritis (Edwards et al., Rheumatoid arthritis: The predictable effect of small immune complexes in which antibody is also antigen, Br J Rheumatol. 1998). High RF titers in RA patients are associated with higher disease activity, disease progression, and a reduced response to TNFα inhibitor treatment (Bobbio-Pallavicini F, et al., Ann Rheum Dis. 2007). Specifically, high RF titers of 50 U / mL or higher are significantly associated with RA disease activity compared to low-titer or negative RF. In summary, high-titer RF is associated with more severe forms of RA that do not respond well to TNFα inhibitor treatment.

[0010] Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by loss of tolerance to chromatin and production of antinuclear antibodies (e.g., anti-double-stranded DNA, anti-Sm, anti-Ro, and anti-La antibodies). The symptoms of the disease are polymorphic and include rash, arthritis, fever, cytopenia, glomerulonephritis, and central nervous system disorders. Anti-double-stranded DNA antibodies are typically associated with more severe forms of the disease (i.e., lupus nephritis), while anti-Ro or anti-La antibodies are preferentially found in patients with non-nephritis symptoms such as rash or arthritis.

[0011] Rheumatoid factor (RF) is often found in 20% of patients with systemic lupus erythematosus (SLE), in association with anti-Ro antibodies or anti-La antibodies and the development of non-renal symptoms (Witte et al., Rheumatoid factors in systemic lupus erythematosus: association with clinical and laboratory parameters, Rheumatol Int 2000).

[0012] Treatment for SLE requires corticosteroids and other immunosuppressants, such as azathioprine, mycophenolate mofetil, cyclophosphamide, or calcineurin inhibitors. Biologics (e.g., rituximab, belimumab) are also increasingly used in patients with SLE and those with a severe or refractory disease course.

[0013] Primary Sjögren's syndrome (pSS) is a rare autoimmune disease characterized by polyclonal B cell activation, production of antinuclear antibodies, lymphocyte infiltration of the lacrimal and salivary glands, and a range of systemic symptoms including arthritis, pancreatitis, or interstitial nephropathy. Rheumatoid factor is found in approximately 50% of pSS patients and is often at high titers. Treatment options for pSS are limited, and biologics are being developed to treat patients with severe symptoms of the disease.

[0014] Juvenile idiopathic arthritis is a group of rheumatic diseases affecting one or more joints for at least six weeks in children under 16 years of age. Arthritis, fever, rash, adenopathy, splenomegaly, and iridocyclitis are typical of some forms. Treatment includes intra-articular corticosteroids, nonsteroidal anti-inflammatory drugs (NSAIDs), and disease-modifying antirheumatic drugs (DMARDs), including biological DMARDs such as certain TNFα inhibitors.

[0015] Therefore, individualized treatment approaches are needed for patients with rheumatoid arthritis, juvenile idiopathic arthritis, SLE, and Sjögren's syndrome, and those with high RF titers. [Overview of the project]

[0016] TNFα inhibitors have been successfully used for the treatment of rheumatoid arthritis (RA) for over 20 years, but there is still a subgroup of RA patients who do not initially respond well to such treatment with TNFα inhibitors, do not respond at all, or cannot maintain therapeutic effects over the course of treatment. A specific subgroup of patients in which this is a problem is RA patients with high titers of rheumatoid factor (RF). Typically, RF titers are measured in vitro in serum samples from patients.

[0017] This disclosure provides further analysis of data from six clinical trials: C-OPERA (NCT01451203), the pooled RAPID trials (RAPID-1 [NCT00152386], RAPID-2 [NCT00160602], J-RAPID [NCT00791999], RAPID-C [NCT02151851]), and EXXELERATE (NCT01500278). Patients receiving certolizumab pegol (CZP) or placebo / comparative adalimumab (ADA) with methotrexate (MTX) were classified by baseline RF quartile. The efficacy of CZP in patients with early and established RA across baseline RF levels was evaluated using disease activity score-28 erythrocyte sedimentation rate (DAS28-ESR). This post-hoc analysis of multiple clinical trials (Phase 3 and Phase 4) clarifies the efficacy of CZP across baseline RF quartiles in patients with early-stage RA and established RA.

[0018] This analysis of clinical data now shows that certolizumab pegol, a pegylated Fab' fragment of a TNFα-blocking antibody, exhibits the same level of efficacy in RA patients with high RF titers compared to those with low RF titers. This contrasts with other TNFα inhibitors (such as adalimumab, infliximab, etanercept, or golimumab) which exhibit lower efficacy in RA patients with high RF titers. Furthermore, this analysis demonstrates that certolizumab pegol (CZP) is significantly more effective than adalimumab (ADA) in patients with high rheumatoid factor rheumatoid arthritis titers at baseline. The higher efficacy of certolizumab pegol in patients with high RF titers is associated with maintaining drug plasma concentrations compared to adalimumab in patients with low RF titers, where those concentrations decreased over time in patients with high RF titers compared to those with low RF titers.

[0019] Accordingly, this disclosure describes a method for treating rheumatic disorders in human patients identified as having rheumatoid factor greater than 100 IU / ml. In some embodiments, the human patient is identified as having rheumatoid factor greater than 121.4 IU / ml. In some embodiments, the human patient is identified as having rheumatoid factor greater than 125 IU / ml. In some embodiments, the human patient is identified as having rheumatoid factor greater than 145.9 IU / ml. In some embodiments, the human patient is identified as having rheumatoid factor greater than 150 IU / ml. In some embodiments, the human patient is identified as having rheumatoid factor greater than 175 IU / ml. In some embodiments, the human patient is identified as having rheumatoid factor greater than 200 IU / ml. In some embodiments, the human patient is identified as having rheumatoid factor greater than 204 IU / ml. In some embodiments, the human patient is identified as having rheumatoid factor of at least 275 IU / ml.

[0020] Those skilled in the art will understand that this finding is applicable to other rheumatic diseases in patients with high RF titers, such as juvenile idiopathic arthritis, SLE, and Sjögren's syndrome.

[0021] Accordingly, a first aspect of the present disclosure is a method for treating rheumatic disorders in human patients who are seronegative for rheumatoid factor, comprising administering a biologic lacking an Fc fragment to a human patient identified as having more than 100 IU / ml, 121.4 IU / ml, 125 IU / ml, 145.9 IU / ml, 150 IU / ml, 175 IU / ml, 200 IU / ml or 204 IU / ml of rheumatoid factor in their serum, wherein (i) the therapeutic effect of the biologic lacking an Fc fragment is not diminished by RF in the patient, and / or (ii) the treatment induces low disease activity in the patient or achieves substantial clinical benefit.

[0022] In some embodiments, the present disclosure provides a method for treating rheumatoid arthritis in human patients who are serologically positive for rheumatoid factor, comprising administering certolizumab pegol to human patients identified as having rheumatoid factor in serum greater than 100 IU / ml, 121.4 IU / ml, 125 IU / ml, 145.9 IU / ml, 150 IU / ml, 175 IU / ml, 200 IU / ml, more preferably 204 IU / ml, wherein (i) the therapeutic effect of certolizumab pegol is not diminished by RF in the patient, and / or (ii) the treatment induces low disease activity in the patient or achieves substantial clinical benefit.

[0023] In some embodiments, the present disclosure provides a method for treating rheumatoid arthritis in a human patient who is serologically positive for rheumatoid factor, comprising: (a) determining the titer of rheumatoid factor in a sample from the patient, preferably a serum sample; and (b) administering certolizumab pegol to the patient if the titer of rheumatoid factor in the serum is greater than 100 IU / ml, 121.4 IU / ml, 125 IU / ml, 145.9 IU / ml, 150 IU / ml, 175 IU / ml, 200 IU / ml, more preferably 204 IU / ml, wherein (i) the therapeutic effect of certolizumab pegol is not diminished by the patient's RF, and / or (ii) the treatment induces low disease activity in the patient or achieves substantial clinical benefit.

[0024] In some embodiments, the present disclosure provides a method for maintaining low disease activity or remission of a rheumatic disease in a human subject in need, comprising administering to the subject a dose of a bDMARD lacking an Fc fragment effective in maintaining low disease activity or remission, wherein the subject is identified as having elevated baseline rheumatoid factor (RF) serum levels greater than 100 IU / ml. [Brief explanation of the drawing]

[0025] [Figure 1] This is a figure showing data from a prospective trial comparing certolizumab pegol in combination with methotrexate with TNFi having an Fc fragment (adalimumab) in patients with moderate to severe rheumatoid arthritis. The effects of both drugs on disease activity (DAS28-CRP in the upper panel, proportion of patients reaching LDA in the lower panel) are the same across the patient population.

[0026] [Figure 2] This is a figure showing that when patients are classified according to RF titer, certolizumab pegol presents a different response pattern to different treatments compared with TNFi having an Fc fragment (adalimumab). In patients with high-titer RF, compared with patients with low RF titer, the response to TNFi having an Fc fragment (adalimumab) is reduced, and higher DAS28-CRP values are obtained (upper panel). In contrast, the effect of certolizumab pegol is not affected by the RF titer (lower panel), and the DAS28-CRP values are incorporated.

[0027] [Figure 3A] This is a figure showing that certolizumab pegol and TNFi having an Fc fragment (adalimumab) show similar clinical efficacy (DAS28-CRP score) in patients with low RF titer (upper panel of Figure 3a). In contrast, in patients with high RF titer, administration of certolizumab pegol results in lower DAS28-CRP scores (lower panel).

[0028] [Figure 3B]This figure shows responses to CZP and ADA up to week 104, stratified by RF quartile (RF ≤ 204 UI / mL or RF > 204 UI / mL) at baseline [OC;NRI], as measured by (Panel A) DAS28-CRP and (Panel B) DAS28-CRP LDA. Complete analysis set at week 12; complete analysis set at week 12 from week 18. Data reported according to treated patients were from the time of measurement (i.e., any patients who switched to TNFi at week 12 were not in the initially randomized group but were subsequently included in the group for the new treatment). N is for OC data. [a] Defined as DAS28-CRP ≤ 2.7. [b] N at week 2. ADA: Adalimumab; CRP: C-reactive protein; CZP: Certolizumab pegol; DAS28: Disease activity score -28 joint count; LDA: Low disease activity; MTX: Methotrexate; NRI: Non-responder complement; OC: Observed case; Q3: Third quartile; RF: Rheumatoid factor; SD: Standard deviation; TNFi: Tumor necrosis factor inhibitor.

[0029] [Figure 4] The figure shows that in RA patients with high RF titers, the proportion of patients treated with TNFi (adalimumab) with Fc fragments reaching LDA is lower compared to RA patients with low RF titers. This pattern is not observed with certolizumab pegol. Patients treated with certolizumab pegol reach LDA at a similar rate, regardless of whether they have low or high TF titers.

[0030] [Figure 5A] This figure illustrates how high RF titers affect the plasma drug concentrations of TNFi (adalimumab) containing Fc fragments, while certolizumab pegol is not affected. Drug concentrations of certolizumab pegol (left panel) and adalimumab (right panel) are shown as functions of RF titer. High RF titers are associated with lower adalimumab drug concentrations compared to lower RF titers. In contrast, the drug concentration of certolizumab pegol does not differ between high and low RF titers.

[0031] [Figure 5B] This figure shows the mean plasma drug concentrations (Panel A) of CZP and (Panel B) of ADA up to week 104, stratified by RF quartile (RF ≤ 204 UI / mL or RF > 204 UI / mL) at baseline [OC]. Complete analysis set at week 12; complete analysis set at week 12 from week 18. Data reported according to treated patients were from the time of measurement (i.e., any patients who switched to TNFi at week 12 were not in the initially randomized group but were subsequently included in the group for the new treatment). ADA: adalimumab; CZP: certolizumab pegol; MTX: methotrexate; OC: observed cases; Q3: third quartile; RF: rheumatoid factor; SD: standard deviation.

[0032] [Figure 6] This figure shows the clinical trial designs for RAPID-1, RAPID-2, J-RAPID, RAPID-C, C-OPERA, and EXXELERATE. ACR20: ≥20% improvement based on American College of Rheumatology criteria; ADA: adalimumab; CZP: certolizumab pegol; DAS28(ESR): Disease activity score 28 erythrocyte sedimentation rate; MTX: methotrexate; OLE: open label expansion; PBO: placebo; Q2W: every 2 weeks; Q4W: every 4 weeks; RCT: randomized controlled trial; Wk: week.

[0033] [Figure 7]Panels (a) to (c) show the DAS28(ESR) LDA and REM rates at weeks 12 and 24 for the (Panel a) C-OPERA, (Panel b) Pooled RAPID, and (Panel c) EXXELERATE trials. The RF quartiles at week 24 were defined as ≤32.0 IU / mL, >32.0 to ≤74.0 IU / mL, >74.0 to ≤204.0 IU / mL, and >204 IU / mL for Q1 to Q4, respectively. DAS28(ESR) 2.6-≤3.2 was classified as LDA, and DAS28(ESR) <2.6 was classified as REM. ADA: Adalimumab; CZP: Certolizumab pegol; DAS28(ESR): Disease activity score 28 erythrocyte sedimentation rate; LDA: Low disease activity; MTX: Methotrexate; PBO: Placebo; Q: Interquartiles; REM: Remission; RF: Rheumatoid factor.

[0034] [Figure 8A] This figure shows the mean DAS28(ESR) over 24 weeks for the C-OPERA trial. [Figure 8B] This figure shows the mean DAS28(ESR) over 24 weeks for pooled RAPID trials. [Figure 8C] This figure shows the mean DAS28(ESR) over 24 weeks for the EXXELERATE trial. The data for week 24 is mean (SD). ADA: adalimumab; CZP: certolizumab pegol; DAS28(ESR): disease activity score 28 erythrocyte sedimentation rate; MTX: methotrexate; PBO: placebo; Q: quartiles; RF: rheumatoid factor; SD: standard deviation.

[0035] [Figure 8D]This figure shows responses to CZP and ADA up to week 104, stratified by RF quartile (RF ≤ 204 UI / mL or RF > 204 UI / mL) at baseline [OC;NRI], as measured by (Panel A) DAS28-ESR and (Panel B) DAS28-ESR LDA. Complete analysis set at week 12; complete analysis set at week 12 from week 18. Data reported according to treated patients were from the time of measurement (i.e., any patients who switched to TNFi at week 12 were not in the initially randomized group but were subsequently included in the group for the new treatment). N is for OC data. [a] Defined as DAS28-ESR ≤ 3.2. [b] N at week 2. ADA: Adalimumab; CZP: Certolizumab pegol; DAS28: Disease activity score -28 joint count; ESR: Erythrocyte sedimentation rate; LDA: Low disease activity; MTX: Methotrexate; NRI: Non-responder complement; OC: Observed case; Q3: Third quartile; RF: Rheumatoid factor; SD: Standard deviation; TNFi: Tumor necrosis factor inhibitor.

[0036] [Figure 9] This figure shows that in an in vitro ELISA experiment, anti-IgG Fc antibodies significantly bound to seven different biological drugs used to treat RA and other rheumatic diseases, but did not bind to certolizumab pegol. In the ELISA, plastic plates were coated with eight different biological drugs: abatacept (ABT), tocilizumab (TCZ), sarilumab (SAR), etanercept (ETN), infliximab (IFX), adalimumab (ADA), golimumab (GLM), and certolizumab pegol (CZP). Subsequently, the following secondary antibodies conjugated with alkaline phosphatase—(1) antibody against IgG Fc, (2) antibody against IgM Fc, (3) antibody against κ-type antibody light chain, and (4) antibody against λ-type antibody light chain—were added to the above coated ELISA plates in separate experiments.

[0037] [Figure 10]The ELISA experiment shown in Figure 9 above demonstrates that the anti-IgM Fc antibody did not bind to eight biological drugs, including certolizumab pegol. This confirms the specificity of the binding of the anti-IgG Fc antibody shown in Figure 9.

[0038] [Figure 11] Figure 9 above shows that in the ELISA experiment, the anti-κ antibody light chain antibodies bound to TCZ, SAR, IFX, ADA, GLM, and CZP all possessed a κ antibody light chain. ABT and ETN did not bind. ABT and ETN are fusion proteins that do not have a light chain. This confirms that the binding of the anti-IgG Fc antibody shown in Figure 9 is specific.

[0039] [Figure 12] This figure shows data obtained from experiments similar to those in Figure 13, focusing on two positive and negative serum samples. Optical density is higher for all bDMARDs except CZP when RF is positive. In the two cases using RF-negative serum, the OD is 0 because RF cannot bind to the Fc region of the bDMARD (all), or in the case of CZP, the Fc region is not present in the drug.

[0040] [Figure 13]This figure shows that in in vitro ELISA experiments, seven different biologics used for the treatment of RA and other rheumatic diseases [abatacept (ABT), tocilizumab (TCZ), sarilumab (SAR), etanercept (ETN), infliximab (IFX), adalimumab (ADA), and golimumab (GLM)] formed immune complexes when contacted with diluted serum containing RF, but certolizumab pegol (CZP) did not. As a control, it is also shown that none of the seven drugs, nor certolizumab pegol, formed immune complexes when contacted with diluted serum without RF. This also shows the formation and size of immune complexes formed with different bDMARDs (CZP only) of RF with and without an Fc region. Both aspects are measured by the mean of OD (optical density, higher optical density means more and / or larger immune complexes). All bDMARDs exhibit high OD (OD=0) experimentally when exposed to RF-positive serum. No binding is observed when the serum is RF-negative. Only CZP shows no binding of any type (OD=0) when exposed to either RF-positive or RF-negative serum.

[0041] [Figure 14] This figure shows the response to CZP and ADA up to week 104, stratified by RF quartile (RF ≤ 204 UI / mL or RF > 204 UI / mL) at baseline [OC], as measured by (Panel A) CDAI and (Panel B) CDAI LDA. Complete analysis set at week 12; complete analysis set at week 12 from week 18. Data reported according to treatment were from the time of measurement (i.e., any patient who switched to TNFi at week 12 was included in the group for the new treatment, not the group initially randomized to). [a] Defined as CDAI ≤ 10. [b] N at week 2. ADA: Adalimumab; CDAI: Clinical Disease Activity Index; CZP: Certolizumab pegol; MTX: Methotrexate; OC: Observed Case; Q3: Third Quartile; RF: Rheumatoid Factor; SD: Standard Deviation; TNFi: Tumor Necrosis Factor Inhibitor.

[0042] [Figure 15] This figure shows responses to CZP and ADA up to week 104, stratified by RF quartile (RF ≤ 204 UI / mL or RF > 204 UI / mL) at baseline [OC], as measured by (Panel A) SDAI and (Panel B) SDAI LDA. Complete analysis set at week 12; complete analysis set at week 12 from week 18. Data reported according to treated patients were those at the time of measurement (i.e., any patients who switched to TNFi at week 12 were not in the initially randomized group but were subsequently included in the group for the new treatment). Higher SDAI scores indicate increased disease severity. [a] Defined as SDAI ≤ 11. [b] N at week 2. ADA: Adalimumab; CDAI: Clinical Disease Activity Index; CZP: Certolizumab pegol; MTX: Methotrexate; OC: Observed Cases; Q3: Third Quartile; RF: Rheumatoid Factor; SD: Standard Deviation; SDAI: Simple Disease Activity Index; TNFi: Tumor Necrosis Factor Inhibitor.

[0043] [Figure 16] This figure shows HAQ-DI scores in CZP and ADA-treated patients up to week 104, stratified by RF quartile (RF ≤ 204 UI / mL or RF > 204 UI / mL) at baseline [OC]. Complete analysis set at week 12; complete analysis set from week 18 to week 12. Data reported according to treated patients were measured at the time (i.e., any patients who switched to TNFi at week 12 were not in the initially randomized group but were subsequently included in the group for the new treatment). ADA: adalimumab; CZP: certolizumab pegol; MTX: methotrexate; HAQ-DI: Health Assessment Questionnaire - Disability Index; OC: Observed Case; Q3: Third Quartile; RF: Rheumatoid Factor; SD: Standard Deviation; TNFi: Tumor Necrosis Factor Inhibitor.

[0044] [Figure 17]This figure shows the response to CZP and ADA up to week 104, measured by the proportion of patients who achieved Boolean remission, stratified by RF quartile (RF ≤ 204 UI / mL or RF > 204 UI / mL) at baseline [NRI]. Complete analysis set at week 12; complete analysis set from week 18 to week 12. Data reported according to treated patients were from the time of measurement (i.e., any patients who switched to TNFi at week 12 were not in the initially randomized group but were subsequently included in the group for the new treatment). Boolean remission is defined as SJC ≤ 1 and TJC ≤ 1, and PtGADA ≤ 2 and CRP ≤ 1. ADA: Adalimumab; CRP: C-reactive protein; CZP: Certolizumab pegol; MTX: Methotrexate; NRI: Non-responder complementation; PtGADA: Overall assessment of patient disease activity; Q3: Third quartile; RF: Rheumatoid factor; SJC: Swelling joint count; TJC: Tender joint count; TNFi: Tumor necrosis factor inhibitor.

[0045] [Figure 18] This figure shows the mean DAS28-CRP (Panel A) and DAS28-ESR (Panel B) up to week 104 [OC] in CZP and ADA-treated patients, stratified by RF quartile (RF ≤ 204 UI / mL or RF > 204 UI / mL), after excluding patients with high levels of anti-drug antibodies (>50th percentile). A complete analysis set up at week 12; a complete analysis set from week 18 to week 12. Data reported according to treated patients were measured at the time of measurement (i.e., any patients who switched to TNFi at week 12 were not in the initially randomized group but were subsequently included in the group for the new treatment). ADA: Adalimumab; CRP: C-reactive protein; CZP: Certolizumab pegol; DAS28: Disease activity score -28 joint count; ESR: Erythrocyte sedimentation rate; MTX: Methotrexate; OC: Observed cases; Q3: Third quartile; RF: Rheumatoid factor; SD: Standard deviation; TNFi: Tumor necrosis factor inhibitor.

[0046] [Figure 19]The mean DAS28-CRP LDA (Panel A) and DAS28-ESR LDA (Panel B) in CZP and ADA-treated patients, stratified by RF quartile (RF ≤ 204 UI / mL or RF > 204 UI / mL), after excluding patients with high levels of anti-drug antibodies (>50th percentile), are shown up to 104 weeks [OC]. The quartile represents the RF level at baseline. Complete analysis set. Data reported according to treated patients were at the time of measurement (i.e., any patients who switched to TNFi at week 12 were not in the initially randomized group but were subsequently included in the group for the new treatment). [a] Defined as DAS28-CRP ≤ 2.7. [b] N at week 2. [c] Defined as DAS28-ESR ≤ 3.2. ADA: Adalimumab; CRP: C-reactive protein; CZP: Certolizumab pegol; DAS28: Disease activity score -28 joint count; ESR: Erythrocyte sedimentation rate; LDA: Low disease activity; MTX: Methotrexate; OC: Observed case; Q3: Third quartile; RF: Rheumatoid factor; TNFi: Tumor necrosis factor inhibitor.

[0047] [Figure 20] This figure shows responses to CZP and ADA up to week 104, stratified by ACPA levels at baseline [OC], as measured by (Panel A) DAS28-CRP and (Panel B) DAS28-ESR. Complete analysis set at week 12; complete analysis set from week 18 to week 12. Data reported according to treated patients were from the time of measurement (i.e., any patients who switched to TNFi at week 12 were not in the initially randomized group but were subsequently included in the group for the new treatment). ACPA: Anti-citrullinated protein antibody; ADA: Adalimumab; CRP: c-reactive protein; CZP: Certolizumab pegol; DAS28: Disease activity score - 28 joint count; ESR: Erythrocyte sedimentation rate; MTX: Methotrexate; OC: Observed case; Q3: Third quartile; SD: Standard deviation; TNFi: Tumor necrosis factor inhibitor.

[0048] [Figure 21]This diagram illustrates how IgM-type rheumatoid factor generally binds to the Fc region of IgG, including therapeutic antibodies such as TNF inhibitors, to form large immune complexes. These immune complexes are internalized by macrophages via the Fc gamma receptor and degraded by lysosomes.

[0049] [Figure 22] This figure shows the molecular structure of a bDMARD that has a predominantly Fc region. An example of a bDMARD that does not have an Fc region is certolizumab pegol.

[0050] [Figure 23] This figure shows the setup for an IgM-RF binding ELISA assay. A bDMARD is coated onto a microtiter plate, and then IgM RF from serum is added to the plate. The binding of IgM RF is then detected with an anti-human IgM antibody.

[0051] [Figure 24] This figure shows the four quartiles of RF concentration in the population after PS-ITPW from the FIRST Registry.

[0052] [Figure 25] This figure shows graphs of CDAI at weeks 0, 2, and 4 for patients in the FIRST Registry after PS-ITPW treated with adalimumab (ADA) or CZP. Patients treated with CZP had significantly lower disease activity in those with a baseline RF of ≥ 121.4 (p=0.034).

[0053] [Figure 26] This figure shows the CDAI remission rates in patients after PS-ITPW treated with adalimumab (ADA) or CZP. The subjects in Q4 (RF > 121.4 IU / ml) showed a significantly higher CDAI remission rate (p = 0.008) when treated with CZP compared to ADA.

[0054] [Figure 27]This figure shows the baseline RF quartiles.

[0055] [Figure 28] This figure compares CDAI remission rates across different anti-TNF drugs (bDMARDs) Q1-Q3 vs. Q4. [Modes for carrying out the invention]

[0056] Surprisingly, the inventors found that a TNFα inhibitor lacking the Fc fragment (certolizumab pegol) exhibited a different response pattern to treatment compared to a TNFα inhibitor containing the Fc fragment (adalimumab) in patients with high-titer versus low-titer RF. The inventors observed differences in plasma drug concentration patterns between the two bDMARDs. Thus, the mean adalimumab drug concentration was lower in patients with high-titer RF compared to patients with low-titer RF. In contrast, this difference was not observed with certolizumab pegol, which maintained similar drug concentrations in patients with high RF titers compared to patients with low RF titers.

[0057] In summary, our observations indicate that certolizumab pegol does not behave as expected in patients with high-titer RF. Compared to adalimumab, certolizumab pegol maintains the therapeutic response and plasma drug concentrations in patients with high-titer RF, similar to those observed in patients with low-titer RF.

[0058] This disclosure provides a method for treating rheumatic disorders in human patients identified as having rheumatoid factor (Rheumatoid Factor) levels greater than 100 IU / ml. In some embodiments, the human patient is identified as having Rheumatoid Factor levels greater than 121.4 IU / ml. In some embodiments, the human patient is identified as having Rheumatoid Factor levels greater than 125 IU / ml. In some embodiments, the human patient is identified as having Rheumatoid Factor levels greater than 145.9 IU / ml. In some embodiments, the human patient is identified as having Rheumatoid Factor levels greater than 150 IU / ml. In some embodiments, the human patient is identified as having Rheumatoid Factor levels greater than 175 IU / ml. In some embodiments, the human patient is identified as having Rheumatoid Factor levels greater than 200 IU / ml. In some embodiments, the human patient is identified as having Rheumatoid Factor levels greater than 204 IU / ml. In some embodiments, the human patient is identified as having Rheumatoid Factor levels greater than 225 IU / ml. In some embodiments, human patients are identified as having rheumatoid factor levels greater than 250 IU / ml. In some embodiments, human patients are identified as having at least 275 IU / ml of rheumatoid factor.

[0059] Accordingly, in a first embodiment, the present disclosure provides a method for treating rheumatoid arthritis in a human patient who is seronegative for rheumatoid factor, comprising administering a bDMARD lacking an Fc fragment, preferably certolizumab pegol, to a human patient identified as having rheumatoid factor in serum greater than 100 IU / ml, 121.4 IU / ml, 125 IU / ml, 145.9 IU / ml, 150 IU / ml, 175 IU / ml, 200 IU / ml, more preferably 204 IU / ml, wherein (i) the therapeutic effect of the bDMARD lacking an Fc fragment, preferably certolizumab pegol, is not diminished by the patient's RF, and / or (ii) the treatment induces low disease activity in the patient or achieves substantial clinical benefit. In some embodiments, the human patient is identified as having rheumatoid factor greater than 100 IU / ml. In some embodiments, human patients are identified as having rheumatoid factor greater than 121.4 IU / ml. In some embodiments, human patients are identified as having rheumatoid factor greater than 125 IU / ml. In some embodiments, human patients are identified as having rheumatoid factor greater than 145.9 IU / ml. In some embodiments, human patients are identified as having rheumatoid factor greater than 150 IU / ml. In some embodiments, human patients are identified as having rheumatoid factor greater than 175 IU / ml. In some embodiments, human patients are identified as having rheumatoid factor greater than 200 IU / ml. In some embodiments, human patients are identified as having rheumatoid factor greater than 204 IU / ml. In some embodiments, human patients are identified as having rheumatoid factor greater than 225 IU / ml. In some embodiments, human patients are identified as having rheumatoid factor greater than 250 IU / ml. In some embodiments, human patients are identified as having at least 275 IU / ml of rheumatoid factor.

[0060] A second embodiment of the present disclosure is a method for treating rheumatoid arthritis in a human patient who is seronegative for rheumatoid factor, comprising: (a) determining the titer of rheumatoid factor in the patient; and (b) administering to the patient an Fc-fragment-deficient bDMARD, preferably certolizumab pegol, if the titer of rheumatoid factor in serum is greater than 100 IU / ml, 125 IU / ml, 150 IU / ml, 175 IU / ml, or 200 IU / ml, more preferably 204 IU / ml, wherein (i) the therapeutic effect of the Fc-fragment-deficient bDMARD, preferably certolizumab pegol, is not reduced by RF in the patient, and / or (i) the treatment induces low disease activity in the patient or achieves substantial clinical benefit. In some embodiments, the titer of rheumatoid factor in the patient is greater than 100 IU / ml. In some embodiments, the titer of rheumatoid factor in the patient is greater than 121.4 IU / ml. In some embodiments, the titer of rheumatoid factor in the patient is greater than 125 IU / ml. In some embodiments, the titer of rheumatoid factor in the patient is greater than 145.9 IU / ml. In some embodiments, the titer of rheumatoid factor in the patient is greater than 150 IU / ml. In some embodiments, the titer of rheumatoid factor in the patient is greater than 175 IU / ml. In some embodiments, the titer of rheumatoid factor in the patient is greater than 200 IU / ml. In some embodiments, the titer of rheumatoid factor in the patient is greater than 204 IU / ml. In some embodiments, the human patient is identified as having a rheumatoid factor of greater than 225 IU / ml. In some embodiments, the human patient is identified as having a rheumatoid factor of greater than 250 IU / ml. In some embodiments, human patients are identified as having at least 275 IU / ml of rheumatoid factor.

[0061] The surprising finding that the activity of bio-DMARDs (bDMARDs) lacking Fc fragments, such as certolizumab pegol, is not diminished in patients with high-titer RF will be understood by those skilled in the art as being applicable to other rheumatic diseases and other Fc-fragment-lacking bDMARDs with necessary modifications. Therefore, the aforementioned Fc-fragment-lacking bDMARDs (e.g., certolizumab pegol, dapirorizumab pegol, or ozoralizumab) may be preferred drugs for the treatment of patients with rheumatic diseases and high RF titers (e.g., juvenile idiopathic arthritis, vasculitis, SLE, and Sjögren's syndrome).

[0062] In a third embodiment, the present disclosure relates to a method for treating juvenile idiopathic arthritis in human patients who are serum-positive for rheumatoid factor, wherein the human patient is identified as having rheumatoid factor in serum at a concentration greater than 100 IU / ml, greater than 121.4 IU / ml, greater than 125 IU / ml, greater than 145.9 IU / ml, greater than 150 IU / ml, greater than 175 IU / ml, or greater than 200 IU / ml, more preferably greater than 204 IU / ml, using a bDMARD lacking an Fc fragment, preferably dapyrolizumab pegol or ozoralizumab, most preferably A method is provided for treating juvenile idiopathic arthritis in human patients who are serologically positive for rheumatoid factor, comprising administering certolizumab pegol, wherein (i) the therapeutic effect of a bDMARD lacking an Fc fragment, preferably dapyrolizumab pegol or ozoralizumab, most preferably certolizumab pegol, is not reduced by RF in the patient, and / or (ii) the treatment induces low disease activity in the patient or achieves substantial clinical benefit. In some embodiments, the human patient is identified as having rheumatoid factor greater than 100 IU / ml. In some embodiments, the human patient is identified as having rheumatoid factor greater than 121.4 IU / ml. In some embodiments, the human patient is identified as having rheumatoid factor greater than 125 IU / ml. In some embodiments, the human patient is identified as having rheumatoid factor greater than 145.9 IU / ml. In some embodiments, human patients are identified as having rheumatoid factor greater than 150 IU / ml. In some embodiments, human patients are identified as having rheumatoid factor greater than 175 IU / ml. In some embodiments, human patients are identified as having rheumatoid factor greater than 200 IU / ml. In some embodiments, human patients are identified as having rheumatoid factor greater than 204 IU / ml. In some embodiments, human patients are identified as having at least 275 IU / ml of rheumatoid factor.

[0063] A fourth embodiment of the present disclosure is a method for treating juvenile idiopathic arthritis in a human patient who is serum-positive for rheumatoid factor, comprising: (a) determining the titer of rheumatoid factor in the patient; and (b) if the titer of rheumatoid factor is greater than 100 IU / ml, 121.4 IU / ml, 125 IU / ml, 145.9 IU / ml, 150 IU / ml, 175 IU / ml, 200 IU / ml, more preferably 204 IU / ml, a bDMARD lacking an Fc fragment, preferably dapyrolizumab pegol or A method for treating juvenile idiopathic arthritis in a human patient serologically positive for rheumatoid factor, comprising administering ozoralizumab, most preferably certolizumab pegol, to the patient, wherein (i) the therapeutic effect of a bDMARD lacking an Fc fragment, preferably dapyrolizumab pegol, or ozoralizumab, most preferably certolizumab pegol, is not reduced by RF in the patient, and / or (i) the treatment induces low disease activity in the patient or achieves substantial clinical benefit. In some embodiments, the human patient is identified as having rheumatoid factor greater than 100 IU / ml. In some embodiments, the human patient is identified as having rheumatoid factor greater than 121.4 IU / ml. In some embodiments, the human patient is identified as having rheumatoid factor greater than 125 IU / ml. In some embodiments, the human patient is identified as having rheumatoid factor greater than 145.9 IU / ml. In some embodiments, human patients are identified as having rheumatoid factor greater than 150 IU / ml. In some embodiments, human patients are identified as having rheumatoid factor greater than 175 IU / ml. In some embodiments, human patients are identified as having rheumatoid factor greater than 200 IU / ml. In some embodiments, human patients are identified as having rheumatoid factor greater than 204 IU / ml. In some embodiments, human patients are identified as having rheumatoid factor greater than 225 IU / ml. In some embodiments, human patients are identified as having rheumatoid factor greater than 250 IU / ml. In some embodiments, human patients are identified as having at least 275 IU / ml of rheumatoid factor.

[0064] In a fifth embodiment, the present disclosure provides a method for treating systemic lupus erythematosus (SLE) in human patients who are serologically positive for rheumatoid factor, comprising administering a bDMARD lacking an Fc fragment, preferably dapirolloizumab pegol, to human patients identified as having rheumatoid factor in serum greater than 100 IU / ml, 121.4 IU / ml, 125 IU / ml, 145.9 IU / ml, 150 IU / ml, 175 IU / ml, 200 IU / ml, more preferably 204 IU / ml, wherein (i) the therapeutic effect of the bDMARD lacking an Fc fragment, preferably dapirolloizumab pegol, is not diminished by the patient's RF, and / or (ii) the treatment induces low disease activity in the patient or achieves substantial clinical benefit. In some embodiments, human patients are identified as having rheumatoid factor levels exceeding 100 IU / ml. In some embodiments, human patients are identified as having rheumatoid factor levels exceeding 121.4 IU / ml. In some embodiments, human patients are identified as having rheumatoid factor levels exceeding 125 IU / ml. In some embodiments, human patients are identified as having rheumatoid factor levels exceeding 145.9 IU / ml. In some embodiments, human patients are identified as having rheumatoid factor levels exceeding 150 IU / ml. In some embodiments, human patients are identified as having rheumatoid factor levels exceeding 175 IU / ml. In some embodiments, human patients are identified as having rheumatoid factor levels exceeding 200 IU / ml. In some embodiments, human patients are identified as having rheumatoid factor levels exceeding 204 IU / ml. In some embodiments, human patients are identified as having rheumatoid factor levels exceeding 225 IU / ml. In some embodiments, human patients are identified as having rheumatoid factor levels exceeding 250 IU / ml. In some embodiments, human patients are identified as having at least 275 IU / ml of rheumatoid factor.

[0065] A sixth embodiment of the present disclosure is a method for treating systemic lupus erythematosus (SLE) in a human patient who is seronegative for rheumatoid factor, comprising: (a) determining the titer of rheumatoid factor in the patient; and (b) administering to the patient an Fc-fragment-deficient bDMARD, preferably dapirolizumab pegol, if the titer of rheumatoid factor is greater than 100 IU / ml, 125 IU / ml, 150 IU / ml, 175 IU / ml, or 200 IU / ml, more preferably 204 IU / ml in serum, wherein (i) the therapeutic effect of the Fc-fragment-deficient bDMARD, preferably dapirolizumab pegol, is not diminished by the patient's RF, and / or (i) the treatment induces low disease activity in the patient or achieves substantial clinical benefit. In some embodiments, the rheumatoid factor titer in the patient is greater than 100 IU / ml. In some embodiments, the rheumatoid factor titer in the patient is greater than 121.4 IU / ml. In some embodiments, the rheumatoid factor titer in the patient is greater than 125 IU / ml. In some embodiments, the rheumatoid factor titer in the patient is greater than 145.9 IU / ml. In some embodiments, the rheumatoid factor titer in the patient is greater than 150 IU / ml. In some embodiments, the rheumatoid factor titer in the patient is greater than 175 IU / ml. In some embodiments, the rheumatoid factor titer in the patient is greater than 200 IU / ml. In some embodiments, the rheumatoid factor titer in the patient is greater than 204 IU / ml. In some embodiments, the human patient is identified as having a rheumatoid factor titer greater than 225 IU / ml. In some embodiments, human patients are identified as having rheumatoid factor levels greater than 250 IU / ml. In some embodiments, human patients are identified as having at least 275 IU / ml of rheumatoid factor.

[0066] In the seventh embodiment, the present disclosure relates to a method for treating Sjögren's syndrome, preferably primary Sjögren's syndrome (pSS), in human patients who are serologically positive for rheumatoid factor, comprising an Fc-deficient bDMARD, preferably certolizumab pegol or ozoralizumab, most preferably dapirolizumab pegol, administered to serum at concentrations of 100 IU / ml, 121.4 IU / ml, 125 IU / ml, 145.9 IU / ml, 150 IU / ml, 175 IU / ml, and 200 IU / ml. The present invention provides a method comprising administering to a human patient identified as having rheumatoid factor greater than U / ml or 200 IU / ml, more preferably 204 IU / ml, wherein (i) the therapeutic effect of a bDMARD lacking an Fc fragment, preferably certolizumab pegol or ozoralizumab, most preferably dapyrolizumab pegol, is not reduced by RF in the patient, and / or (ii) the treatment induces low disease activity in the patient or achieves substantial clinical benefit. In some embodiments, the human patient is identified as having rheumatoid factor greater than 100 IU / ml. In some embodiments, the human patient is identified as having rheumatoid factor greater than 121.4 IU / ml. In some embodiments, the human patient is identified as having rheumatoid factor greater than 125 IU / ml. In some embodiments, the human patient is identified as having rheumatoid factor greater than 145.9 IU / ml. In some embodiments, the human patient is identified as having rheumatoid factor greater than 150 IU / ml. In some embodiments, human patients are identified as having rheumatoid factor greater than 175 IU / ml. In some embodiments, human patients are identified as having rheumatoid factor greater than 200 IU / ml. In some embodiments, human patients are identified as having rheumatoid factor greater than 204 IU / ml. In some embodiments, human patients are identified as having rheumatoid factor greater than 225 IU / ml. In some embodiments, human patients are identified as having rheumatoid factor greater than 250 IU / ml. In some embodiments, human patients are identified as having at least 275 IU / ml of rheumatoid factor.

[0067] An eighth embodiment of the present disclosure is a method for treating Sjögren's syndrome, preferably primary Sjögren's syndrome (pSS), in a human patient who is serologically positive for rheumatoid factor, comprising: (a) determining the titer of rheumatoid factor in the patient; and (b) if the titer of rheumatoid factor is greater than 100 IU / ml, 121.4 IU / ml, 125 IU / ml, 145.9 IU / ml, 150 IU / ml, 175 IU / ml, 200 IU / ml, more preferably 204 IU / ml, a bDMARD lacking an Fc fragment, preferably certolizumab pegor. A method for treating Sjögren's syndrome, preferably primary Sjögren's syndrome (pSS), in a human patient who is seronegative for rheumatoid factor, comprising (i) administering to the patient certolizumab pegol or ozoralizumab, most preferably dapirozumab, the therapeutic effect of a bDMARD lacking an Fc fragment, preferably certolizumab pegol or ozoralizumab, most preferably dapirozumab, is not reduced by RF in the patient, and / or (i) the treatment induces low disease activity in the patient or achieves substantial clinical benefit. In some embodiments, the human patient is identified as having rheumatoid factor greater than 100 IU / ml. In some embodiments, the human patient is identified as having rheumatoid factor greater than 121.4 IU / ml. In some embodiments, the human patient is identified as having rheumatoid factor greater than 125 IU / ml. In some embodiments, the human patient is identified as having rheumatoid factor greater than 145.9 IU / ml. In some embodiments, human patients are identified as having rheumatoid factor greater than 150 IU / ml. In some embodiments, human patients are identified as having rheumatoid factor greater than 175 IU / ml. In some embodiments, human patients are identified as having rheumatoid factor greater than 200 IU / ml. In some embodiments, human patients are identified as having rheumatoid factor greater than 204 IU / ml. In some embodiments, human patients are identified as having rheumatoid factor greater than 225 IU / ml. In some embodiments, human patients are identified as having rheumatoid factor greater than 250 IU / ml. In some embodiments, human patients are identified as having at least 275 IU / ml of rheumatoid factor.

[0068] In further embodiments, the present disclosure relates to a method for treating vasculitis in a human patient who is serum-positive for rheumatoid factor, wherein the human patient is identified as having rheumatoid factor in serum at a concentration of 100 IU / ml, 121.4 IU / ml, 125 IU / ml, 145.9 IU / ml, 150 IU / ml, 175 IU / ml, or greater than 200 IU / ml, more preferably greater than 204 IU / ml, and is treated with a bDMARD lacking an Fc fragment, preferably dapyrolizumab pegol or ozolalisma. The present invention provides a method for treating vasculitis in human patients serologically positive for rheumatoid factor, comprising, most preferably, administering certolizumab pegol, wherein (i) the therapeutic effect of a bDMARD lacking an Fc fragment, preferably dapyrolizumab pegol or ozoralizumab, most preferably certolizumab pegol, is not diminished by the patient's RF, and / or (ii) the treatment induces low disease activity in the patient or achieves substantial clinical benefit. In some embodiments, the human patient is identified as having rheumatoid factor greater than 100 IU / ml. In some embodiments, the human patient is identified as having rheumatoid factor greater than 121.4 IU / ml. In some embodiments, the human patient is identified as having rheumatoid factor greater than 125 IU / ml. In some embodiments, the human patient is identified as having rheumatoid factor greater than 145.9 IU / ml. In some embodiments, the human patient is identified as having rheumatoid factor greater than 150 IU / ml. In some embodiments, human patients are identified as having rheumatoid factor greater than 175 IU / ml. In some embodiments, human patients are identified as having rheumatoid factor greater than 200 IU / ml. In some embodiments, human patients are identified as having rheumatoid factor greater than 204 IU / ml. In some embodiments, human patients are identified as having rheumatoid factor greater than 225 IU / ml. In some embodiments, human patients are identified as having rheumatoid factor greater than 250 IU / ml. In some embodiments, human patients are identified as having at least 275 IU / ml of rheumatoid factor.

[0069] Further embodiments of the present disclosure describe a method for treating vasculitis in a human patient who is serologically positive for rheumatoid factor, comprising: (a) determining the titer of rheumatoid factor in the patient; and (b) if the titer of rheumatoid factor is greater than 100 IU / ml, 121.4 IU / ml, 125 IU / ml, 145.9 IU / ml, 150 IU / ml, 175 IU / ml, 200 IU / ml, more preferably 204 IU / ml, a bDMARD lacking Fc fragments, preferably The method comprises administering to the patient (i) a bDMARD lacking an Fc fragment, preferably dapirolizumab pegol or ozoralizumab, most preferably certolizumab pegol, such that the therapeutic effect of the bDMARD lacking an Fc fragment, preferably dapirolizumab pegol or ozoralizumab, most preferably certolizumab pegol, is not reduced by RF in the patient, and / or (i) the treatment induces low disease activity in the patient or achieves substantial clinical benefit. In some embodiments, the human patient is identified as having rheumatoid factor greater than 100 IU / ml. In some embodiments, the human patient is identified as having rheumatoid factor greater than 121.4 IU / ml. In some embodiments, the human patient is identified as having rheumatoid factor greater than 125 IU / ml. In some embodiments, the human patient is identified as having rheumatoid factor greater than 145.9 IU / ml. In some embodiments, the human patient is identified as having rheumatoid factor greater than 150 IU / ml. In some embodiments, human patients are identified as having rheumatoid factor greater than 175 IU / ml. In some embodiments, human patients are identified as having rheumatoid factor greater than 200 IU / ml. In some embodiments, human patients are identified as having rheumatoid factor greater than 204 IU / ml. In some embodiments, human patients are identified as having rheumatoid factor greater than 225 IU / ml. In some embodiments, human patients are identified as having rheumatoid factor greater than 250 IU / ml. In some embodiments, human patients are identified as having at least 275 IU / ml of rheumatoid factor.

[0070] A ninth embodiment of the present disclosure is a therapeutic method according to any one of the first, second, third, fourth, fifth, or sixth embodiments of the present invention, wherein low disease activity is achieved 90, 100, 104, 120, or 180 days after the first dose of a bDMARD lacking an Fc fragment.

[0071] A tenth embodiment of the present disclosure is a treatment method according to any one of the first, second, third, fourth, fifth, sixth, seventh, eighth, or ninth embodiments of the present invention, wherein a patient's low disease activity or substantial clinical benefit is achieved with a 40%, 45%, 50%, or 55% probability.

[0072] An eleventh embodiment of the present disclosure is a therapeutic method according to any one of the first, second, third, fourth, ninth, or tenth embodiments of the present invention, wherein certolizumab pegol is administered to the patient in step (b) as an initial loading dose of 400 mg and then as a loading dose of 400 mg two weeks later, and thereafter administered to the patient in (i) a maintenance dose of 400 mg every four weeks or (ii) a maintenance dose of 200 mg every two weeks.

[0073] A twelfth embodiment of the present disclosure is a treatment method according to any one of the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, or eleventh embodiments of the present invention, wherein a loading dose is not administered to the patient at the start of treatment.

[0074] A thirteenth embodiment of the present disclosure is a therapeutic method according to any one of the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, or twelfth embodiments of the present invention, wherein the rheumatoid factor is of the IgM, IgG, IgD, IgE, or IgA isotype.

[0075] A fourteenth embodiment of the present disclosure is a treatment method according to any one of the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, or thirteenth embodiment of the present invention, wherein a bDMARD, preferably certolizumab pegol in the case of treatment of RA or juvenile idiopathic arthritis and dapirolizumab in the case of treatment of SLE, is administered in combination with another antirheumatic drug, preferably a nonbiological DMARD, such as methotrexate or leflunomide, or an NSAID.

[0076] A fifteenth embodiment of the present disclosure is a treatment method according to any one of the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, or fourteenth embodiments of the present invention, in which a patient has not responded to treatment with a biological DMARD (bDMARD) having an Fc fragment, such as a TNFα inhibitor, such as adalimumab, infliximab, etanercept, or golimumab; a T cell costimulatory inhibitor, such as abatacept; an IL-6 or IL-6 receptor inhibitor such as tocilizumab, sarilumab, or orokizumab, or an anti-CD20 antibody such as rituximab; or anakinra; or belimumab.

[0077] A sixteenth embodiment of this disclosure is a treatment method according to the fifteenth embodiment of this disclosure, wherein the treatment failure is a primary failure.

[0078] A 17th embodiment of this disclosure is a treatment method according to a 15th embodiment of the present invention, wherein the treatment failure is a secondary failure.

[0079] An eighteenth embodiment of the present disclosure is a treatment method according to any one of the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, or seventeenth embodiment of the present invention, wherein the patient has not responded to treatment with nonbiological DMARDs.

[0080] A 19th embodiment of the present disclosure is a therapeutic method according to the 18th embodiment of the present invention, wherein the DMARD is methotrexate, leflunomide, sulfasalazine, chloroquine, hydroxychloroquine, gold, azathioprine, cyclosporine, mycophenolate tomofetil, or cyclophosphamide.

[0081] A 20th embodiment of the present disclosure relates to a bDMARD lacking an Fc fragment, preferably certolizumab pegol in the case of treatment for patients with RA or juvenile arthritis, and dapirolilizumab pegol in the case of treatment for patients with SLE, in serum concentrations exceeding 100 IU / ml, 121.4 IU / ml, 125 IU / ml, 145.9 IU / ml, 150 IU / ml, 175 IU / ml, 200 IU / ml, or 204 IU / ml. A treatment method according to any one of the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fifteenth, eighteenth, sixteenth, seventeenth, or nineteenth embodiments of the present invention, administered to a patient identified as having rheumatoid factor at regular intervals, for example, for at least three months, six months, nine months, twelve months, fifteenth, eighteenth, two years, or more than two years.

[0082] A 21st embodiment of the present disclosure is a treatment method according to any one of the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, or twentieth embodiment of the present invention, wherein the patient's RF does not decrease the concentration of a bDMARD lacking an Fc fragment after administration, preferably certolizumab pegol in the case of treatment of patients with RA or juvenile arthritis and dapirolizumab pegol in the case of treatment of patients with SLE.

[0083] The titer of rheumatoid factor in patients with RA, juvenile arthritis, SLE, Sjögren's syndrome, or other rheumatic diseases can be determined by large-scale automated methods, including, for example, nephelometric and turbidimetric methods. While these methods are not isotype-nonspecific, they primarily detected IgM RF. Isotype-specific ELISAs and other enzyme immunoassays can be used to detect and quantify RF in patients overcoming this disorder. Commercially available addressable laser bead immunoassays (ALBIA) can also be used to measure RF titer in patients (Ronnelid et al., Autoantibodies in Rheumatoid Arthritis - Laboratory and Clinical Perspectives, Front.Immunol., 2021).

[0084] The methods of this disclosure may be used to treat rheumatic disorders or diseases in human subjects that require such treatment, including diseases in which the patient has high RF serum levels. In some embodiments of the methods of this disclosure, the human subject has rheumatoid arthritis (RA). In some embodiments of the methods of this disclosure, the human subject has a rheumatic disease such as juvenile idiopathic arthritis, SLE, or Sjögren's syndrome.

[0085] In some embodiments of the methods of this disclosure, human subjects have high or elevated RF serum levels. In some embodiments, human subjects have high titer RF when measured in vitro from a serum sample. The rheumatoid factor measured may be of the IgM, IgG, IgD, IgE, or IgA isotype.

[0086] In some embodiments, subjects are identified as having or possessing an RF serum level (or titer) greater than 100 IU / ml. In some embodiments, subjects have an RF serum level greater than 121.4 IU / ml. In some embodiments, subjects have an RF serum level greater than 125 IU / ml. In some embodiments, subjects have an RF serum level greater than 145.9 IU / ml. In some embodiments, subjects have an RF serum level greater than 150 IU / ml. In some embodiments, subjects have an RF serum level greater than 175 IU / ml. In some embodiments, subjects have an RF serum level greater than 200 IU / ml. In some embodiments, subjects have an RF serum level greater than 204 IU / ml. In some embodiments, subjects have an RF serum level greater than 225 IU / ml. In some embodiments, subjects have an RF serum level greater than 250 IU / ml. In some embodiments, subjects have an RF serum level of at least 275 IU / ml.

[0087] The methods of this disclosure provide maintenance of plasma drug levels of a bDMARD administered to a subject, even when the subject has certain elevated RF levels. In some embodiments of the methods of this disclosure, the method comprises administering a bDMARD lacking an Fc fragment. In some embodiments, the bDMARD lacking an Fc fragment is certolizumab pegol. It is understood that any convenient salt form of the bDMARD is encompassed in the drug names described herein. In some embodiments, the bDMARD is dapirolilizumab pegol.

[0088] In some embodiments of the method of the present disclosure, a human patient maintains low disease activity or remission of a rheumatic disease for 90, 100, 104, 120, or 180 days after the first dose of a bDMARD lacking an Fc fragment.

[0089] In some embodiments of the method of the present disclosure, in step (b), certolizumab pegol is administered to the patient first at a loading dose of 400 mg, then at a loading dose of 400 mg two weeks later, followed by a maintenance dose. In some embodiments of the method of the present disclosure, the loading dose is not administered to the patient at the start of treatment.

[0090] In some embodiments of the methods of this disclosure, certolizumab pegol is administered in a dose of 400 mg. In some embodiments of the methods of this disclosure, certolizumab pegol is administered in a dose of 200 mg. In some embodiments of the methods of this disclosure, certolizumab pegol is administered subcutaneously.

[0091] In some embodiments of the methods of the present disclosure, certolizumab pegol is administered at a dose of 400 mg every four weeks. In some embodiments of the methods of the present disclosure, certolizumab pegol is administered at a dose of 200 mg every two weeks.

[0092] In some embodiments of the methods of the present disclosure, a bDMARD is administered chronically, for example, regularly, to a patient identified as having elevated rheumatoid factor, for at least 3 months, 6 months, 9 months, 12 months, 15 months, 18 months, 2 years, or more than 2 years.

[0093] In some embodiments of the methods of the present disclosure, a bDMARD is administered in combination with an additional agent, such as an antirheumatic drug. In some embodiments, the additional agent administered concurrently is an antirheumatic drug that is a non-biological DMARD, such as methotrexate or leflunomide, or an NSAID.

[0094] In some embodiments of the methods of the present disclosure, the patient is resistant to one or more conventional therapies. In some embodiments of the methods of the present disclosure, the patient did not respond to treatment with bDMARDs having an Fc fragment, e.g., TNFα inhibitors, e.g., adalimumab, infliximab, etanercept, or golimumab; T cell costimulatory inhibitors, e.g., abatacept; IL-6 or IL-6 receptor inhibitors such as tocilizumab, sarilumab, or olokizumab, or anti-CD20 antibodies such as rituximab; or anakinra; or belimumab. In some embodiments of the methods of the present disclosure, the patient did not respond to treatment with nonbiological DMARDs. In some embodiments, the DMARD is methotrexate, leflunomide, sulfasalazine, chloroquine, hydroxychloroquine, gold, azathioprine, cyclosporine, mycophenolate, tomofetil, or cyclophosphamide.

[0095] definition As used herein, the term "at baseline" refers to the moment of treatment decision, for example, when a patient is evaluated by a physician and a treatment decision is made.

[0096] As used herein, the term “CDAI” refers to the Clinical Disease Activity Index (CDAI), a composite measure of disease activity in rheumatoid arthritis, which integrates the number of swollen joints, the number of tender joints, the patient-global assessment of disease activity, and the physician-global assessment of disease activity (Takanashi et al., CDAI and DAS28 in the management of rheumatoid arthritis in clinical practice, Ann Rheum Dis. 2020).

[0097] As used herein, the term “DAS28-CRP” refers to the Disease Activity Score (DAS) in rheumatoid arthritis, which integrates the number of tender and swollen joints (systematically evaluating 28 joints), a patient-wide assessment of disease activity, and serum CRP concentration (Takanashi et al., CDAI and DAS28 in the management of rheumatoid arthritis in clinical practice, Ann Rheum Dis. 2020 and Greenmyer et al., DAS28-CRP Cutoffs for High Disease Activity and Remission Are Lower Than DAS28-ESR in Rheumatoid Arthritis, ACR Open Rheumatol. 2020).

[0098] As used herein, the term “disease-modifying antirheumatic drugs [DMARDs]” refers to a group of drugs commonly used in patients with rheumatic diseases, particularly rheumatoid arthritis, but also with ankylosing spondylitis, juvenile idiopathic arthritis, psoriatic arthritis, and systemic lupus erythematosus, as is known in the art. DMARDs include non-biological DMARDs such as methotrexate, sulfasalazine, leflunomide, antimalarial drugs (e.g., chloroquine or hydroxychloroquine), azathioprine, and cyclosporine, as well as biological DMARDs (bDMARDs) such as etanercept, infliximab, adalimumab, certolizumab pegol, golimumab, abatacept, rituximab, tocilizumab, sarilumab, olokizumab, anakinra, and belimumab.

[0099] As used herein, the term “unresponsive to treatment” refers to failure to reach the therapeutic target, i.e., low disease activity (LDA).

[0100] As used herein, the term "having an Fc fragment" refers to a molecule containing an immunoglobulin Fc fragment, such as a polypeptide chain of an antibody derivative such as a full-length antibody or etanercept.

[0101] As used herein, the term “lacking Fc fragment” refers to a molecule that does not contain the polypeptide chain of an immunoglobulin Fc fragment. Such molecules may be peptides or polypeptides, such as antibody derivatives, e.g., Fab, modified Fab, Fab', modified Fab', F(ab')2, Fv, Fab-Fv, Fab-dsFv, Fab-Fv-Fv, scFv, and Bis-scFv fragments. Such fragments may also be diabody, tribody, TrYbe®, triabody, tetrabody, minibody, single-domain antibodies (dAb), e.g., sdAb, VL, VH, VHH, or camel antibodies (e.g., from camels or llamas such as Nanobody®), and other fragments of antibodies lacking a VNAR fragment or an Fc fragment. Molecules may be modified, for example, by the binding of polyethylene glycol (PEG). Molecules lacking the polypeptide chain of an immunoglobulin Fc fragment may be DMARDs, e.g., biological DMARDs or non-biological DMARDs. Examples of molecules that do not contain the polypeptide chain of an immunoglobulin Fc fragment are certolizumab pegol and dapyrolizumab pegol.

[0102] As used herein, the term “loading dose” refers to the drug dose used at the start of treatment to ensure that plasma drug concentrations reach the therapeutic range rapidly.

[0103] As used herein, the term “low disease activity or LDA” refers to therapeutic targets in RA (CDAI ≤ 10, DAS28-ESR ≤ 3.2 or DAS28-CRP ≤ 3.2), JIA (juvenile idiopathic arthritis DAS27 ≤ 3.8), and SLE (1. no activity in major organ systems (kidneys, central nervous system (CNS), cardiopulmonary, vasculitis, fever), no hemolytic anemia or gastrointestinal activity, SLE Disease Activity Index (SLEDAI)-2K ≤ 4; 2. no new lupus disease activity compared to previous assessments; 3. a safety of estrogen in the Global Assessment of Lupus Erythematosus (SELENA)-SLEDAI physician-wide assessment (scale 0-3) ≤ 1; 4. current prednisolone (or equivalent) dose ≤ 7.5 mg / day; and 5. well-tolerated standard maintenance doses of immunosuppressants and approved biological agents).

[0104] As used herein, the term “maintenance dose” refers to a drug dose used chronically, for example, through repeated administration over a long period, to ensure that plasma drug concentrations are maintained within a therapeutic range.

[0105] As used herein, the term "no efficacy response" refers to the inability to reach the therapeutic target (e.g., LDA).

[0106] As used herein, the term “primary failure” refers to the inability to reach a treatment goal (e.g., LDA) within 12 to 18 months of treatment, meaning that the drug is unable to suppress disease activity.

[0107] As used herein, the term "remission" refers to the disappearance of disease symptoms, for example, in rheumatoid arthritis (RA) inflammatory symptoms (in RA, DAS28-CRP ≤ 2.6).

[0108] As used herein, the term “SDAI” refers to a composite measure of disease activity in rheumatoid arthritis that integrates the Simplified Disease Activity Index (SDAI), number of swollen joints, number of tender joints, serum CRP, patient-global assessment of disease activity, and physician-global assessment of disease activity. (Smolen et al., A simplified disease activity index for rheumatoid arthritis for use in clinical practice, Rheumatology (Oxford), 2003).

[0109] As used herein, the term “secondary failure” refers to the loss of the drug’s ability to reach a therapeutic target (e.g., LDA) after the initial ability to reach the therapeutic target (e.g., LDA) within 12 to 18 months of treatment. In many cases, secondary failure of bDMARDs is due to the development of anti-drug antibodies.

[0110] As used herein, the term "seropositive for rheumatoid factor" refers to the presence of rheumatoid factor in at least one serum sample from a patient that exceeds the upper limit of normal (the definition may vary depending on the measurement technique or test) (Ingegnoli et al., Rheumatoid Factors: Clinical Applications, Dis Markers. 2013 and Trier et al, Determination of Rheumatoid Factors by ELISA, Methods Mol Biol, 2019).

[0111] As used herein, the term “substantial clinical benefit” refers to an improvement in clinical symptoms that exceeds the minimum clinically significant difference (e.g., delta-CDAI > 1 in RA when baseline CDAI ≤ 10).

[0112] Additional Embodiments This disclosure is further described by the following non-limiting clauses.

[0113] Article 1. A method for treating rheumatic diseases in human patients with rheumatoid factor, This includes administering a bDMARD lacking an Fc fragment to human patients identified as having rheumatoid factor in serum at concentrations greater than 100 IU / ml, 121.4 IU / ml, 125 IU / ml, 145.9 IU / ml, 150 IU / ml, 175 IU / ml, 200 IU / ml, or 204 IU / ml. (i) The therapeutic effect of bDMARDs lacking Fc fragments is not reduced by RF in the patient, and / or (i) the treatment induces low disease activity in the patient or achieves substantial clinical benefit. A method for treating rheumatic diseases in human patients with rheumatoid factor.

[0114] Article 2. A method for treating rheumatic diseases in human patients with rheumatoid factor, To determine the titer of rheumatoid factor in a sample from the patient, preferably a serum sample, If the serum rheumatoid factor titer is greater than 100 IU / ml, greater than 121.4 IU / ml, greater than 125 IU / ml, greater than 145.9 IU / ml, greater than 150 IU / ml, greater than 175 IU / ml, greater than 200 IU / ml, greater than 204 IU / ml, greater than 225 IU / ml, greater than 250 IU / ml, or greater than 275 IU / ml, this includes administering a bDMARD lacking an Fc fragment to the patient. (i) The therapeutic effect of bDMARDs lacking Fc fragments is not reduced by RF in the patient, and / or (i) the treatment induces low disease activity in the patient or achieves substantial clinical benefit. A method for treating rheumatic diseases in human patients with rheumatoid factor.

[0115] Article 3. A method for treating rheumatoid arthritis in human patients with rheumatoid factor, This includes administering certolizumab pegol to human patients identified as having rheumatoid factor levels greater than 100 IU / ml, 121.4 IU / ml, 125 IU / ml, 145.9 IU / ml, 150 IU / ml, 175 IU / ml, 200 IU / ml, or 204 IU / ml in their serum. (i) The therapeutic effect of certolizumab pegol is not diminished by RF in the patient, and / or (i) the treatment induces low disease activity or achieves substantial clinical benefit in the patient. A method for treating rheumatoid arthritis in human patients with rheumatoid factor.

[0116] Article 4. A method for treating rheumatoid arthritis in human patients with rheumatoid factor, To determine the titer of rheumatoid factor in a sample from the patient, preferably a serum sample, If the serum rheumatoid factor titer is greater than 100 IU / ml, greater than 121.4 IU / ml, greater than 125 IU / ml, greater than 145.9 IU / ml, greater than 150 IU / ml, greater than 175 IU / ml, greater than 200 IU / ml, greater than 204 IU / ml, greater than 225 IU / ml, greater than 250 IU / ml, or greater than 275 IU / ml, then certolizumab pegol should be administered to the patient. Includes, (i) The therapeutic effect of certolizumab pegol is not diminished by RF in the patient, and / or (i) the treatment induces low disease activity or achieves substantial clinical benefit in the patient. A method for treating rheumatoid arthritis in human patients with rheumatoid factor.

[0117] Clause 5. The method according to any one of Clauses 1 to 4, wherein low disease activity is achieved 90, 100, 104, 120, or 180 days after the first dose of certolizumab pegol.

[0118] Clause 6. The method described in any one of Clauses 1 to 5, wherein the patient's low disease activity is achieved with a 40%, 45%, 50%, or 55% probability.

[0119] The method according to any one of the paragraphs 3 to 6, wherein in step (b), certolizumab pegol is administered to the patient first as a loading dose of 400 mg and then as a loading dose of 400 mg two weeks later, followed by (i) a maintenance dose of 400 mg every four weeks or (ii) a maintenance dose of 200 mg every two weeks.

[0120] Clause 8. The method described in any one of Clauses 1 to 7, wherein the loading dose is not administered to the patient at the start of treatment.

[0121] Clause 9. The method according to any one of Clauses 1 to 8, wherein the rheumatoid factor is of the IgM, IgG, IgD, IgE, or IgA isotype.

[0122] Clause 10. The method according to any one of Clauses 3 to 9, wherein certolizumab pegol is administered in combination with another antirheumatic drug.

[0123] Clause 11. The method according to Clause 10, wherein the antirheumatic drug is methotrexate or leflunomide.

[0124] Clause 12. The method described in any one of Clauses 1 to 11, for patients who have previously not responded to treatment with a DMARD.

[0125] Clause 13. The method described in Clause 12, for patients who have not previously responded to treatment with a biological DMARD containing an Fc fragment.

[0126] Clause 14. The method described in Clause 12, for patients who have not previously responded to treatment with non-biological DMARDs.

[0127] Clause 15. The method described in Clause 13 or 14, wherein the treatment failure is a primary failure.

[0128] Clause 16. The method described in Clause 13 or 14, wherein the treatment failure is a secondary failure.

[0129] The method according to any one of the clauses 1 to 16, wherein a bDMARD lacking an Fc fragment is administered at regular intervals for at least three months.

[0130] Clause 18. The method according to any one of Clauses 1 to 17, wherein the plasma concentration of a bDMARD lacking an Fc fragment does not decrease in the patient after administration thereof.

[0131] Article 19. A method for maintaining low disease activity or remission of a rheumatic disease in human subjects requiring maintenance of low disease activity or remission of a rheumatic disease, The treatment includes administering a dose of a bDMARD lacking an Fc fragment that is effective in maintaining low disease activity or remission in the subject. The subjects are identified as having elevated baseline rheumatoid factor (RF) serum levels greater than 100 IU / ml. A method for maintaining low disease activity or remission in human subjects who require maintenance of low disease activity or remission of rheumatic disease.

[0132] Clause 20. The method according to Clause 19, wherein the subject has rheumatoid arthritis (RA).

[0133] Clause 21. The method described in Clause 20, wherein the subject has early RA.

[0134] Clause 22. The method according to Clause 20, wherein the subject had active RA for at least 6 months prior to treatment.

[0135] Clause 23. The method described in any one of Clauses 19-22, wherein the bDMARD is certolizumab pegol.

[0136] Clause 24. The method according to Clause 23, wherein certolizumab pegol is administered to the subject first as a loading dose of 400 mg, then a loading dose of 400 mg two weeks later, followed by a maintenance dose.

[0137] Clause 25. The method according to Clause 23, wherein the loading dose is not administered to the patient at the start of treatment with the maintenance dose.

[0138] Clause 26. The method according to Clause 25, wherein certolizumab pegol is administered to the subject at a maintenance dose of 400 mg every four weeks.

[0139] Clause 27. The method according to Clause 25, wherein certolizumab pegol is administered to the subject at a maintenance dose of 200 mg every two weeks.

[0140] Clause 28. The method described in any one of Clauses 19-27, wherein a bDMARD is administered to the subject for at least 12 weeks.

[0141] Clause 29. The method described in any one of Clauses 19-28, wherein a bDMARD is administered to the subject for at least 24 weeks.

[0142] Clause 30. The method described in any one of Clauses 19-29, wherein a bDMARD is administered to the subject for at least one year.

[0143] Clause 31. The method described in any one of Clauses 19-30, wherein a bDMARD is administered to the subject for at least two years.

[0144] Clause 32. The method described in any one of Clauses 19 to 31, wherein low disease activity or remission is achieved within 12 weeks after the first dose of a bDMARD and maintained throughout the course of treatment.

[0145] Clause 33. The method according to any one of Clauses 19-32, wherein the subject is identified as having a baseline RF serum level greater than 121.4 IU / ml.

[0146] Clause 34. The method according to any one of Clauses 19-32, wherein the subject is identified as having a baseline RF serum level greater than 125 IU / ml.

[0147] Clause 35. The method according to any one of Clauses 19-32, wherein the subject is identified as having a baseline RF serum level greater than 145.9 IU / ml.

[0148] Clause 36. The method according to any one of Clauses 19-32, wherein the subject is identified as having a baseline RF serum level greater than 150 IU / ml.

[0149] Clause 37. The method according to any one of Clauses 19-32, wherein the subject is identified as having a baseline RF serum level greater than 175 IU / ml.

[0150] Clause 38. The method according to any one of Clauses 19-32, wherein the subject is identified as having a baseline RF serum level greater than 200 IU / ml.

[0151] Clause 39. The method according to any one of Clauses 19-32, wherein the subject is identified as having a baseline RF serum level greater than 204 IU / ml.

[0152] Clause 40. The method according to any one of Clauses 19-32, wherein the subject is identified as having a baseline RF serum level greater than 225 IU / ml.

[0153] Clause 41. The method according to any one of Clauses 19-32, wherein the subject is identified as having a baseline RF serum level greater than 250 IU / ml.

[0154] Clause 42. The method according to any one of Clauses 19 to 32, wherein the subject is identified as having a baseline RF serum level of at least 275 IU / ml.

[0155] Clause 43. The method according to any one of Clauses 19 to 43, further comprising the preceding step of measuring the serum level of RF in a subject having a rheumatic disease.

[0156] Clause 44. The method described in any one of Clauses 19 to 44, wherein RF is an IgM, IgG, IgD, IgE, or IgA isotype.

[0157] Clause 45. The method described in any one of Clauses 19 to 44, wherein a bDMARD is administered in combination with another antirheumatic drug.

[0158] Clause 46. The method according to Clause 45, wherein the antirheumatic drug is methotrexate or leflunomide. [Examples]

[0159] Example 1 The inventors conducted a post-hoc analysis of the EXXELERATE phase IV trial comparing two TNF inhibitors, adalimumab and certolizumab pegol, in combination with methotrexate in patients with rheumatoid arthritis and moderate to severe disease activity. While adalimumab is a fully monoclonal antibody, certolizumab pegol is a PEGylated Fab fragment of the antibody. Therefore, certolizumab pegol does not contain an Fc fragment. 453 patients were randomized to certolizumab pegol, and 454 to adalimumab. Both treatments demonstrated similar efficacy (Figure 1) and tolerability.

[0160] In our post-hoc analysis, we examined the response to treatment (i.e., the proportion of patients achieving low disease activity (LDA) or disease remission based on mean DAS28-CRP, mean DAS28-ESR, mean CDAI, mean SDAI, and DAS28-CRP) and drug plasma concentrations up to week 104 in patients stratified by RF titer quartile (Q1: 0-32 IU / mL, Q2: 32-75 IU / mL, Q3: 75-204 IU / mL, Q4: >204 IU / mL) and drug plasma concentrations up to week 104. Baseline characteristics showed higher disease activity, HAQ, and ACPA titers in patients with RF Q4, consistent with the well-known association between high-titer RF and disease severity. There were no differences in baseline characteristics between patients treated with certolizumab pegol and those treated with adalimumab in each quartile.

[0161] In patients treated with adalimumab, we predictably found that the measured disease activity was less favorable in patients with high RF titers compared to those with low RF titers. Consequently, the mean DAS28-CRP values ​​over time were higher in response to adalimumab at RF Q4 compared to patients with RF Q1–3 [Figure 2]. In contrast, such a difference was not observed in patients treated with certolizumab pegol: the mean DAS28-CRP progression over time was similar in patients with high or low RF titers, indicating that the efficacy of certolizumab pegol was not affected by the RF titer of these patients [Figure 2 (continued)].

[0162] Therefore, in patients with low RF titers, DAS28-CRP scores were superimposed for certolizumab pegol and adalimumab. However, in patients with high RF titers, DAS28-CRP scores were generally lower in adalimumab-treated patients compared to certolizumab-pegol-treated patients, indicating a stronger clinical improvement in response to certolizumab pegol in patients with severe disease in this category [Figures 3A-3B]. A similar pattern was observed for all disease activity outcome measures (DAS28-ESR, CDAI, SDAI). Looking at the proportion of patients achieving low disease activity or remission, we observed that these proportions were similar for certolizumab pegol and adalimumab in patients with low RF titers. The proportion of patients with low disease activity or remission was lower with adalimumab in patients with high RF titers. Surprisingly, however, this was not the case for certolizumab pegol, where the proportion of patients with low disease activity or remission was similar in patients with high and low RF titers. These differences between certolizumab pegol and adalimumab were observed in both “per protocol” and “intention to treat” analyses of the data (Figure 4).

[0163] In parallel with these different patterns of treatment response between certolizumab pegol and adalimumab in patients with high and low titer RF, we observed differences in plasma drug concentration patterns between the two biologics. Thus, mean adalimumab drug concentrations were lower in high-titer RF patients compared to low-titer RF patients. In contrast, this difference was not observed with certolizumab pegol, which maintained similar drug concentrations in high-titer RF patients compared to low-titer RF patients [Figure 5A].

[0164] In summary, our observations indicate that certolizumab pegol does not behave as expected in patients with high-titer RF. Compared to adalimumab, certolizumab pegol maintains the therapeutic response and plasma drug concentrations in patients with high-titer RF, similar to those observed in patients with low-titer RF.

[0165] Example 2 Test design This post-hoc analysis included data from six clinical trials of certolizumab pegol in RA patients: C-OPERA (NCT01451203), RAPID-1 (NCT00152386), RAPID-2 (NCT00160602), J RAPID (NCT00791999), RAPID-C (NCT02151851), and EXXELERATE (NCT01500278). The trial designs are shown in Figure 1. The complete trial designs, patient populations, and results from all six clinical trials have been previously published. Data from RAPID-1, RAPID-2, J RAPID, and RAPID-C were pooled for this trial.

[0166] Test participants C-OPERA included Japanese patients with early-stage rheumatoid arthritis (RA). In short, methotrexate-naive patients aged 20–64 years with active RA (defined by the 2010 ACR / EULAR classification criteria) of 12 months or less were randomized to receive either placebo (PBO) Q2W + methotrexate (PBO + MTX) or certolizumab pegol 200 mg Q2W (loading dose of certolizumab pegol 400 mg at weeks 0 / 2 / 4) + MTX (certolizumab pegol + MTX) for 52 weeks.

[0167] The pooled RAPID population included patients from two global trials (RAPID-110 and RAPID-211), a Japanese trial (J-RAPID), and a Chinese trial (RAPID-C). Briefly, patients aged 18 years or older (20 years or older for J-RAPID) with active RA for at least 6 months (as defined by the ACR1987 criteria) and who had received MTX for at least 6 months prior to baseline (at least 3 months for RAPID C) were randomized to receive PBO + MTX, or certolizumab pegol 400 mg Q2W + MTX, or certolizumab pegol 200 mg Q2W (loading dose of certolizumab pegol 400 mg in weeks 0 / 2 / 4) + MTX (certolizumab pegol + MTX) for at least 24 weeks (52 weeks for RAPID-1, and 24 weeks for RAPID-2, J RAPID, and RAPID-C).

[0168] EXXELERATE was a head-to-head superiority trial comparing certolizumab pegol and ADA in patients with active RA who had prognostic factors for severe disease progression. In short, patients aged 18 years or older with active RA (as defined by the 2010 ACR / EULAR classification criteria) were randomized to receive either certolizumab pegol 200 mg Q2W (loading dose of certolizumab pegol 400 mg at 0 / 2 / 4 weeks) + MTX (certolizumab pegol + MTX) or ADA 40 mg Q2W + MTX (ADA + MTX) for 104 weeks.

[0169] Assessment of rheumatoid factor levels RF levels (IgM RF) were measured using immunoassays valid at local hospitals, either by nephelometry or enzyme-linked immunosorbent assay (ELISA). Despite potential variability in cutoff levels, there is good correlation between the two methods of RF quantification; both methods are sufficiently sensitive to routine experimental purposes. Twenty-six patients were classified into quartiles (Q) based on their overall baseline RF levels for each trial. For C-OPERA, RF quartiles were defined as <59.0 IU / mL, ≥59.0-<93.0 IU / mL, ≥93.0-<275.0 IU / mL, and ≥275.0 IU / mL for Q1-4, respectively. For pooled RAPID, RF quartiles were defined as <25.0 IU / mL, ≥25.0-<78.5 IU / mL, ≥78.5-<207.0 IU / mL, and ≥207.0 IU / mL for Q1-4, respectively. In the case of EXXELERATE, the RF quartiles were defined for Q1-Q4 as ≤32.0 IU / mL, >32.0- ≤75.0 IU / mL, >75.0- ≤204.0 IU / mL, and >204 IU / mL, respectively.

[0170] result The efficacy of certolizumab pegol was evaluated using DAS28-erythrocyte sedimentation rate (DAS28[ESR]). Efficacy evaluation (mean DAS28[ESR]) was performed from week 0 to 24. In this analysis, DAS28(ESR) 2.6-≤3.2 was classified as low disease activity (LDA), and DAS28(ESR) <2.6 was classified as remission (REM). The proportion of patients achieving DAS28(ESR) LDA and REM was evaluated at weeks 12 and 24.

[0171] statistical analysis Unless otherwise specified, all analyses were performed using the complete analysis set. The complete analysis set included all patients who received one or more doses of the study drug and subsequently provided efficacy data. We report the observed data regarding DAS28(ESR) responses. As this was a post-hoc subgroup analysis, all reported data are descriptive only.

[0172] result Patient demographics and baseline characteristics In the C-OPERA study, 316 patients (certolizumab pegol + MTX n=159; PBO + MTX n=157) were included in this post-hoc analysis. In the pooled RAPID study, 1,537 patients (certolizumab pegol + MTX n=1,025; PBO + MTX n=512) were included in this post-hoc analysis. In the EXXELERATE study, 908 patients (certolizumab pegol + MTX n=454; ADA + MTX n=454) were included in the complete set of analyses used for baseline demographics and efficacy outcomes from weeks 0 to 12 in this post-hoc analysis. For weeks 12–24, we analyzed a complete analysis set at week 12 (certolizumab pegol + MTX n=352; ADA + MTX n=361), consisting of certolizumab pegol + MTX patients who responded at week 12 and were randomized to certolizumab pegol and continued with certolizumab pegol, and ADA + MTX patients who responded at week 12 and were randomized to ADA and continued with ADA. At baseline, patient demographics and disease characteristics were similar among the C-OPERA, pooled RAPID, and EXXELERATE treatment groups. Within each treatment group (PBO+MTX, certolizumab pegol+MTX, or ADA+MTX), mean DAS28(ESR) scores at baseline were similar across the RF quartile for C-OPERA, pooled RAPID, and EXXELERATE.

[0173] DAS28(ESR)LDA and REM rates In C-OPERA, DAS28(ESR)LDA and REM rates were numerically higher in the certolizumab pegol + MTX group compared to the PBO + MTX group at weeks 12 and 24 across the RF quartile. In the certolizumab pegol + MTX group, DAS28(ESR)LDA and REM rates improved from week 12 to week 24 across the RF quartile. At weeks 12 and 24, DAS28(ESR)LDA and REM rates were similar across the RF quartile in the certolizumab pegol + MTX group [Figure 7 Panel (a)].

[0174] For pooled RAPID, DAS28(ESR)LDA and REM rates were numerically higher in the certolizumab pegol + MTX group compared to the PBO + MTX group at weeks 12 and 24 across the RF quartile. In the certolizumab pegol + MTX group, DAS28(ESR)LDA and REM rates improved from week 12 to week 24 across the RF quartile. At weeks 12 and 24, DAS28(ESR)LDA and REM rates were similar across the RF quartile in the certolizumab pegol + MTX group [Figure 7 Panel (b)].

[0175] For EXXELERATE, DAS28(ESR)LDA and REM rates were similar in certolizumab pegol + MTX compared to ADA + MTX at weeks 12 and 24 across all RF quartiles. In both the certolizumab pegol + MTX and ADA + MTX groups, DAS28(ESR)LDA and REM rates improved across RF quartiles [Figure 7, Panel (c)] from week 12 to week 24. In the certolizumab pegol + MTX group, this improvement was consistent across RF quartiles. In the ADA + MTX group, the improvement was numerically lower in the subgroup with the highest RF level (Q4) compared to other RF quartiles.

[0176] Average DAS28 (ESR) over 24 weeks For C-OPERA and pooled RAPID, mean DAS28(ESR) decreased across the RF quartile from week 0 to week 24 in both the certolizumab pegol + MTX group and the PBO + MTX group [Figure 8A and (b)]. Mean DAS28(ESR) was numerically lower in the certolizumab pegol + MTX group compared to PBO + MTX over 24 weeks across the RF quartile.

[0177] In the EXXELERATE study, mean DAS28 (ESR) decreased across the RF quartile from weeks 0–12 and 12–24 in both the certolizumab pegol + MTX group and the ADA + MTX group [Figure 8C]. Mean DAS28 (ESR) in both the certolizumab pegol + MTX group and the ADA + MTX group remained similar across the RF quartile over 24 weeks.

[0178] Consideration In this post-hoc analysis, the efficacy of certolizumab pegol was remarkably similar across baseline RF subgroups over 24 weeks in patients with early RA (C-OPERA) and established RA (pooled RAPID and EXXELERATE). Furthermore, in patients with established RA (EXXELERATE), certolizumab pegol demonstrated consistent efficacy across baseline RF quartiles up to week 104 (data not shown).

[0179] In established RA (exxelerate) patients, the proportion of patients with high baseline RF levels (Q4) achieving DAS28(ESR)LDA or REM at week 24 was approximately 10 percentage points higher in the certolizumab pegol + MTX group (45.0%) compared to the ADA + MTX group (35.1%). While this analysis did not perform speculative statistics, a slightly lower but still comparable proportion of patients with high baseline RF levels (Q4) responded to certolizumab pegol + MTX treatment at week 24 compared to other RF quartiles (49.4–60.8% vs. 45.0%, respectively). However, only 35.1% of patients with high baseline RF levels (Q4) in the ADA + MTX group responded at week 24, lower than the 48.3–54.7% observed in other RF quartiles. This suggests that the effect of high baseline RF levels is not as clear as the effect of ADA compared to certolizumab pegol. A similar trend was observed at week 104 (data not shown; inferential statistics not performed), with approximately 15 percentage points more patients achieving DAS28(ESR)LDA or REM in the certolizumab pegol + MTX group than in the ADA + MTX group in the highest baseline RF level quartile (Q4). Indeed, a recent trial of Japanese RA patients grouped by RF quartile similarly reported higher efficacy of certolizumab pegol compared to other currently available TNFis (analyzed together) in the highest baseline RF level quartile (Q4: 166-7,555 IU / mL). At 3, 6, and 12 months post-treatment, improvement in DAS28(ESR) from baseline was significantly greater in patients treated with certolizumab pegol compared to other TNFis in the highest baseline RF level quartile.

[0180] Previous trials of TNFi have observed lower efficacy in patients with high RF levels compared to those with low RF levels. However, certolizumab pegol demonstrated consistent efficacy across all RF groups in this trial, including those at the highest RF quartile, compared to the decrease in ADA efficacy at the same quartile. This observation may be partly related to its unique molecular Fc-free structure. It is reasonable to assume that TNFα inhibitors that are complete monoclonal antibodies, as well as the IgG1-TNFR2 fusion protein etanercept, contain an IgG1-Fc fragment to which IgM RF binds, and that the bioavailability of TNFi drugs decreases when the resulting immune complex is removed. Therefore, higher RF levels have a greater impact on the clearance of TNFα inhibitors that are either complete monoclonal antibodies or contain an Fc fragment, which may explain the lower efficacy observed in patients with high RF levels compared to those with low RF levels. In this context, certolizumab pegol, which does not contain Fc, is eliminated at a lower rate even in the presence of high RF levels and remains available to inhibit TNF pro-inflammatory effects. Interestingly, RF positivity is associated with a better response to rituximab and tocilizumab (both monoclonal antibodies containing an IgG1-Fc fragment) in RA patients. However, for these treatments, the association may be related to RF positivity as a B-cell activation marker rather than its role in drug clearance.

[0181] Anti-citrullinated peptide antibodies (ACPAs) are also important in the pathophysiology of rheumatoid arthritis (RA) and potentially influence efficacy outcomes in RA patients. In a post-hoc analysis of Japanese patients with RA, a combination of high baseline RF (≥160 IU / ml) and ACPA (≥100 U / ml) levels was associated with low drug (infliximab) levels and reduced clinical response. Considering that patients with higher baseline ACPA levels often also have high baseline RF levels, there may be confounding effects on any speculation regarding baseline ACPA levels and TNFi efficacy. In this study, the inventors classified patients by RF level solely due to the assumed effect of RF on the clearance of certolizumab pegol and other TNFis. Since ACPA targets citrullinated proteins and not IgG11, it is unlikely to be involved in the IgG1-Fc clearance process. Furthermore, RF-positive patients were found to have high levels of RA disease activity regardless of ACPA levels, suggesting that the value determining the baseline ACPA level may be RF-negative or low-titer RF-positive patients, rather than patients with very high baseline RF levels.

[0182] The strength of this trial lies in the fact that the included patients come from diverse populations and represent a range of disease duration and severity. However, the relatively low number of patients in individual clinical trial subgroups may limit the interpretation of the results. Furthermore, this diversity may also represent limitations due to variations in inclusion and exclusion criteria as well as trial duration. The six clinical trials were conducted over different periods (C-OPERA: 2011-2013, RAPID-1 and RAPID2: 2005-2006, J-RAPID: 2008-2010, RAPID C: 2014-2016, and EXXELERATE: 2011-2013) and may reflect changes in clinical practice. Nevertheless, our findings demonstrate that certolizumab pegol showed a consistent trend of efficacy across heterogeneous trial populations and trial durations.

[0183] Other potential limitations of the analysis include the fact that observed case data were presented considering responders who continued at least until week 24, while non-responders who dropped out of the trial were excluded. In this trial, RF assays may vary between local hospitals, but all assays were performed using validated techniques. Given that the effect on efficacy is evident only in patients with very high baseline RF levels, the potential variability of the RF assay used is most likely to have a negligible impact on the inferences drawn in this trial. In addition, although only IgM RF levels were assayed in this trial, other RF isotypes have also been associated with response rates in patients with RA. For example, high levels (>100 U / mL) of IgA RF were found to predict poor response rates to TNFi treatment compared to low levels (20-100 U / mL) or negative levels (<20 U / mL). Nevertheless, the most commonly detected RF subtype in RA patients is IgM-RF, and RF levels measured in clinical diagnostic settings usually refer to IgM-RF. Because this was a post-hoc analysis, the inventors do not provide quantitative statistical inference. This study was not effective for hypothesis testing. Nevertheless, the inventors discussed the numerical differences and potential clinical significance of such differences. Finally, this post-hoc analysis did not assess the safety of certolizumab pegol specific to baseline RF levels. However, complete safety results from all six clinical trials have been previously published, and most adverse events were mild or moderate.

[0184] In conclusion, this post-hoc analysis provides evidence supporting the clinical benefit of MTX-related certolizumab pegol treatment in RA, regardless of baseline RF status. The efficacy of certolizumab pegol was consistent across RF quartiles, including patients in the highest quartile with the highest baseline RF levels at risk of disease progression.

[0185] Example 3. The effect of high levels of rheumatoid arthritis factor on treatment outcomes of certolizumab pegol and adalimumab in patients with rheumatoid arthritis: A post-hoc analysis of the Phase 4 Exxelerate trial. Study design and patients The Phase 4 Exxelerate trial (NCT01500278) was a 104-week randomized, single-blind (double-blind until week 12, then investigator-blinded), parallel-group, head-to-head, superiority trial of CZP for ADA in patients with RA. Eligible patients were 18 years of age or older who, despite having received at least 12 weeks of methotrexate (MTX) treatment prior to screening, had been diagnosed with active RA at screening and baseline, defined as a disease activity score 28 erythrocyte sedimentation rate (DAS28-ESR) > 3.2, 4 / 28 or more swollen joints, and increased acute-phase reactants (high-sensitivity C-reactive protein [hsCRP] ≥ 10 mg / L and / or ESR ≥ 28 mm / h). The patient was naive to biological disease-modifying antirheumatic drugs (b-DMARDs) and had prognostic factors for severe progression (RF and / or positive results for anti-citrullinated protein antibodies [ACPA]) after stable MTX treatment for at least 28 days.

[0186] At baseline, patients were randomized in a 1:1 ratio to receive either CZP (400 mg at weeks 0, 2, and 4, followed by 200 mg every two weeks [Q2W]) and methotrexate (+MTX) or ADA 40 mg Q2W + MTX. During the first 12 weeks of the study, patients receiving ADA also received placebo injections at weeks 0, 2, and 4 to maintain blinding during the administration of the loading dose of CZP. At week 12, patients were classified as responders (by achieving low disease activity [LDA]: DAS28-ESR ≤ 3.2 or DAS28-ESR reduction ≥ 1.2 from baseline) or non-responders. Patients classified as non-responders to their randomized TNFi were switched to another TNFi without a washout period. Patients switched to ADA received 40 mg ADA Q2W + MTX. Patients who switched to CZP received a loading dose of 400 mg CZP at weeks 12, 14, and 16, followed by CZP 200 mg Q2W + MTX. RF levels were measured by Roche Tina-quant®.

[0187] result The inventors report the following outcomes in CZP and ADA-treated patients up to 104 weeks, stratified by baseline RF quartile (≤Q3 or >Q3; quartile cutoff selected to allow a reasonable number of patients in each subgroup): drug plasma concentration (Sanquin test; the primary test), mean DAS28-CRP and proportion of patients achieving low disease activity (LDA) on DAS28-CRP; number needed to treat (NNT) for DAS28-CRP LDA; mean DAS28-ESR and proportion of patients achieving DAS28-ESR LDA; Clinical Disease Activity Index (CDAI) score; Simplified Disease Activity Index (SDAI) score; proportion of patients achieving CDAI LDA (CDAI ≤ 10) and SDAI LDA (SDAI ≤ 11); Health Assessment Questionnaire Disability Index (HAQ-DI) score; and proportion of patients achieving modified Boolean remission.

[0188] To assess whether the effects of high RF levels are mediated by anti-drug antibodies, sensitivity analyses were performed on the proportion of patients achieving DAS28-CRP and DAS28-ESR, as well as DAS28-CRP LDA and DAS28-ESR LDA, after excluding patients with high levels of anti-drug antibodies (>50th percentile; an arbitrarily selected threshold based on the knowledge that higher titers are associated with a higher prevalence of neutralizing antibodies; measured by the Sanquin assay).

[0189] To evaluate whether outcomes are confounded by factors such as disease activity and to ensure that our observations are specific to RF levels, we also report DAS28-CRP and DAS28-ESR in CZP and ADA-treated patients stratified by ACPA quartiles (≤Q3 or >Q3; measured by immunoassay and performed in a central laboratory) up to week 104.

[0190] analysis The analysis of outcomes from week 0 to week 12 included all patients with baseline and post-baseline efficacy measures (complete analysis set); the analysis of outcomes beyond week 12 included randomized patients who received at least one dose of the study drug after week 12 and had effective baseline, week 12, and post-week 12 efficacy measures (complete analysis set at week 12). At week 12, patients who were unresponsive to TNFi at baseline were randomized to switch to another TNFi, and outcomes were analyzed according to the treatment the patient was receiving at measurement.

[0191] The area under the curve (AUC) for CZP and ADA plasma concentrations beyond week 12 was calculated. Patients who switched treatments at week 12 were not included in the AUC analysis.

[0192] Data were reported as observed cases (OCs) for all outcomes except modified Boolean remission (non-responder complementation [NRI]). DAS28-CRP LDA and DAS28-ESR LDA were reported as OCs and NRIs. The reported p-values ​​were not pre-specified and are therefore nominal values, and should be interpreted with caution.

[0193] result Patient demographics and baseline characteristics Baseline data by RF quartile were available for 453 CZP randomized patients (≤Q3[RF≤204IU / mL]:n=334; >Q3[RF>204IU / mL]:n=119) and 454 ADA randomized patients (≤204IU / mL:n=347; >204IU / mL:n=107). At week 12, 66 CZP randomized patients switched to ADA and 59 ADA randomized patients switched to CZP. Baseline demographics and characteristics were similar between the ADA and CZP randomized groups with RF ≤204IU / mL and >204IU / mL, respectively, but patients with higher RF levels had a longer mean disease duration (Table 1). [Table 1]

[0194] Drug concentrations stratified by RF level Figure 5B shows the plasma drug concentrations of CZP 200 mg and ADA 40 mg up to week 104. From week 12 onward, the AUC of ADA drug concentration was lower in patients with RF levels > 204 IU / mL than in patients with RF levels ≤ 204 IU / mL. The AUC of CZP concentration was similar in patients with RF ≤ 204 IU / mL and > 204 IU / mL.

[0195] Effectiveness stratified by RF level Clinical outcomes were worse in patients with RF levels >204 IU / mL treated with ADA compared to patients treated with CZP. In patients with RF ≤ 204 IU / mL, mean (SD) DAS28-CRP was similar between CZP-treated and ADA-treated patients at week 104 (CZP: 2.5[1.2]; ADA: 2.5[1.1]; nominal p=0.917; Figure 3b). However, for patients with RF > 204 IU / mL, mean (SD) DAS28-CRP was lower in CZP-treated patients compared to ADA-treated patients at week 104 (CZP: 2.5[1.2]; ADA: 2.9[1.2]; nominal p=0.046; Figure 3b). The proportion of patients with RF ≤ 204 IU / mL who achieved DAS28-CRP LDA was similar at week 104 between CZP-treated patients (127 / 196; 64.8%) and ADA-treated patients (151 / 232; 65.1%) (OC data; Figure 3b). However, among patients with RF > 204 IU / mL, the proportion achieving DAS28-CRP LDA was higher at week 104 in CZP-treated patients (46 / 70; 65.7%) than in ADA-treated patients (28 / 58; 48.3%) (36% relative increase; OC data). Findings were similar when NRI was used (Figure 3b). In patients with RF ≤ 204 IU / mL, the NNT at week 104 for DAS28-CRP LDA was 52.1 for CZP versus ADA (95% confidence interval: 193.5–297.6), while in patients with RF > 204 IU / mL, it was 5.5 (95% confidence interval: 0.3–10.7). Similar patterns were observed for DAS28-ESR and DAS28-ESR LDA (Figure 8D).

[0196] The responses to CZP and ADA, as measured by CDAI and CDAI LDA, are shown in Figure 13. SDAI and SDAI LDA can be found in Figure 14. At week 104, mean (SD) CDAI was similar in CZP and ADA-treated patients with RF levels ≤ 204 IU / mL (CZP: 7.3[9.5]; ADA: 7.6[9.3]). In patients with RF levels > 204 IU / mL, mean (SD) CDAI was numerically lower in ADA-treated patients compared to CZP-treated patients (CZP: 7.2[9.8]; ADA: 9.1[9.6]). The proportion of patients achieving CDAI LDA was similar for patients with RF levels ≤204 IU / mL at week 104 (CZP: 75.9%; ADA: 74.9%), but among patients with RF >204 IU / mL, the proportion of patients achieving CDAI LDA was higher in ADA-treated patients compared to CZP-treated patients (CZP: 78.6%; ADA: 68.3%; Figure 13). Similar patterns were observed for SDAI and SDAI LDA (Figure 14). HAQ-DI scores were similar between CZP-treated and ADA-treated patients with RF levels ≤204 IU / mL and >204 IU / mL at week 104 (Figure 15).

[0197] The treatment response, as measured by modified Boolean remission, is shown in Figure 16. From week 64, a higher percentage of CZP-treated patients achieved Boolean remission compared to ADA-treated patients in patients with RF levels >204 IU / mL (CZP: 8.5% at week 104; ADA: 2.9% at week 104).

[0198] Sensitivity analysis: Exclusion of patients with high levels of anti-drug antibodies. To evaluate whether the effects of high RF levels on ADA and CZP treatment are mediated by anti-drug antibodies, DAS28-CRP, DAS28-ESR, DAS28-CRP LDA, and DAS28-ESR LDA were analyzed after excluding patients with high levels of anti-drug antibodies (>50th percentile). The DAS28-CRP, DAS28-ESR, DAS28-CRP LDA, and DAS28-ESR LDA after excluding patients with high levels of anti-drug antibodies (>50th percentile) are shown in Figure 28. The values ​​were 17 and 18, which are consistent with the findings from the entire study population. In patients with RF levels ≤ 204 IU / mL, mean (SD) DAS28-CRP and DAS28-ESR were similar between CZP-treated and ADA-treated patients at week 104 after excluding patients with high levels of anti-drug antibodies (DAS28-CRP: 2.4[1.1]CZP and 2.4[1.1]ADA; DAS28-ESR: 2.9[1.4]CZP and 3.0[1.3]ADA) (Figure 17). However, in patients with RF levels exceeding 204 IU / mL, after excluding patients with high levels of anti-drug antibodies, mean DAS28-CRP and DAS28-ESR were lower in CZP-treated patients compared to ADA-treated patients at week 104 (DAS28-CRP: 2.2[0.8]CZP and 2.8[1.1]ADA; DAS28-ESR: 2.9[1.0]CZP and 3.5[1.3]ADA).

[0199] The proportion of patients achieving DAS28-CRP LDA and DAS28-ESR LDA after excluding patients with high levels of anti-drug antibodies was similar among patients with RF levels ≤ 204 IU / mL at week 104 (67.8% CZP and 66.5% ADA; DAS28-ESR: 67.1% CZP and 62.1% ADA; Figure 18). However, there were differences among patients with RF levels > 204 IU / mL at week 104 (DAS28-CRP LDA: 78.0% CZP and 52.8% ADA; DAS28-ESR: 65.9% CZP and 44.4% ADA).

[0200] Sensitivity analysis: Effectiveness stratified by ACPA level DAS28-CRP and DAS28-ESR were similar between CZP-treated and ADA-treated patients throughout weeks 0–104, with ACPA levels being both ≤761.4 IU / mL and >761.4 IU / mL (Figure 19). At week 104, in patients with ACPA levels >761.4 IU / mL, the mean (SD) DAS29-CRP was 2.5 (1.1) in CZP-treated patients and 2.5 (1.1) in ADA-treated patients. The mean (SD) DAS28-ESR was 3.2 (1.3) in ADA-treated patients and 3.0 (1.4) in CZP-treated patients. The correlation between RF levels and ACPA levels was low (data not shown).

[0201] Consideration This post-hoc analysis of the EXXELERATE trial provides a direct comparison of CZP versus ADA in patients with RA and high RF levels. In patients in the highest RF level quartile, clinical outcomes were better in patients treated with CZP compared to those treated with ADA. Furthermore, drug concentrations were lower in patients with high RF levels compared to those with lower RF levels in ADA-treated patients, but no such difference was observed in CZP-treated patients. Sensitivity analyses to evaluate the effects of anti-drug antibodies and ACPA levels indicate that these findings were not confounded by factors such as the presence of anti-drug antibodies or disease activity.

[0202] Previous analyses of the effect of ADA plasma concentrations on treatment response among patients with high RF levels showed that higher ADA levels were associated with better response and improved drug survival. That study suggested a lower treatment threshold of 6.0 mg / L, and in this post-hoc analysis, plasma ADA levels reached 4.8 ug / mL at week 104 in patients with RF > 204 IU / mL, suggesting that lower serum drug concentrations in ADA-treated patients with high RF levels may have resulted in lower efficacy compared to CZP. Conversely, CZP-treated patients with RA and high RF levels had similar drug concentrations and maintained clinical outcomes compared to patients with lower RF levels.

[0203] In patients with RA and RF levels >204 IU / mL, the proportion of patients achieving DAS28-CRP LDA and DAS28-ESR LDA at week 104 was 36% and 38% higher, respectively, in CZP-treated patients compared to ADA-treated patients, with little difference between CZP-treated and ADA-treated patients in RF levels ≤204 IU / mL. Responses to CZP and ADA, as measured by CDAI and SDAI, were also greater in CZP-treated RA patients compared to ADA patients with RF levels >204 IU / mL, but not in patients with RF levels ≤204 IU / mL.

[0204] In this analysis, the observed difference in CDAI between CZP-treated patients and ADA-treated patients with high RF levels was clinically significant. The cutoff for the minimum clinically significant difference in CDAI was previously defined as 1 when CDAI < 10. Here, in patients with RF levels > 204 IU / mL, CDAI was 1.9 points lower in CZP-treated patients compared to ADA-treated patients at week 104. Furthermore, the NNT for DAS28-CRP LDA at week 104 was approximately 10 times greater in patients with RF levels ≤ 204 IU / mL than in patients with RF levels > 204 IU / mL (≤ 204 IU / mL: 52.1; > 204 IU / mL: 5.5), indicating that the clinical benefit of CZP compared to ADA was greater in patients with higher RF levels than in patients with lower RF levels. The inventors found that DAS28-CRP and DAS28-ESR were similar in CZP and ADA-treated patients with high and low levels of ACPA. The absence of an effect of high levels of ACPA on the response to CZP and ADA indicates that the inventors' observations were not confounded by ACPA levels as an autoantibody characteristic of RA that does not bind to the Fc portion of IgG, and therefore suggest a true biological effect of RF.

[0205] The inventors also found similar efficacy results when patients with high concentrations of anti-drug antibodies were excluded from the analysis. This suggests that anti-drug antibodies do not contribute to the differences observed in clinical outcomes between patients with RA and those with high RF levels when treated with either CZP or ADA.

[0206] These findings are consistent with previous reports from indirect comparisons suggesting consistent efficacy of CZP regardless of baseline RF levels, although patients with high RF levels who received Fc-containing TNF appeared to have a lower drug concentration and response to treatment. Notably, the data from the current analysis were obtained from randomized controlled trials directly comparing CZP with ADA.

[0207] conclusion Patients with RA and high levels of RF represent a subgroup of patients with poor clinical outcomes. In ADA-treated patients, those with high RF levels had poorer clinical outcomes and lower drug concentrations compared to those with lower RF levels. However, in CZP-treated patients, those with high RF levels had similar drug concentrations and clinical outcomes to those with low RF levels. Therefore, the current data are the first from a head-to-head trial comparing CZP and ADA to demonstrate that the response to treatment in patients with RA and high levels of RF is influenced by the presence or absence of the Fc portion, which is consistent with previous findings.

[0208] Example 4 Evaluation of efficacy outcomes in rheumatoid arthritis (RA) patients treated with certolizumab pegol (CZP) (Fc-free TNFi) or adalimumab (ADA) (Fc-containing TNFi), stratified by RF level.

[0209] Clinical data: Study design in a retrospective analysis of the FIRST Registry in a Japanese population segmented by RF quartiles: FIRST registry (n=5,077): RA patients who initiated molecularly targeted anti-rheumatic drug therapy. Patients who initiated ADA or CZP were included in the January 2012 registry.a [a] The year our hospital followed JCR references for standardization of RF measurements.

[0210] Patients were stratified by RF level according to the following groups:

[0211] Group 1: RF<13.4 (n=163),

[0212] Group 2: 13.4≦RF<46.0 (n=164),

[0213] Group 3: 46.0 ≤ RF < 121.4 (n=164), and

[0214] Group 4: 121.4≦RF (n=164).

[0215] [Table 2]

[0216] [Table 3]

[0217] [Table 4]

[0218] [Table 5]

[0219] Evaluation efficacy outcomes in RA patients treated with CZP (Fc-free TNFi) or ADA (Fc-containing TNFi), stratified by RF level.

[0220] FIRST Registry trial design for a retrospective analysis of the Japanese FIRST Registry comparing patients treated with CZP or ADA for more than one year, stratified by baseline RF quartile. To limit bias in statistical analysis, only patients with similar characteristics (adjusted for confounding factors) were included in the comparison.

[0221] FIRST registry (n=5,077): RA patients who initiated molecularly targeted anti-rheumatic drug therapy. Patients who initiated ADA or CZP were included in the January 2012 registry. a [a] The year our hospital followed JCR references for standardization of RF measurements.

[0222] Patients were stratified by RF level according to the following groups:

[0223] Group 1: RF<16.9 (n=315),

[0224] Group 2: 16.9≦RF<53.8 (n=318)

[0225] Group 3: 53.8≦RF<145.9 (n=310)

[0226] Group 4: 145.9≦RF (n=310).

[0227] [Table 6]

[0228] Incorporation by equivalents and references While the present invention has been specifically shown and described with reference to preferred embodiments and various alternative embodiments, it will be understood by those skilled in the art that various modifications of form and detail can be made without departing from the spirit and scope of the invention.

[0229] All references, published patents, and patent applications cited herein are incorporated herein by reference in their entirety for all purposes.

Claims

1. A method for treating rheumatic diseases in human patients with rheumatoid factor, The treatment involves administering a bDMARD lacking an Fc fragment to human patients identified as having rheumatoid factor in serum at concentrations greater than 100 IU / ml, 121.4 IU / ml, 125 IU / ml, 145.9 IU / ml, 150 IU / ml, 175 IU / ml, 200 IU / ml, or 204 IU / ml. (i) The therapeutic effect of bDMARD lacking the Fc fragment is not reduced by RF in the patient, and / or (i) the treatment induces low disease activity in the patient or achieves substantial clinical benefit. A method for treating rheumatic diseases in human patients with rheumatoid factor.

2. A method for treating rheumatic diseases in human patients with rheumatoid factor, a) Determining the titer of rheumatoid factor in a sample from the patient, preferably a serum sample, b) If the serum rheumatoid factor titer is greater than 100 IU / ml, greater than 121.4 IU / ml, greater than 125 IU / ml, greater than 145.9 IU / ml, greater than 150 IU / ml, greater than 175 IU / ml, greater than 200 IU / ml, greater than 204 IU / ml, greater than 225 IU / ml, greater than 250 IU / ml, or greater than 275 IU / ml, administer a bDMARD lacking the Fc fragment to the patient. Includes, (i) The therapeutic effect of bDMARD lacking the Fc fragment is not reduced by RF in the patient, and / or (i) the treatment induces low disease activity in the patient or achieves substantial clinical benefit. A method for treating rheumatic diseases in human patients with rheumatoid factor.

3. A method for treating rheumatoid arthritis in human patients with rheumatoid factor, The treatment involves administering certolizumab pegol to human patients identified as having rheumatoid factor levels greater than 100 IU / ml, 121.4 IU / ml, 125 IU / ml, 145.9 IU / ml, 150 IU / ml, 175 IU / ml, 200 IU / ml, or 204 IU / ml in their serum. (i) The therapeutic effect of certolizumab pegol is not reduced by RF in the patient, and / or (i) If the treatment induces low disease activity or achieves substantial clinical benefit in the patient, A method for treating rheumatoid arthritis in human patients with rheumatoid factor.

4. A method for treating rheumatoid arthritis in human patients with rheumatoid factor, a) Determining the titer of rheumatoid factor in a sample from the patient, preferably a serum sample, b) If the serum rheumatoid factor titer is greater than 100 IU / ml, greater than 121.4 IU / ml, greater than 125 IU / ml, greater than 145.9 IU / ml, greater than 150 IU / ml, greater than 175 IU / ml, greater than 200 IU / ml, greater than 204 IU / ml, greater than 225 IU / ml, greater than 250 IU / ml, or greater than 275 IU / ml, administer certolizumab pegol to the patient. Includes, (i) The therapeutic effect of certolizumab pegol is not reduced by RF in the patient, and / or (i) If the treatment induces low disease activity or achieves substantial clinical benefit in the patient, A method for treating rheumatoid arthritis in human patients with rheumatoid factor.

5. The method according to any one of claims 1 to 4, wherein the low disease activity is achieved 90, 100, 104, 120, or 180 days after the first dose of certolizumab pegol.

6. The method according to any one of claims 1 to 5, wherein the patient's low disease activity is achieved with a probability of 40%, 45%, 50%, or 55%.

7. The method according to any one of claims 3 to 6, wherein in step (b), certolizumab pegol is administered to the patient first as a loading dose of 400 mg and then as a loading dose of 400 mg two weeks later, followed by (i) a maintenance dose of 400 mg every four weeks or (ii) a maintenance dose of 200 mg every two weeks.

8. The method according to any one of claims 1 to 7, wherein the loading dose is not administered to the patient at the start of treatment.

9. The method according to any one of claims 1 to 8, wherein the rheumatoid factor is an IgM, IgG, IgD, IgE, or IgA isotype.

10. The method according to any one of claims 3 to 9, wherein certolizumab pegol is administered in combination with another antirheumatic drug.

11. The method according to claim 10, wherein the antirheumatic drug is methotrexate or leflunomide.

12. The method according to any one of claims 1 to 11, wherein the patient has previously not responded to DMARD treatment.

13. The method according to claim 12, wherein the patient had previously not responded to treatment with a biological DMARD having an Fc fragment.

14. The method according to claim 12, wherein the patient had previously not responded to treatment with nonbiological DMARDs.

15. The method according to claim 13 or 14, wherein the treatment failure is a primary failure.

16. The method according to claim 13 or 14, wherein the treatment failure is a secondary failure.

17. The method according to any one of claims 1 to 16, wherein a bDMARD lacking an Fc fragment is administered at regular intervals for at least three months.

18. The method according to any one of claims 1 to 17, wherein the plasma concentration of the bDMARD lacking the Fc fragment does not decrease in the patient after administration thereof.

19. A method for maintaining low disease activity or remission of rheumatic disease in human subjects who require maintenance of low disease activity or remission of rheumatic disease, This includes administering to the subject a dose of bDMARD lacking an Fc fragment that is effective in maintaining low disease activity or remission in the subject. The subject is identified as having elevated baseline rheumatoid factor (RF) serum levels greater than 100 IU / ml. A method for maintaining low disease activity or remission in human subjects who require maintenance of low disease activity or remission of rheumatic disease.

20. The method according to claim 19, wherein the subject has rheumatoid arthritis (RA).

21. The method according to claim 20, wherein the subject has early RA.

22. The method according to claim 20, wherein the subject had active RA for at least six months prior to treatment.

23. The method according to any one of claims 19 to 22, wherein the bDMARD is certolizumab pegol.

24. The method according to claim 23, wherein the certolizumab pegol is administered to the subject first as a loading dose of 400 mg, then as a loading dose of 400 mg two weeks later, followed by a maintenance dose.

25. The method according to claim 23, wherein the loading dose is not administered to the patient at the start of treatment with the maintenance dose.

26. The method according to claim 25, wherein the certolizumab pegol is administered to the subject at a maintenance dose of 400 mg every four weeks.

27. The method according to claim 25, wherein the certolizumab pegol is administered to the subject at a maintenance dose of 200 mg every two weeks.

28. The method according to any one of claims 19 to 27, wherein the bDMARD is administered to the subject for at least 12 weeks.

29. The method according to any one of claims 19 to 28, wherein the bDMARD is administered to the subject for at least 24 weeks.

30. The method according to any one of claims 19 to 29, wherein the bDMARD is administered to the subject for at least one year.

31. The method according to any one of claims 19 to 30, wherein the bDMARD is administered to the subject for at least two years.

32. The method according to any one of claims 19 to 31, wherein low disease activity or remission is achieved within 12 weeks after the first dose of bDMARD and maintained throughout the course of treatment.

33. The method according to any one of claims 19 to 32, wherein the subject is identified as having a baseline RF serum level greater than 121.4 IU / ml.

34. The method according to any one of claims 19 to 32, wherein the subject is identified as having a baseline RF serum level greater than 125 IU / ml.

35. The method according to any one of claims 19 to 32, wherein the subject is identified as having a baseline RF serum level greater than 145.9 IU / ml.

36. The method according to any one of claims 19 to 32, wherein the subject is identified as having a baseline RF serum level greater than 150 IU / ml.

37. The method according to any one of claims 19 to 32, wherein the subject is identified as having a baseline RF serum level greater than 175 IU / ml.

38. The method according to any one of claims 19 to 32, wherein the subject is identified as having a baseline RF serum level greater than 200 IU / ml.

39. The method according to any one of claims 19 to 32, wherein the subject is identified as having a baseline RF serum level greater than 204 IU / ml.

40. The method according to any one of claims 19 to 32, wherein the subject is identified as having a baseline RF serum level greater than 225 IU / ml.

41. The method according to any one of claims 19 to 32, wherein the subject is identified as having a baseline RF serum level greater than 250 IU / ml.

42. The method according to any one of claims 19 to 32, wherein the subject is identified as having a baseline RF serum level of at least 275 IU / ml.

43. The method according to any one of claims 19 to 43, further comprising the preceding step of measuring the serum level of RF in a subject having a rheumatic disease.

44. The method according to any one of claims 19 to 44, wherein the RF is an IgM, IgG, IgD, IgE, or IgA isotype.

45. The method according to any one of claims 19 to 44, wherein the bDMAD is administered in combination with another antirheumatic drug.

46. The method according to claim 45, wherein the antirheumatic drug is methotrexate or leflunomide.

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