Detecting method for blood marker associated with ANCA-related vasculitis, and use thereof

Abstract

To provide a biomarker for evaluating disease activity of an ANCA-related vasculitis that can contribute to meeting demands in clinical environment of the ANCA-related vasculitis.SOLUTION: It is found that the problem to be solved can be solved by: providing a detecting method for detecting a decrease or increase in one or more kinds of blood protein selected between (1) a decrease in protein selected between (A) OPA1 and AACT and (2) an increase in protein selected among ITPR3, ARHG6, HDHD3, PCYOX, ABCB6, CBG, SPP24, ALS, ITIH1, and DHX30 of a blood specimen of a patient of ANCA-related vasculitis who is being treated by remission induction therapy; providing an acquiring method for information related to therapeutic effect which uses the decrease or increase in blood protein detected by the detecting method as an index for determining the effectiveness of the remission induction therapy on the ANCA-related vasculitis; and relating the result further to BVAS and nephritis.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to a means for detecting a biological signal. More specifically, the present invention relates to a means for obtaining, as information on the increase or decrease of a specific blood protein, an index of the effect of remission induction treatment in MPA and GPA among ANCA-related vasculitis.

Background Art

[0002] ANCA-associated vasculitis is a type of systemic vasculitis, including three diseases: microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA), and eosinophilic granulomatosis with polyangiitis (EGPA). All of them are designated intractable diseases eligible for medical expense subsidy and are often abbreviated as AAV from the English name "Anti-neutrophil cytoplasmic antibody-Associated Vasculitis". Note that GPA and EGPA were formerly named after people, Wegener's granulomatosis and Churg-Strauss syndrome respectively, but were changed to the current names since 2012. Vasculitis is a general term for diseases caused by inflammation in various blood vessels, resulting in impaired blood flow. In the latest international classification, it is classified into 7 categories and 26 diseases, and AAV is classified into the category of small vessel vasculitis, which predominantly invades small blood vessels (capillaries, venules, arterioles, small arteries). Pathologically, it is a necrotizing vasculitis with poor deposition of immune complexes, and anti-neutrophil cytoplasmic antibody (ANCA), an autoantibody, is often detected in the serum, which is the origin of the disease name. ANCA is not just a disease marker but is thought to be closely involved in the pathogenesis. However, the etiology and pathogenesis of ANCA-associated vasculitis are still mostly unclear. ANCA has two staining patterns: c-ANCA, which shows diffuse granular fluorescence in the cytoplasm, and p-ANCA, which shows fluorescence around the nucleus, detected by indirect immunofluorescence antibody method using ethanol-fixed neutrophils. The corresponding antigens of c-ANCA and p-ANCA detected in the serum of patients with ANCA-associated vasculitis are proteinase 3 (PR3) and myeloperoxidase (MPO) respectively. PR3-ANCA and MPO-ANCA are very important for the diagnosis and classification as disease markers of ANCA-associated vasculitis and are frequently used in the daily medical treatment of ANCA-associated vasculitis. Among the three diseases of ANCA-associated vasculitis, EGPA has different pathological characteristics such as increased peripheral blood eosinophils and prominent eosinophil infiltration around blood vessels histopathologically, so it is often treated under a different regimen from MPA and GPA.As will be described later, the background art related to the present invention pertains to "MPA and GPA among ANCA-associated vasculitides," and the background art of EGPA is not the subject.

[0003] Both MPA and GPA are severe systemic autoimmune diseases, and if appropriate treatment is not carried out, they can lead to life-threatening situations or irreversible organ damage. Clinically, at the onset of these diseases, after diagnosis, disease type classification, and evaluation of organ damage and disease state, remission induction treatment is performed. Since ANCA-associated vasculitis is a refractory disease of unknown cause, "cure" in the state where the disease is completely cured is not expected, and treatment is aimed at "remission," a state in which symptoms and test abnormalities due to the disease disappear. Remission induction treatment is a treatment stage towards remission by actively using drugs. Generally, high-dose steroids, biological agents, and immunosuppressive drugs are used in combination, which have strong treatment effects but also many adverse events. Continuing this even after remission is achieved is not advisable as the harm caused by treatment becomes greater. Therefore, it is necessary to judge the effectiveness of remission induction treatment over time and shift to remission maintenance treatment that restricts drug administration when the treatment becomes effective. Alternatively, if the reactivity of the initial treatment is judged to be insufficient, the treatment policy needs to be changed, and for this judgment as well, it is necessary to appropriately judge the effectiveness of remission induction treatment. As indicators and markers (ANCA disease activity markers) for judging the effectiveness of remission induction treatment for this ANCA-associated vasculitis, BVAS (Birmingham Vasculitis Activity Score), C-reactive protein (CRP), MPO-ANCA, PR3-ANCA, etc. are known. Also, as prior patent documents in this field, Patent Documents 1-3, etc. can be cited.

Prior Art Documents

Patent Documents

[0004]

Patent Document 1

Patent Document 2

Patent Document 3

Summary of the Invention

Problems to be Solved by the Invention

[0005] ANCA-associated vasculitis is a severe intractable disease that often poses a life-threatening risk. Moreover, even if remission is achieved once and remission maintenance treatment is carried out, about 10% of patients are said to relapse annually. On the other hand, the symptoms of ANCA-associated vasculitis are often non-specific such as fever and proteinuria, and it is not easy to distinguish from diseases with completely different treatment policies such as infectious diseases. Therefore, it is difficult to determine based only on clinical symptoms. Also, even if remission induction therapy or re-remission induction therapy is performed after the disease condition becomes severe, the treatment responsiveness is poor. Even if remission is reached, there is a risk of irreversible organ damage such as end-stage renal failure, blindness, and deafness, as well as adverse events associated with treatment drugs such as osteoporosis, fragility fractures, diabetes, and infectious diseases. Therefore, it is very important to judge the increase in disease activity and the effectiveness of treatment as early as possible. Nevertheless, currently, none of the disease activity markers for ANCA-associated vasculitis that are in practical use in clinical practice can be said to have sufficient performance. In this specification, when collectively abbreviating "disease activity of ANCA-associated vasculitis" or "disease activity against ANCA-associated vasculitis", it is denoted as "ANCA disease activity".

[0006] The Birmingham Vasculitis Activity Score (BVAS) is a comprehensive index that assigns scores as units of activity associated with ANCA disease activity for a number of clinical symptoms and general examinations, and then adds them up to evaluate the score. That is, in BVAS, high scores are assigned to symptoms and test abnormalities that are considered to indicate high ANCA disease activity, and low scores are assigned to symptoms and test abnormalities that are considered to only indicate relatively low ANCA disease activity. The score obtained by summing them is used as an index of ANCA disease activity. Due to its substantiality related to such specific clinical aspects, BVAS is used in clinical trials and clinical research, etc., but it is too cumbersome for daily medical practice and not practical. Furthermore, it relies heavily on the subjective judgment of medical personnel, and it is considered to have problems with objectivity unless it is used by experienced specialists who have received special training on how to assign scores. C-reactive protein (CRP) is widely used as an inflammatory marker and is also inexpensive, but it can also be elevated in infectious diseases and other pathological conditions, and deviations from the pathological condition of ANCA-associated vasculitis are often observed. Myeloperoxidase-ANCA (MPO-ANCA) and proteinase 3-ANCA (PR3-ANCA) have antibody titers that are somewhat related to ANCA disease activity, but this only applies to some patients. Furthermore, it is known that they can also be elevated in other diseases, and positive results have even been observed in healthy individuals.

[0007] The main method for determining the efficacy of remission induction therapy for ANCA-associated vasculitis is to directly evaluate the improvement or disappearance of clinical symptoms based on pre-treatment vasculitis. Evaluation using biomarkers related to ANCA disease activity is only supplementary. However, in practice, for example, when proteinuria and glomerular filtration rate (GFR) have not improved, it is difficult to determine whether there is still vasculitis activity or if irreversible kidney damage has already occurred based only on the presence or absence and amount of proteinuria and creatinine levels. In such cases, it is of great significance to determine the presence or absence of ANCA disease activity using biomarkers. Also, when ANCA-associated vasculitis coexists with an infectious disease, it is extremely useful if the presence, absence, or intensity of ANCA disease activity can be evaluated using biomarkers when trying to reduce the treatment intensity.

[0008] Therefore, the first object of the present invention is to provide a biomarker for evaluating the disease activity of ANCA-associated vasculitis, which can contribute to meeting the demands in the clinical field of ANCA-associated vasculitis as described above.

[0009] Among the conventional evaluation indices for remission induction treatment for ANCA-associated vasculitis, BVAS is an index corresponding to the most specific clinical symptoms, but as described above, it has problems such as being complicated. As a means of solving this problem of BVAS, the development of a simple-to-evaluate index correlated with the evaluation of BVAS can be mentioned. And among the evaluation items of BVAS, the most clinically important one is nephritis.

[0010] Therefore, the second object of the present invention is to provide a simple-to-evaluate biomarker that correlates with the evaluation of BVAS and further shows a recognized association with nephritis.

Means for Solving the Problems

[0011] The present inventors have conducted a comprehensive proteomics analysis using a mass spectrometer on blood specimens of patients with ANCA-associated vasculitis, and found that 13 blood proteins are extremely useful as biomarkers that can address the above problems, either alone or in combination, and thus completed the present invention.

[0012] The above 13 blood proteins are as shown in Table 1.

[0013]

Table 1

[0014] In Table 1, the first column from the left shows the "accession number", the second column shows the "abbreviation", the third column shows the "official name", and the fourth column shows the "relationship with remission induction treatment". Specifically, for the first row (OPA1: abbreviation), the first column shows the "accession number of OPA1: O60313", the third column shows the "official name of OPA1: Dynamin-like 120kDa protein, mitochondrial", and the fourth column shows that "when the remission induction treatment for ANCA-associated vasculitis (MPA / GPA) is effective, the blood concentration of OPA1 decreases". For the blood proteins shown in Table 1 other than OPA1 and AACT, when the remission induction treatment for ANCA-associated vasculitis (MPA / GPA) is effective, the blood concentration decreases.

[0015] That is, the present invention first provides a detection method (hereinafter also referred to as the detection method 1 of the present invention) for detecting a decrease or increase in one or more blood proteins selected from the following (1): (1) A decrease in any protein selected from OPA1 and AACT; and the following (2): (2) An increase in any protein selected from HRG, ITPR3, ARHG6, HDHD3, PCYOX, ABCB6, CBG, SPP24, ALS, ITIH1, and DHX30; in a blood sample of a patient with MPA and / or GPA among those with ANCA-associated vasculitis undergoing remission induction treatment. Further, the present invention provides a method for obtaining information regarding the treatment effect (hereinafter also referred to as the information acquisition method 1 of the present invention) that uses the decrease or increase in the blood protein detected by the detection method 1 of the present invention as an indicator for determining the effectiveness of the remission induction treatment for MPA and / or GPA.

[0016] The present inventors further examined the correlation with BVAS and the significant differences between patients with and without nephritis among the evaluation items of BVAS for the increase and decrease indices of the above 13 blood proteins. As a result, among the above 13, a correlation with BVAS was recognized for 7. Then, it was found that a relationship with nephritis was recognized for 6 of the above 7 for which a correlation with BVAS was recognized, excluding "decrease in AACT", and the inventors provide an invention based on these findings.

[0017] That is, secondly, the present invention provides, in a blood sample of a patient with MPA and / or GPA among ANCA-associated vasculitides undergoing remission induction treatment, the following (1): (1) Decrease in any protein selected from OPA1 and AACT; and (2) Increase in any protein selected from HRG, ARHG6, PCYOX, ALS, and ITIH1; a detection method for detecting a decrease or increase in one or more blood proteins selected therefrom (hereinafter, also referred to as the detection method 2 of the present invention). Further, the present invention provides a method for obtaining information on treatment effects (hereinafter, also referred to as the information acquisition method 2 of the present invention), which uses the decrease or increase in blood proteins detected by the detection method 2 of the present invention as an index for determining the effectiveness of remission induction treatment correlated with BVAS for MPA and / or GPA.

[0018] Thirdly, the present invention provides, in a blood sample with nephritis of a patient with MPA and / or GPA among ANCA-associated vasculitides undergoing remission induction treatment, the following (1): (1) Decrease in OPA1; and (2) Increase in any protein selected from HRG, ARHG6, PCYOX, ALS, and ITIH1; Provided is a detection method (hereinafter, also referred to as the detection method 3 of the present invention) for detecting a decrease or increase in one or more blood proteins selected from the group consisting of, and further provided is a method for obtaining information regarding treatment efficacy (hereinafter, also referred to as the information acquisition method 3 of the present invention), which uses a decrease or increase in blood proteins detected by the detection method 3 of the present invention as an indicator for determining the efficacy of remission induction treatment in cases accompanied by nephritis against MPA and / or GPA.

[0019] Also, including the above-described detection methods 1-3 of the present invention, it is also referred to as the detection method of the present invention, and including the information acquisition methods 1-3 of the present invention, it is also referred to as the information acquisition method of the present invention.

[0020] The detection method of the present invention is claimed as a patent suitable for a position (such as a clinical testing company) where the implementer bears the main responsibility for providing information on the increase or decrease of blood proteins serving as blood markers. In contrast, the information acquisition method of the present invention is claimed as a patent suitable for a position (such as a medical institution) that bears the main responsibility for utilizing the obtained information on the increase or decrease of blood proteins.

[0021] The blood specimen may be a whole blood specimen, a serum specimen, or a plasma specimen, and can be selected as needed.

[0022] As the means for detecting the above blood proteins from the blood specimen, it is possible to use means according to known principles, and it is also possible to use means newly provided in the future. It may be manual detection or detection by an automatic device.

[0023] Specifically, enzyme immunoassay, immunoturbidimetry, radioimmunoassay, latex agglutination or turbidimetry, immunochromatography, mass spectrometry, etc. can be used.

[0024] Examples of enzyme immunoassays include, for example, EIA (Enzyme Immunoassay), ELISA (Enzyme-Linked immunosorbent assay), FEIA (Fluorescence Enzyme Immunoassay), CLEIA (CLIA) (Chemiluminescent Enzyme Immunoassay), CLIA (Chemiluminescent Immunoassay), etc.

[0025] Examples of immunoturbidimetry include, for example, Nephelometry, TIA (Turbidimetric Immunoassay), etc.

[0026] Examples of radioimmunoassays include, for example, RIA (Radio Immunoassay), CPBA (Competitive Protein Binding Assay), etc.

[0027] Examples of latex agglutination or turbidimetry include, for example, LA (Latex Agglutination), LA (Latex Agglutination turbidimetric Immunoassay), LPIA (Latex Photometric Immunoassay), KIMS (Kinetic Interaction of Microparticles), Colloidal Gold Immunoassay, etc.

[0028] Examples of mass spectrometry methods include liquid chromatography-mass spectrometry (LC-MS), liquid chromatography-tandem mass spectrometry (LC-MS / MS), high performance liquid chromatography-mass spectrometry (HPLC-MS), high performance liquid chromatography-tandem mass spectrometry (HPLC-MS / MS), and the like.

[0029] For the detection of a predetermined blood protein performed for the detection method 1 or information acquisition method 1 of the present invention, it is preferable to perform it in a time-course monitoring format from the start of remission induction treatment for ANCA-associated vasculitis along with its progression. As described above, ANCA-associated vasculitis is a refractory disease of unknown cause classified as an autoimmune disease, and specific symptoms also vary greatly among individuals. Therefore, it is necessary to make an individual and specific determination according to each patient regarding the effectiveness of remission induction treatment. Accordingly, regarding whether the biomarker according to the present invention, which is an effective index for remission induction treatment, is positive or not, when an increase or decrease in the biomarker value of each patient in the positive direction is detected compared to before remission induction treatment or in the early stage of remission induction treatment, information acquisition of "effective remission treatment (positive)" is made, and when the biomarker value shows a flat or opposite direction to the positive direction, it is reasonable to make information acquisition of "not yet in remission (negative)". In addition, in the determination of positive and negative, combining two or more biomarkers is useful because ANCA-associated vasculitis is a refractory disease with large individual differences as described above.

[0030] Regarding what the content of the "relapse" index is after remission is recognized by remission induction treatment and the treatment shifts to remission maintenance treatment, at present, there is no prediction at all as to whether the increase or decrease of the above 13 types, or 7 to 6 types of blood proteins according to the index used in the present invention moves straightforwardly in the opposite direction during relapse.

Effects of the Invention

[0031] According to the present invention, it becomes possible to provide and obtain information for evaluating the effect of remission maintenance treatment for patients with ANCA-associated vasculitis (MPA and / or GPA). By performing the detection methods 1-3 of the present invention on blood samples during the remission induction treatment, it becomes possible to obtain an information source for evaluating the effect of remission maintenance treatment for patients with ANCA-associated vasculitis (MPA and / or GPA). For this information source, oneself or another person provided with the information source performs the information acquisition methods 1-3 of the present invention on the information source to evaluate the biomarker according to the present invention (confirmation of the effect of remission induction treatment), thereby obtaining information for shifting to remission maintenance treatment (monitoring based on drug reduction). The detection methods 1-3 to information acquisition methods 1-3 of the present invention, particularly the same 2-3, are highly practical in medical institutions in that when a patient has nephritis, an infectious disease, etc., information for determining drug reduction for ANCA-associated vasculitis can be independently obtained.

Brief Description of the Drawings

[0032]

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Mode for Carrying Out the Invention

[0033] As forms of the detection method or information acquisition method of the present invention, mainly three practical modes can be considered. First, it is a mode of examining the effect of remission induction treatment for MPA. Second, it is a mode of examining the effect of remission induction treatment for GPA. Third, it is a mode of examining the effect of remission induction treatment for both MPA and GPA. Hereinafter, regarding these practical modes, the detection methods 1-3 and information acquisition methods 1-3 of the present invention will be described respectively.

[0034] 1. Mode of examining the effect of remission induction treatment for MPA The symptoms of MPA (microscopic polyangiitis) appear as systemic symptoms such as fever, weight loss, and easy fatigue, along with signs due to tissue bleeding and ischemia / infarction. Necrotizing crescentic glomerulonephritis is the most important and frequent symptom, with the appearance of urinary occult blood, red blood cell casts, and urinary protein, and an increase in serum creatinine levels. Renal failure progresses rapidly, and if the intervention is delayed, dialysis therapy often results. Therefore, it is extremely important to diagnose as early as possible and perform appropriate remission induction treatment.

[0035] In remission induction therapy, in addition to corticosteroids, rituximab (anti-CD20 monoclonal antibody), cyclophosphamide (immunosuppressive drug), etc. are used in combination. The causes of death are often due to the primary disease, sepsis, or pulmonary infection.

[0036] (1) Aspects of Detection Method 1 or Information Acquisition Method 1 of the Present Invention In Detection Method 1 or Information Acquisition Method 1 of the present invention, when selecting one biomarker for determining the effect of remission induction therapy with MPA, a decrease in OPA1, an increase in HRG, an increase in ITPR3, or an increase in ARHG6 is preferable. That is, when performing Detection Method 1 or Information Acquisition Method 1 of the present invention using one biomarker, using a decrease in OPA1, an increase in HRG, an increase in ITPR3, or an increase in ARHG6 as an indicator indicating that the remission induction therapy with MPA is effective is preferable.

[0037] Also, the more biomarkers are used, the higher the reliability of judging the effect of remission induction therapy. However, when two biomarkers are used to judge the effect of remission induction therapy with MPA, the combination of a decrease in OPA1 and an increase in HDHD3; the combination of a decrease in OPA1 and an increase in ITPR3; the combination of a decrease in AACT and an increase in ITPR3; the combination of an increase in HRG and an increase in ITPR3; the combination of an increase in HRG and an increase in HDHD3; the combination of an increase in HRG and an increase in ABCB6; the combination of an increase in HRG and an increase in ITIH1; the combination of an increase in ITPR3 and an increase in HDHD3; the combination of an increase in ITPR3 and an increase in ABCB6; the combination of an increase in ITPR3 and an increase in ITIH1; the combination of an increase in ITPR3 and an increase in DHX30; or the combination of an increase in HDHD3 and an increase in DHX30; is preferably selected.

[0038] When there are three types of biomarkers used to determine the effect of the remission induction treatment with MPA, the combinations are: the combination of a decrease in OPA1, an increase in ABCB6, and an increase in HRG; the combination of a decrease in OPA1, an increase in HDHD3, and an increase in HRG; the combination of a decrease in OPA1, an increase in ITPR3, and an increase in DHX30; the combination of a decrease in OPA1, an increase in HDHD3, and an increase in ITPR3; the combination of a decrease in AACT, an increase in ABCB6, and an increase in HRG; the combination of a decrease in AACT, an increase in DHX30, and an increase in HDHD3; the combination of an increase in ITIH1, an increase in ITPR3, and an increase in DHX30; the combination of an increase in ITIH1, an increase in ITPR3, and an increase in ABCB6; the combination of an increase in HDHD3, an increase in HRG, and an increase in DHX30; the combination of an increase in ABCB6, an increase in HRG, and an increase in ITIH1; the combination of an increase in HDHD3, an increase in ITPR3, and an increase in ITIH1; the combination of an increase in ABCB6, an increase in HRG, and an increase in ARHG6; the combination of an increase in ABCB6, an increase in HRG, and an increase in ITPR3; the combination of a decrease in OPA1, an increase in ITPR3, and an increase in ABCB6; the combination of a decrease in OPA1, an increase in ITPR3, and an increase in CBG; the combination of a decrease in OPA1, an increase in ITPR3, and an increase in ARHG6; the combination of a decrease in OPA1, an increase in ITPR3, and an increase in PCYOX; the combination of a decrease in OPA1, an increase in ITPR3, and an increase in SPP24; the combination of a decrease in OPA1, an increase in ITPR3, and an increase in ALS; the combination of a decrease in OPA1, an increase in DHX30, and an increase in HDHD3; the combination of a decrease in OPA1, an increase in HDHD3, and an increase in HRG; the combination of a decrease in OPA1, a decrease in AACT, and an increase in ITPR3; the combination of an increase in ITIH1, an increase in ITPR3, and an increase in HRG; the combination of an increase in ABCB6, an increase in HRG, and an increase in HDHD3; the combination of an increase in HDHD3, an increase in HRG, and an increase in ARHG6; the combination of an increase in HDHD3, an increase in ITPR3, and an increase in ARHG6; or the combination of an increase in HDHD3, an increase in ITPR3, and an increase in PCYOX; it is preferable to select.

[0039] When the number of biomarkers used to determine the effect of the remission induction treatment with MPA is four or more, any combination can be preferably selected. Therefore, from the viewpoint of obtaining an effect commensurate with the number of biomarkers selected, it is preferable that the upper limit of the number of biomarkers used to determine the effect of the remission induction treatment with MPA is four.

[0040] (2) Aspects of the detection method 2 or information acquisition method 2 of the present invention In the detection method 2 or information acquisition method 2 of the present invention, when selecting one type of biomarker, a decrease in OPA1, an increase in HRG, or an increase in ARHG6 is preferable. That is, it is preferable to use a decrease in OPA1, an increase in HRG, or an increase in ARHG6 as an index indicating that the remission induction treatment with MPA is effective when performing the detection method 2 or information acquisition method 2 of the present invention using one type of biomarker.

[0041] Also in the detection method 2 or information acquisition method 2 of the present invention, the more biomarkers are used, the higher the reliability of judging the effect of remission induction treatment. However, when two types of biomarkers are used to judge the effect of remission induction treatment with MPA, it is preferable to select a combination of an increase in HRG and an increase in ITIH1.

[0042] (3) Aspects of the detection method 3 or information acquisition method 3 of the present invention In the detection method 3 or information acquisition method 3 of the present invention, when selecting one type of biomarker, a decrease in OPA1, an increase in HRG, or an increase in ARHG6 is preferable. That is, it is preferable to use a decrease in OPA1, an increase in HRG, or an increase in ARHG6 as an index indicating that the remission induction treatment with MPA is effective when performing the detection method 3 or information acquisition method 3 of the present invention using one type of biomarker.

[0043] Also in the detection method 3 or information acquisition method 3 of the present invention, the more biomarkers are used, the higher the reliability of judging the effect of remission induction treatment. However, when two types of biomarkers are used to judge the effect of remission induction treatment with MPA, it is preferable to select a combination of an increase in HRG and an increase in ITIH1.

[0044] 2. Aspects of examining the effect of remission induction treatment for GPA The symptoms of GPA (granulomatosis with polyangiitis) include systemic symptoms such as fever and weight loss, upper respiratory tract symptoms such as epistaxis, otitis media, and pharyngeal ulcers; pulmonary symptoms such as hemoptysis and dyspnea; rapidly progressive glomerulonephritis, etc. Secondary infections are likely to occur in the upper respiratory tract and lungs.

[0045] For remission induction treatment, in addition to corticosteroids, rituximab (anti-CD20 monoclonal antibody), or cyclophosphamide (immunosuppressive drug), etc. are used in combination. The causes of death are often due to the original disease, sepsis, or lung infections.

[0046] (1) Aspects of the detection method 1 or information acquisition method 1 of the present invention For a biomarker for determining the effect of such GPA remission induction treatment, when selecting one type of biomarker, a decrease in OPA1, an increase in HRG, an increase in ITPR3, or an increase in ARHG6 is preferred. That is, it is suitable to use a decrease in OPA1, an increase in HRG, an increase in ITPR3, or an increase in ARHG6 as an indicator indicating that the GPA remission induction treatment is effective when performing the detection method or information acquisition method of the present invention using one type of biomarker.

[0047] Moreover, the greater the number of biomarkers used, the higher the reliability of judging the effect of remission induction therapy. However, when two types of biomarkers are used to judge the effect of GPA remission induction therapy, the combinations are: the combination of a decrease in OPA1 and a decrease in AACT; the combination of a decrease in OPA1 and an increase in PCYOX; the combination of a decrease in OPA1 and an increase in SPP24; the combination of a decrease in OPA1 and an increase in ARHG6; the combination of a decrease in AACT and an increase in ITPR3; the combination of a decrease in AACT and an increase in ARHG6; the combination of a decrease in AACT and an increase in HDHD3; the combination of a decrease in AACT and an increase in PCYOX; the combination of a decrease in AACT and an increase in SPP24; the combination of a decrease in AACT and an increase in ITIH1; the combination of an increase in HRG and an increase in PCYOX; the combination of an increase in ITPR3 and an increase in PCYOX; the combination of an increase in ARHG6 and an increase in PCYOX; the combination of an increase in HDHD3 and an increase in PCYOX; the combination of an increase in ARHG6 and an increase in SPP24; the combination of a decrease in AACT and an increase in HRG; the combination of a decrease in AACT and an increase in ABCB6; the combination of a decrease in AACT and an increase in CBG; the combination of a decrease in AACT and an increase in DHX30; the combination of an increase in HRG and an increase in ARHG6; the combination of an increase in ITPR3 and an increase in ARHG6; the combination of an increase in ARHG6 and an increase in HDHD3; the combination of an increase in ARHG6 and an increase in ABCB6; the combination of an increase in ARHG6 and an increase in CBG; the combination of an increase in ARHG6 and an increase in ALS; the combination of an increase in ARHG6 and an increase in DHX30; the combination of an increase in PCYOX and an increase in ABCB6; the combination of an increase in PCYOX and an increase in CBG; the combination of an increase in PCYOX and an increase in SPP24; the combination of an increase in PCYOX and an increase in ALS; the combination of an increase in PCYOX and an increase in ITIH1; the combination of an increase in PCYOX and an increase in DHX30; the combination of a decrease in OPA1 and an increase in HDHD3; the combination of a decrease in AACT and an increase in ALS; or the combination of an increase in CBG and an increase in SPP24; and it is preferable to select these combinations.

[0048] When three or more types of biomarkers are used to judge the effect of GPA remission induction therapy, any combination can be preferably selected. Therefore, from the perspective of obtaining an effect commensurate with the number of biomarkers selected, it is preferable that the upper limit of the number of biomarkers used to judge the effect of GPA remission induction therapy is three types.

[0049] (2) Aspects of the detection method 2 or information acquisition method 2 of the present invention In the detection method 2 or information acquisition method 2 of the present invention, when selecting one type of biomarker, a decrease in OPA1, an increase in HRG, or an increase in ARHG6 is preferable. That is, it is preferable that a decrease in OPA1, an increase in HRG, or an increase in ARHG6 be used as an indicator indicating the effectiveness of remission induction treatment for GPA when performing the detection method 2 or information acquisition method 2 of the present invention using one type of biomarker.

[0050] Also in the detection method 2 or information acquisition method 2 of the present invention, the more biomarkers are used, the higher the reliability of judging the effect of remission induction treatment. However, when two types of biomarkers are used to judge the effect of remission induction treatment for GPA, a combination of a decrease in OPA1 and a decrease in AACT; a combination of a decrease in OPA1 and an increase in PCYOX; a combination of a decrease in OPA1 and an increase in ARHG6; a combination of a decrease in AACT and an increase in PCYOX; a combination of a decrease in AACT and an increase in ITIH1; a combination of an increase in HRG and an increase in PCYOX; a combination of an increase in ARHG6 and an increase in PCYOX; a combination of a decrease in AACT and an increase in HRG; a combination of an increase in HRG and an increase in ARHG6; a combination of an increase in ARHG6 and an increase in ALS; a combination of an increase in PCYOX and an increase in ALS; a combination of an increase in PCYOX and an increase in ITIH1; or a combination of a decrease in AACT and an increase in ALS; is preferably selected.

[0051] (3) Aspects of the detection method 3 or information acquisition method 3 of the present invention In the detection method 3 or information acquisition method 3 of the present invention, when selecting one type of biomarker, a decrease in OPA1, an increase in HRG, or an increase in ARHG6 is preferable. That is, it is preferable that a decrease in OPA1, an increase in HRG, or an increase in ARHG6 be used as an indicator indicating the effectiveness of remission induction treatment for MPA when performing the detection method 3 or information acquisition method 3 of the present invention using one type of biomarker.

[0052] Also in the detection method 3 or information acquisition method 3 of the present invention, the more biomarkers used, the higher the reliability of judging the effect of remission induction treatment. However, when two types of biomarkers are used to judge the effect of remission induction treatment for GPA, the combination of a decrease in OPA1 and an increase in PCYOX; the combination of a decrease in OPA1 and an increase in ARHG6; the combination of an increase in HRG and an increase in PCYOX; the combination of an increase in ARHG6 and an increase in PCYOX; the combination of an increase in HRG and an increase in ARHG6; the combination of an increase in ARHG6 and an increase in ALS; the combination of an increase in PCYOX and an increase in ALS; or the combination of an increase in PCYOX and an increase in ITIH1; is preferably selected.

[0053] 3. Aspect of examining the effect of remission induction treatment for both MPA and GPA As described above, although the pathological conditions of MPA and GPA are different, as the specific content of remission induction treatment, for both ANCA-associated vasculitides, in addition to adrenal corticosteroids, rituximab (anti-CD20 monoclonal antibody) or cyclophosphamide (immunosuppressive drug) is generally used in combination, and usually there is no significant difference. Therefore, in clinical practice, there are many cases where information about the effect of remission induction treatment is desired without distinguishing between MPA and GPA.

[0054] (1) Aspect of the detection method 1 or information acquisition method 1 of the present invention In such a case, when selecting one type of biomarker for judging the effect of remission induction treatment, the decrease in OPA1, the increase in HRG, the increase in ITPR3, or the increase in ARHG6 is preferably used, which is the same as in the case of MPA and GPA individually described above. That is, when performing the detection method or information acquisition method of the present invention using one type of biomarker, it is preferable to use the decrease in OPA1, the increase in HRG, the increase in ITPR3, or the increase in ARHG6 as an indicator indicating that the remission induction treatment for MPA or GPA is effective.

[0055] Also, similarly, the more biomarkers used, the higher the reliability of judging the effect of remission induction treatment. When two types of biomarkers are used to judge the effect of remission induction treatment with MPA or GPA, the combination of a decrease in OPA1 and an increase in HDHD3; the combination of a decrease in OPA1 and an increase in ITPR3; the combination of a decrease in OPA1 and an increase in PCYOX; the combination of a decrease in OPA1 and an increase in CBG; the combination of a decrease in AACT and an increase in ITPR3; the combination of a decrease in AACT and an increase in HDHD3; the combination of an increase in ITPR3 and an increase in HDHD3; the combination of a decrease in AACT and an increase in DHX30; the combination of an increase in HRG and an increase in ITPR3; or the combination of an increase in ITPR3 and an increase in ITIH1; is preferably selected.

[0056] When three types of biomarkers are used to judge the effect of remission induction treatment with MPA or GPA, the combination of a decrease in OPA1, an increase in HDHD3, and an increase in HRG; the combination of a decrease in OPA1, an increase in HDHD3, and an increase in CBG; the combination of a decrease in OPA1, an increase in CBG, and an increase in ABCB6; the combination of a decrease in OPA1, an increase in PCYOX, and an increase in HDHD3; the combination of a decrease in AACT, an increase in HDHD3, and an increase in ARHG6; the combination of a decrease in AACT, a decrease in OPA1, and an increase in HDHD3; the combination of a decrease in AACT, an increase in HDHD3, and an increase in DHX30; the combination of a decrease in AACT, an increase in ITPR3, and an increase in HRG; the combination of a decrease in AACT, an increase in HDHD3, and an increase in HRG; the combination of a decrease in AACT, an increase in HDHD3, and an increase in ABCB6; the combination of a decrease in AACT, an increase in HDHD3, and an increase in SPP24; the combination of a decrease in AACT, an increase in HDHD3, and an increase in PCYOX; the combination of a decrease in AACT, an increase in HDHD3, and an increase in CBG; the combination of a decrease in AACT, an increase in HDHD3, and an increase in ITIH1; the combination of a decrease in AACT, an increase in ITPR3, and an increase in CBG; the combination of an increase in ITPR3, an increase in HDHD3, and an increase in PCYOX; the combination of a decrease in AACT, an increase in HDHD3, and an increase in ITPR3; or the combination of a decrease in AACT, an increase in ITPR3, and an increase in DHX30; is preferably selected.

[0057] When the number of biomarkers used to determine the effect of remission induction therapy with MPA or GPA is four or more, any combination can be selected and is suitable. Therefore, from the perspective of obtaining an effect commensurate with the number of biomarkers selected, it is preferable that the upper limit of the number of biomarkers used to determine the effect of remission induction therapy with MPA or GPA be four types.

[0058] (2) Aspects of the detection method 2 or information acquisition method 2 of the present invention In the detection method 2 or information acquisition method 2 of the present invention, when selecting one type of biomarker, a decrease in OPA1, an increase in HRG, or an increase in ARHG6 is preferable. That is, using a decrease in OPA1, an increase in HRG, or an increase in ARHG6 as an indicator indicating that remission induction therapy with MPA or GPA is effective is suitable when performing the detection method 2 or information acquisition method 2 of the present invention using one type of biomarker.

[0059] Also in the detection method 2 or information acquisition method 2 of the present invention, the greater the number of biomarkers used, the higher the reliability of judging the effect of remission induction therapy. However, when the number of biomarkers used to determine the effect of remission induction therapy with MPA or GPA is two types, it is preferable to select the combination of a decrease in OPA1 and an increase in PCYOX.

[0060] (3) Aspects of the detection method 3 or information acquisition method 3 of the present invention In the detection method 3 or information acquisition method 3 of the present invention, when selecting one type of biomarker, a decrease in OPA1, an increase in HRG, or an increase in ARHG6 is preferable. That is, using a decrease in OPA1, an increase in HRG, or an increase in ARHG6 as an indicator indicating that remission induction therapy with MPA or GPA is effective is suitable when performing the detection method 3 or information acquisition method 3 of the present invention using one type of biomarker.

[0061] Also in the detection method 3 or information acquisition method 3 of the present invention, the more biomarkers used, the higher the reliability of judging the effect of remission induction therapy. However, when the number of biomarkers used to judge the effect of remission induction therapy for MPA or GPA is two, it is preferable to select the combination of decrease in OPA1 and increase in PCYOX.

[0062] 4. Remission induction therapy As described above, the remission induction therapies for MPA and GPA are not basically very different. In particular, in recent years, rituximab, an anti-CD20 monoclonal antibody, has been incorporated into the standard treatment in the remission induction therapy for these ANCA-associated vasculitides. It is preferable that rituximab is also used in the remission induction therapy for which the detection method or information acquisition method of the present invention is performed.

Example

[0063] When creating the present invention, the patient specimens were the plasma collected and stored for the exploratory research purpose of the multi-center prospective observational study "Cohort study on the safety and efficacy of rituximab therapy for anti-neutrophil cytoplasmic antibody-associated vasculitis in Japan (UMIN: 000020329)" registered by the Research Group on Intractable Vasculitis of the Ministry of Health, Labour and Welfare from August 2015 to December 2017. In addition, a comprehensive proteomics analysis using a mass spectrometer was performed on these patients using the stored plasma specimens to create the present invention. This was disclosed as a test example and positioned as an example of the present invention. Therefore, the remission induction therapy described in the present invention is centered on rituximab therapy, and the target diseases are MPA and GPA among ANCA-associated vasculitides, which are the insurance-covered diseases of rituximab. In addition, the above plasma specimens include both primary cases and relapse cases, and the sampling points of the specimens are at the start of remission induction treatment (before treatment) and 6 months after the start of remission treatment (after treatment). In all cases, remission induction treatment was combined with adrenal corticosteroids and rituximab (anti-CD20 monoclonal antibody).

[0064] [Test Example 1] Examination of disease activity markers for ANCA-associated vasculitis (1) Outline of the test Using a screening specimen set (11 ANCA - associated vasculitis patients with pre - and post - treatment specimens), SWATH - MS (Sequential window acquisition of all theoretical fragment - ion spectra mass) analysis was performed using a TripleTOF6600 (SCIEX) to conduct comprehensive proteomic analysis of plasma before and after treatment and analyze the quantitative changes in plasma proteins. ANCA disease activity marker candidates were selected by statistical analysis such as t - test, Mann - Whitney U test, and Wilcoxon's signed - rank test (Wilcoxon matched pairs signed rank test).

[0065] Next, using an evaluation specimen set different from the screening specimen set (48 patients (32 with MPA and 16 with GPA)), the marker candidates were evaluated by the SWATH - MS method. The data obtained by the SWATH - MS method were evaluated by t - test and Mann - Whitney U test for pre - and post - treatment comparison using data from 47 patients before treatment (31 with MPA and 16 with GPA) and 26 patients after treatment (17 with MPA and 9 with GPA), and the data of 25 patients (16 with MPA and 9 with GPA) with both pre - and post - treatment data were evaluated by Wilcoxon's signed - rank test. As a result, 13 markers were obtained (see Table 3 below).

[0066] (2) Comprehensive proteomic analysis <Specimen pretreatment 1> In a general method for performing comprehensive proteomic analysis using plasma, major proteins are removed from the plasma. This removes major proteins such as albumin and immunoglobulins that account for most of the proteins in the plasma, enabling analysis of proteins that are disease markers and are present in extremely low amounts. In this study, from 10 μL of plasma, major proteins were removed using an antibody - bead spin column, the resulting proteins were recovered, and protein quantification (BCA Protein Assay) was performed.

[0067] <Pretreatment of Sample 2> 20 μg of the protein obtained in Sample Pretreatment 1 was added to a solution of 6 M urea, 50 mM Tris-HCl pH 8.0, and 0.5% sodium deoxycholate, and denaturation treatment was performed at 60 °C for 10 minutes in the presence of 10 mM dithiothreitol. Then, 15 mM iodoacetamide was added, and the treatment was carried out in the dark at room temperature for 1 hour. Next, 1 μg of Trypsin / Lys-C Mix was added, and after reacting at 37 °C for 4 hours, dilution was performed with 50 mM Tris-HCl pH 8.0 so that the urea concentration in the reaction solution became 1 M or less, and protein digestion was carried out overnight at 37 °C. Thereafter, trifluoroacetic acid was added to the reaction solution to stop the reaction. Next, the supernatant obtained by centrifugation (13,000 x G, 10 minutes, room temperature) was collected, 600 μL of ethyl acetate was added thereto and stirred, and the aqueous layer was collected by centrifugation (13,000 x G, 10 minutes, room temperature). Nitrogen gas was blown into the collected aqueous layer to remove the remaining ethyl acetate. Next, peptide purification was performed using MonoSpin C18 (GL Sciences Inc.), and nitrogen gas was blown into the purified peptide eluate to dry it. The dried sample was dissolved in 0.1% formic acid and used for mass spectrometry measurement.

[0068] <Comprehensive Proteomics Analysis by Mass Spectrometry> For the comprehensive proteomics analysis using LC-MS / MS, ekspert nanoLC415 (SCIEX) was used for LC and TripleTOF6600 (SCIEX) was used for MS, and the analysis was performed by the SWATH-MS method.

[0069] The column used in nanoLC was NTCC-360 / 75-30-12 (Nikkato Corporation). Mobile phase A: 0.1% formic acid Mobile phase B: Acetonitrile containing 0.1% formic acid

[0070] The gradient conditions are as shown in Table 2 below.

[0071]

Table 2

[0072] <Measurement by mass spectrometry> For the IDA (Information Dependent Acquisition) measurement conditions, the TOFMS scan range was set to 400 - 1500 m / z, and the TOFMSMS scan range of the generated ions was 100 - 1800 m / z. For SWATH-MS measurement, the measurement was performed with 50 variable windows in the range of 400 - 1500 m / z. The ion library based on IDA measurement was created by ProteinPilot 5.0.1 software (SCIEX), and using the created ion library, SWATH-MS data analysis was performed by PeakView 2.2 MS / MS(ALL) with SWATH Acquisition MicroApp. ver2.0.1.2133 software (SCIEX) to identify proteins and calculate relative quantitative values according to the standard method. The obtained data was subjected to t-test etc. according to the standard method by MarkerView 1.3 software (SCIEX).

[0073] The Mann-Whitney U test and Wilcoxon signed-rank test were performed by GraphPad Prism9 ver9.5.1, and the ROC analysis and multivariate analysis for binary variables (logistic regression analysis) were performed by EZR ver.1.61 etc.

[0074] (3) Conclusions of the test As a result of the above tests, the following became clear.

[0075] (a) OPA1, AACT: When the remission induction treatment is effective, the blood concentrations of these blood proteins decrease.

[0076] (b) HRG, ITPR3, ARHG6, HDHD3, PCYOX, ABCB6, CBG, SPP24, ALS, ITIH1, DHX30: When the remission induction treatment is effective, the blood concentrations of these blood proteins increase.

[0077] (4) Specific data Regarding the decrease in OPA1 (Figure 1), the decrease in AACT (Figure 2), the increase in HRG (Figure 3), the increase in ITPR3 (Figure 4), the increase in ARHG6 (Figure 5), the increase in HDHD3 (Figure 6), the increase in PCYOX (Figure 7), the increase in ABCB6 (Figure 8), the increase in CBG (Figure 9), the increase in SPP24 (Figure 10), the increase in ALS (Figure 11), the increase in ITIH1 (Figure 12), and the increase in DHX30 (Figure 12), the data shown in the comparison graph (a) before and after remission induction treatment of ANCA-associated vasculitis, which is the basic data for the Mann-Whitney U test, and the data shown in the comparison graph (b) before and after the treatment of a series of specimens, which is the basic data for the Wilcoxon signed-rank test, were extracted as the basic data of the biomarkers used in the detection method or information acquisition method of the present invention.

[0078] Based on these basic data, the results of these tests are shown in Table 3.

[0079]

Table 3

[0080] Furthermore, Table 4 shows the results of ROC analysis for the data before and after remission induction treatment of ANCA-associated vasculitis for each of the above markers.

[0081]

Table 4

[0082] (5) Examination of the usefulness of single markers From the results of the above tests, among the above 13 biomarkers, it was revealed that the decrease in OPA1, the increase in HRG, the increase in ITPR3, or the increase in ARHG6 is a suitable marker alone in the detection method or information acquisition method of the present invention.

[0083] (6) Examination of the usefulness of marker combinations As described above, in the detection method or information acquisition method of the present invention, it is preferable to combine two or more types of biomarkers to perform desired detection or information acquisition.

[0084] The results of performing multivariate analysis (logistic regression analysis) on binary variables using EZR ver. 1.61 are shown in a table or the like below, and particularly suitable combinations are extracted from the results. However, it is not intended to limit the scope of the present invention to such suitable combinations.

[0085] <Analysis for MPA or GPA target> The results of analyzing the data on MPA plasma and the data on GPA plasma together are shown below. This corresponds to the above-mentioned "aspect of examining the effect of remission induction treatment for both MPA and GPA" (ANCA disease activity).

[0086] (a) Examination of combinations of two biomarkers (ANCA disease activity) Table 5 shows the results of ROC analysis of two types of biomarkers.

[0087]

Table 5

[0088] Table 5 discloses the AUC values of the combinations of biomarkers at the intersections of rows and columns (the same applies hereinafter). When combinations with an AUC of 0.840 or more are extracted as suitable "two - combinations"; The combination of decrease in OPA1 and increase in HDHD3; the combination of decrease in OPA1 and increase in ITPR3; the combination of decrease in OPA1 and increase in PCYOX; the combination of decrease in OPA1 and increase in CBG; the combination of decrease in AACT and increase in ITPR3; the combination of decrease in AACT and increase in HDHD3; the combination of increase in ITPR3 and increase in HDHD3; the combination of decrease in AACT and increase in DHX30; the combination of increase in HRG and increase in ITPR3; or the combination of increase in ITPR3 and increase in ITIH1; results.

[0089] (b) Examination of combinations of three biomarkers (ANCA disease activity) Table 6 extracts the main combinations of three biomarkers for ANCA disease activity. "Before > After" in the upper part of Table 6 represents biomarkers indicating low values of treatment effectiveness, and "Before < After" represents biomarkers indicating high values of treatment effectiveness (the same applies hereinafter).

[0090]

Table 6

[0091] From the combinations of three biomarkers related to ANCA disease activity shown in Table 6, when extracting the combination with an AUC of 0.875 (which means 0.88) as the preferred "combination of three": The combination of decrease in OPA1, increase in HDHD3, and increase in HRG; the combination of decrease in OPA1, increase in HDHD3, and increase in CBG; the combination of decrease in OPA1, increase in CBG, and increase in ABCB6; the combination of decrease in OPA1, increase in PCYOX, and increase in HDHD3; the combination of decrease in AACT, increase in HDHD3, and increase in ARHG6; the combination of decrease in AACT, decrease in OPA1, and increase in HDHD3; the combination of decrease in AACT, increase in HDHD3, and increase in DHX30; the combination of decrease in AACT, increase in ITPR3, and increase in HRG; the combination of decrease in AACT, increase in HDHD3, and increase in HRG; the combination of decrease in AACT, increase in HDHD3, and increase in ABCB6; the combination of decrease in AACT, increase in HDHD3, and increase in SPP24; the combination of decrease in AACT, increase in HDHD3, and increase in PCYOX; the combination of decrease in AACT, increase in HDHD3, and increase in CBG; the combination of decrease in AACT, increase in HDHD3, and increase in ITIH1; the combination of decrease in AACT, increase in ITPR3, and increase in CBG; the combination of increase in ITPR3, increase in HDHD3, and increase in PCYOX; the combination of decrease in AACT, increase in HDHD3, and increase in ITPR3; or the combination of decrease in AACT, increase in ITPR3, and increase in DHX30; It becomes as follows.

[0092] (c) Examination of combinations of four biomarkers (ANCA disease activity) Table 7 shows the extraction of the main combinations of four biomarkers for ANCA disease activity.

[0093]

Table 7

[0094] As shown in Table 7, for the combinations of the four biomarkers related to ANCA disease activity, most of the AUC values are 0.90 (or 0.895) or higher. Therefore, it was shown that when the detection method or information acquisition method of the present invention is applied to ANCA disease activity, if the number of biomarker combinations is 4 or more, almost any combination will be a suitable combination.

[0095] <Analysis for MPA> The results of analyzing only the data for MPA plasma are shown below. This corresponds to the above-mentioned "Aspect of examining the effect of remission induction treatment for MPA" (MPA disease activity).

[0096] (a) Examination of combinations of two biomarkers (MPA disease activity) Table 8 shows the results of the ROC analysis of two biomarkers.

[0097]

Table 8

[0098] When extracting combinations with an AUC of 0.850 or higher as suitable "two - biomarker combinations"; The combination of a decrease in OPA1 and an increase in HDHD3; the combination of a decrease in OPA1 and an increase in ITPR3; the combination of a decrease in AACT and an increase in ITPR3; the combination of an increase in HRG and an increase in ITPR3; the combination of an increase in HRG and an increase in HDHD3; the combination of an increase in HRG and an increase in ABCB6; the combination of an increase in HRG and an increase in ITIH1; the combination of an increase in ITPR3 and an increase in HDHD3; the combination of an increase in ITPR3 and an increase in ABCB6; the combination of an increase in ITPR3 and an increase in ITIH1; the combination of an increase in ITPR3 and an increase in DHX30; or the combination of an increase in HDHD3 and an increase in DHX30; results in.

[0099] (b) Examination of combinations of three biomarkers (MPA disease activity) Table 9 shows the combinations with an AUC of 0.890 or higher extracted as the main combinations of three biomarkers for MPA disease activity.

[0100]

Table 9

[0101] When extracting the combinations with an AUC of 0.890 or higher as the preferred "combination of three", Combinations of a decrease in OPA1, an increase in ABCB6, and an increase in HRG; combinations of a decrease in OPA1, an increase in HDHD3, and an increase in HRG; combinations of a decrease in OPA1, an increase in ITPR3, and an increase in DHX30; combinations of a decrease in OPA1, an increase in HDHD3, and an increase in ITPR3; combinations of a decrease in AACT, an increase in ABCB6, and an increase in HRG; combinations of a decrease in AACT, an increase in DHX30, and an increase in HDHD3; combinations of an increase in ITIH1, an increase in ITPR3, and an increase in DHX30; combinations of an increase in ITIH1, an increase in ITPR3, and an increase in ABCB6; combinations of an increase in HDHD3, an increase in HRG, and an increase in DHX30; combinations of an increase in ABCB6, an increase in HRG, and an increase in ITIH1; combinations of an increase in HDHD3, an increase in ITPR3, and an increase in ITIH1; combinations of an increase in ABCB6, an increase in HRG, and an increase in ARHG6; combinations of an increase in ABCB6, an increase in HRG, and an increase in ITPR3; combinations of a decrease in OPA1, an increase in ITPR3, and an increase in ABCB6; combinations of a decrease in OPA1, an increase in ITPR3, and an increase in CBG; combinations of a decrease in OPA1, an increase in ITPR3, and an increase in ARHG6; combinations of a decrease in OPA1, an increase in ITPR3, and an increase in PCYOX; combinations of a decrease in OPA1, an increase in ITPR3, and an increase in SPP24; combinations of a decrease in OPA1, an increase in ITPR3, and an increase in ALS; combinations of a decrease in OPA1, an increase in DHX30, and an increase in HDHD3; combinations of a decrease in OPA1, an increase in HDHD3, and an increase in HRG; combinations of a decrease in OPA1, a decrease in AACT, and an increase in ITPR3; combinations of an increase in ITIH1, an increase in ITPR3, and an increase in HRG; combinations of an increase in ABCB6, an increase in HRG, and an increase in HDHD3; combinations of an increase in HDHD3, an increase in HRG, and an increase in ARHG6; combinations of an increase in HDHD3, an increase in ITPR3, and an increase in ARHG6; or combinations of an increase in HDHD3, an increase in ITPR3, and an increase in PCYOX; resulting in

[0102] (c) Examination of combinations of four biomarkers (MPA disease activity) When examining combinations of four biomarkers for MPA disease activity, the AUC was 0.9 or higher for almost any combination. It was shown that, when applying the detection method or information acquisition method of the present invention to MPA disease activity, if the number of biomarker combinations is four or more, almost any combination is a suitable combination.

[0103] <Analysis for GPA target> The results of analyzing only the data for GPA plasma are shown below. This corresponds to the above-mentioned "Aspect of examining the effect of remission induction treatment for GPA" (GPA disease activity).

[0104] (a) Examination of combinations of two biomarkers (GPA disease activity) Table 10 shows the results of ROC analysis of two types of biomarkers.

[0105]

Table 10

[0106] When extracting combinations with an AUC of 0.850 or higher as suitable "two - combinations"; The combination of a decrease in OPA1 and a decrease in AACT; the combination of a decrease in OPA1 and an increase in PCYOX; the combination of a decrease in OPA1 and an increase in SPP24; the combination of a decrease in OPA1 and an increase in ARHG6; the combination of a decrease in AACT and an increase in ITPR3; the combination of a decrease in AACT and an increase in ARHG6; the combination of a decrease in AACT and an increase in HDHD3; the combination of a decrease in AACT and an increase in PCYOX; the combination of a decrease in AACT and an increase in SPP24; the combination of a decrease in AACT and an increase in ITIH1; the combination of an increase in HRG and an increase in PCYOX; the combination of an increase in ITPR3 and an increase in PCYOX; the combination of an increase in ARHG6 and an increase in PCYOX; the combination of an increase in HDHD3 and an increase in PCYOX; the combination of an increase in ARHG6 and an increase in SPP24; the combination of a decrease in AACT and an increase in HRG; the combination of a decrease in AACT and an increase in ABCB6; the combination of a decrease in AACT and an increase in CBG; the combination of a decrease in AACT and an increase in DHX30; the combination of an increase in HRG and an increase in ARHG6; the combination of an increase in ITPR3 and an increase in ARHG6; the combination of an increase in ARHG6 and an increase in HDHD3; the combination of an increase in ARHG6 and an increase in ABCB6; the combination of an increase in ARHG6 and an increase in CBG; the combination of an increase in ARHG6 and an increase in ALS; the combination of an increase in ARHG6 and an increase in DHX30; the combination of an increase in PCYOX and an increase in ABCB6; the combination of an increase in PCYOX and an increase in CBG; the combination of an increase in PCYOX and an increase in SPP24; the combination of an increase in PCYOX and an increase in ALS; the combination of an increase in PCYOX and an increase in ITIH1; the combination of an increase in PCYOX and an increase in DHX30; the combination of a decrease in OPA1 and an increase in HDHD3; the combination of a decrease in AACT and an increase in ALS; or the combination of an increase in CBG and an increase in SPP24; becomes.

[0107] (c) Examination of combinations of three biomarkers (GPA disease activity) Tables 11-1, 11-2, and 11-3 all extract the main combinations of three biomarkers for GPA disease activity.

[0108]

Table 11-1

[0109]

Table 11-2

[0110] [Table 11-3]

[0111] As shown in Tables 11-1, 11-2, and 11-3, when considering combinations of three biomarkers for GPA disease activity, the AUC was 0.900 or higher for almost all combinations. It was shown that if the number of biomarker combinations is three or more when applying the detection method or information acquisition method of the present invention to GPA disease activity, almost any combination will be a suitable combination.

[0112] [Test Example 2] Correlation with BVAS, a disease activity marker for ANCA-associated vasculitis BVAS is a comprehensive disease activity index for ANCA-associated vasculitis, which is presented as a comprehensive composite score consisting of 56 clinical symptoms for nine organs. As already described, it is used in clinical trials and observational studies, but it is too complicated to be used in daily medical practice. Also, basically, only the "presence / absence" of each symptom is judged, and the severity of each symptom is not considered. Although points are only given when the symptom is considered to be due to ANCA-associated vasculitis, it has been pointed out that the difficult judgment is entrusted to the doctor in charge, lacking objectivity. However, since it is an index based on specific symptoms, if it can be used simply, it should be expected as a reliable index. Here, the importance of further examining the correlation with BVAS for the 13 disease activity markers of ANCA-associated vasculitis found this time is recognized. If a blood biomarker showing a correlation with BVAS is positive, improvement of specific symptoms can be estimated, which will be a more reliable aid in determining the transition from remission induction treatment to remission maintenance treatment. Among the related symptoms of BVAS, "nephritis" is the most clinically important. Therefore, finding the 13 ANCA disease activity markers having a correlation with nephritis is one of the most important implications of these markers.

[0113] The higher the severity of clinical symptoms, the higher the BVAS score. Although the criteria are updated regularly, basically traditional criteria are used. Also, the score is considered to have a certain degree of quantification and order, but it lacks strictness. Therefore, within the same person, a decrease in the score can be said to indicate an improvement in symptoms. However, when performing statistical processing to obtain a general average correlation, for example, if the score is "5", a simple fitting that the symptoms have improved cannot be made. Thus, since the BVAS itself, which is the object of association, has the problem of "limitation of objectivity", an index that is too strongly correlated with the BVAS is considered to have the same problem as the BVAS itself. Therefore, the correlation coefficient (ρ) that should be evaluated as corresponding to the BVAS is a correlation coefficient showing a correlation that is not too strong, specifically about 0.2 < |ρ| ≤ 0.7.

[0114] In the following tests, the correlation between each marker and the BVAS was evaluated according to this criterion, and at the same time, the significance of the difference in the presence of nephritis was evaluated.

[0115] (1) Outline of the test Using the following method, the correlation between the quantitative values of 13 ANCA disease activity markers found in Test Example 1 and the BVAS, and the significance in patients with and without nephritis were evaluated.

[0116] Regarding the correlation with the BVAS, the pre-treatment BVAS value was extracted from the clinical information of the patients, and the correlation with the pre-treatment quantitative values of 13 ANCA disease activity markers obtained in Test Example 1 was evaluated using the Spearman rank correlation coefficient. For the analysis, the data of 50 patients (32 with MPA and 18 with GPA) whose clinical information included the BVAS value were used.

[0117] Next, for the significance test between patients with nephritis symptoms and those without nephritis symptoms, patients with and without nephritis symptoms were classified based on the clinical information of the patients, and using the pre-treatment quantitative values of 13 ANCA disease activity markers obtained in Test Example 1, a significance test was performed using the Brunner-Munzel test for the cases with and without nephritis symptoms. The analysis used the data of 50 patients (32 patients with nephritis and 18 patients without nephritis) whose clinical information of the patients included the clinical symptoms of nephritis.

[0118] (2) Results of the examination of the correlation with BVAS The correlation between the pre-treatment quantitative values of 13 ANCA disease activity markers obtained in Test Example 1 and the pre-treatment BVAS values of the patients was evaluated using the Spearman rank correlation coefficient. The results are shown in Table 12.

[0119]

Table 12

[0120] Here, among the above 13 ANCA disease activity markers, markers with a weak correlation of 0.2 < |ρ| ≤ 0.4 or 0.4 < |ρ| ≤ 0.7 with BVAS and a significance (p-value) of the correlation coefficient of p < 0.05 were evaluated as "markers with a recognized correlation with BVAS".

[0121] Based on this evaluation criterion, the following 7 ANCA disease activity markers were evaluated and recognized as having a correlation with BVAS. (The values in parentheses are ρ and p-values).

[0122] OPA1 (ρ = +0.42, p = 0.002), AACT (ρ = 0.37, p = 0.009), HRG (ρ = -0.39, p = 0.005), ARHG6 (ρ = -0.58, p < 0.001), PCYOX (ρ = -0.39, p = 0.005), ALS (ρ = -0.39, p = 0.006), ITIH1 (ρ = -0.44, p = 0.002)

[0123] For non - identified markers, as a result, no significance of the correlation coefficient (p < 0.05) was observed for all of them.

[0124] (3) Results of the significance evaluation for the presence of nephritis Regarding the significance of the above - mentioned 13 ANCA disease activity markers for the presence of nephritis in ANCA - associated vasculitis patients, an evaluation was performed by the Brunner - Munzel test between patients with nephritis and those without nephritis. The results are shown in Table 13.

[0125]

Table 13

[0126] Here, markers with a p - value less than 0.05 were evaluated and recognized as ANCA disease activity markers with a significant difference for the presence of nephritis.

[0127] As a result, six markers, namely OPA1 (p = 0.033), HRG (p = 0.044), ARHG6 (p = 0.049), PCYOX (p = 0.008), ALS (p < 0.001), ITIH1 (p = 0.021) were evaluated and recognized as ANCA disease activity markers with a significant difference for the presence of nephritis. For the other ANCA disease activity markers, the p - value was greater than 0.05.

Claims

1. In a blood sample of a patient with MPA (microscopic polyangiitis) and / or GPA (granulomatosis with polyangiitis) among ANCA-associated vasculitides undergoing remission induction therapy, the following (1): (1) Decrease in any protein selected from OPA1 and AACT; And the following (2): (2) Increase in any protein selected from HRG, ITPR3, ARHG6, HDHD3, PCYOX, ABCB6, CBG, SPP24, ALS, ITIH1, and DHX30; A detection method for detecting a decrease or increase in one kind of blood protein selected therefrom.

2. The detection method according to claim 1, wherein in the detection method, a decrease in OPA1, an increase in HRG, an increase in ITPR3, or an increase in ARHG6 is detected.

3. A method for obtaining information on treatment effects, wherein a decrease or increase in blood protein detected by the detection method according to claim 1 or 2 is used as an index for determining the effectiveness of remission induction therapy for MPA and / or GPA.

4. In a blood sample of a patient with MPA and / or GPA among ANCA-associated vasculitides undergoing remission induction therapy, the following (1): (1) Decrease in any protein selected from OPA1 and AACT; And the following (2): (2) Increase in any protein selected from HRG, ITPR3, ARHG6, HDHD3, PCYOX, ABCB6, CBG, SPP24, ALS, ITIH1, and DHX30; A detection method for detecting a decrease or increase in two or more kinds of blood proteins selected therefrom.

5. In the detection method, the ANCA-associated vasculitis patient who is the blood sample provider is an MPA patient, and the detection targets are the following combinations of increases and decreases in two kinds of blood proteins: A combination of a decrease in OPA1 and an increase in HDHD3; a combination of a decrease in OPA1 and an increase in ITPR3; a combination of a decrease in AACT and an increase in ITPR3; a combination of an increase in HRG and an increase in ITPR3; a combination of an increase in HRG and an increase in HDHD3; a combination of an increase in HRG and an increase in ABCB6; a combination of an increase in HRG and an increase in ITIH1; a combination of an increase in ITPR3 and an increase in HDHD3; a combination of an increase in ITPR3 and an increase in ABCB6; a combination of an increase in ITPR3 and an increase in ITIH1; a combination of an increase in ITPR3 and an increase in DHX30; or a combination of an increase in HDHD3 and an increase in DHX30; The detection method according to claim 3.

6. In the detection method, the ANCA-related vasculitis patient who is the blood sample provider is an MPA patient, and the detection target is the following combinations of increases and decreases of three types of blood proteins: A combination of a decrease in OPA1, an increase in ABCB6, and an increase in HRG; a combination of a decrease in OPA1, an increase in HDHD3, and an increase in HRG; a combination of a decrease in OPA1, an increase in ITPR3, and an increase in DHX30; a combination of a decrease in OPA1, an increase in HDHD3, and an increase in ITPR3; a combination of a decrease in AACT, an increase in ABCB6, and an increase in HRG; a combination of a decrease in AACT, an increase in DHX30, and an increase in HDHD3; a combination of an increase in ITIH1, an increase in ITPR3, and an increase in DHX30; a combination of an increase in ITIH1, an increase in ITPR3, and an increase in ABCB6; a combination of an increase in HDHD3, an increase in HRG, and an increase in DHX30; a combination of an increase in ABCB6, an increase in HRG, and an increase in ITIH1; a combination of an increase in HDHD3, an increase in ITPR3, and an increase in ITIH1; a combination of an increase in ABCB6, an increase in HRG, and an increase in ARHG6; a combination of an increase in ABCB6, an increase in HRG, and an increase in ITPR3; a combination of a decrease in OPA1, an increase in ITPR3, and an increase in ABCB6; a combination of a decrease in OPA1, an increase in ITPR3, and an increase in CBG; a combination of a decrease in OPA1, an increase in ITPR3, and an increase in ARHG6; a combination of a decrease in OPA1, an increase in ITPR3, and an increase in PCYOX; a combination of a decrease in OPA1, an increase in ITPR3, and an increase in SPP24; a combination of a decrease in OPA1, an increase in ITPR3, and an increase in ALS; a combination of a decrease in OPA1, an increase in DHX30, and an increase in HDHD3; a combination of a decrease in OPA1, an increase in HDHD3, and an increase in HRG; a combination of a decrease in OPA1, a decrease in AACT, and an increase in ITPR3; a combination of an increase in ITIH1, an increase in ITPR3, and an increase in HRG; a combination of an increase in ABCB6, an increase in HRG, and an increase in HDHD3; a combination of an increase in HDHD3, an increase in HRG, and an increase in ARHG6; a combination of an increase in HDHD3, an increase in ITPR3, and an increase in ARHG6; or a combination of an increase in HDHD3, an increase in ITPR3, and an increase in PCYOX; The detection method according to claim 3, wherein the combination is as described above.

7. In the detection method according to claim 3, the ANCA-related vasculitis patient who is the blood sample provider is an MPA patient, and the number of types of increases and decreases of blood proteins selected as the detection target is four.

8. In the detection method, the ANCA-related vasculitis patient who is the blood sample provider is a GPA patient, and the detection target is the following combinations of increases and decreases of two types of blood proteins: The combination of a decrease in OPA1 and a decrease in AACT; the combination of a decrease in OPA1 and an increase in PCYOX; the combination of a decrease in OPA1 and an increase in SPP24; the combination of a decrease in OPA1 and an increase in ARHG6; the combination of a decrease in AACT and an increase in ITPR3; the combination of a decrease in AACT and an increase in ARHG6; the combination of a decrease in AACT and an increase in HDHD3; the combination of a decrease in AACT and an increase in PCYOX; the combination of a decrease in AACT and an increase in SPP24; the combination of a decrease in AACT and an increase in ITIH1; the combination of an increase in HRG and an increase in PCYOX; the combination of an increase in ITPR3 and an increase in PCYOX; the combination of an increase in ARHG6 and an increase in PCYOX; the combination of an increase in HDHD3 and an increase in PCYOX; the combination of an increase in ARHG6 and an increase in SPP24; the combination of a decrease in AACT and an increase in HRG; the combination of a decrease in AACT and an increase in ABCB6; the combination of a decrease in AACT and an increase in CBG; the combination of a decrease in AACT and an increase in DHX30; the combination of an increase in HRG and an increase in ARHG6; the combination of an increase in ITPR3 and an increase in ARHG6; the combination of an increase in ARHG6 and an increase in HDHD3; the combination of an increase in ARHG6 and an increase in ABCB6; the combination of an increase in ARHG6 and an increase in CBG; the combination of an increase in ARHG6 and an increase in ALS; the combination of an increase in ARHG6 and an increase in DHX30; the combination of an increase in PCYOX and an increase in ABCB6; the combination of an increase in PCYOX and an increase in CBG; the combination of an increase in PCYOX and an increase in SPP24; the combination of an increase in PCYOX and an increase in ALS; the combination of an increase in PCYOX and an increase in ITIH1; the combination of an increase in PCYOX and an increase in DHX30; the combination of a decrease in OPA1 and an increase in HDHD3; the combination of a decrease in AACT and an increase in ALS; or the combination of an increase in CBG and an increase in SPP24; The detection method according to claim 3, which is as described above.

9. In the detection method, the ANCA - associated vasculitis patient who is the blood sample provider is a GPA patient, and the number of types of increases and decreases in blood proteins selected as the detection targets is 3. The detection method according to claim 3.

10. In the detection method, the ANCA - associated vasculitis patient who is the blood sample provider is an MPA patient or a GPA patient, and the detection targets are the following combinations of increases and decreases in two types of blood proteins: A combination of a decrease in OPA1 and an increase in HDHD3; a combination of a decrease in OPA1 and an increase in ITPR3; a combination of a decrease in OPA1 and an increase in PCYOX; a combination of a decrease in OPA1 and an increase in CBG; a combination of a decrease in AACT and an increase in ITPR3; a combination of a decrease in AACT and an increase in HDHD3; a combination of an increase in ITPR3 and an increase in HDHD3; a combination of a decrease in AACT and an increase in DHX30; a combination of an increase in HRG and an increase in ITPR3; or a combination of an increase in ITPR3 and an increase in ITIH1; The detection method according to claim 3.

11. In the method for obtaining information regarding the treatment effect, the ANCA-associated vasculitis patient who is the blood sample provider is an MPA patient or a GPA patient, and the detection target is a combination of increases and decreases in the following three types of blood proteins: A combination of a decrease in OPA1, an increase in HDHD3, and an increase in HRG; a combination of a decrease in OPA1, an increase in HDHD3, and an increase in CBG; a combination of a decrease in OPA1, an increase in CBG, and an increase in ABCB6; a combination of a decrease in OPA1, an increase in PCYOX, and an increase in HDHD3; a combination of a decrease in AACT, an increase in HDHD3, and an increase in ARHG6; a combination of a decrease in AACT, a decrease in OPA1, and an increase in HDHD3; a combination of a decrease in AACT, an increase in HDHD3, and an increase in DHX30; a combination of a decrease in AACT, an increase in ITPR3, and an increase in HRG; a combination of a decrease in AACT, an increase in HDHD3, and an increase in HRG; a combination of a decrease in AACT, an increase in HDHD3, and an increase in ABCB6; a combination of a decrease in AACT, an increase in HDHD3, and an increase in SPP24; a combination of a decrease in AACT, an increase in HDHD3, and an increase in PCYOX; a combination of a decrease in AACT, an increase in HDHD3, and an increase in CBG; a combination of a decrease in AACT, an increase in HDHD3, and an increase in ITIH1; a combination of a decrease in AACT, an increase in ITPR3, and an increase in CBG; a combination of an increase in ITPR3, an increase in HDHD3, and an increase in PCYOX; a combination of a decrease in AACT, an increase in HDHD3, and an increase in ITPR3; or a combination of a decrease in AACT, an increase in ITPR3, and an increase in DHX30; The detection method according to claim 3.

12. In the detection method, the ANCA-associated vasculitis patient who is the blood sample provider is an MPA patient or a GPA patient, and the number of types of increases and decreases in the blood proteins selected as the detection target is 4. The detection method according to claim 3.

13. A method for obtaining information on treatment efficacy, which uses a decrease or increase in blood protein detected by the detection method according to any one of claims 4 to 12 as an indicator for determining the efficacy of remission induction treatment for MPA and / or GPA.

14. In a blood specimen of a patient with MPA and / or GPA among ANCA-associated vasculitis patients undergoing remission induction treatment, the following (1): (1) A decrease in any protein selected from OPA1 and AACT; And the following (2): (2) An increase in any protein selected from HRG, ARHG6, PCYOX, ALS, and ITIH1; A detection method for detecting a decrease or increase in one kind of blood protein selected therefrom.

15. The detection method according to claim 14, wherein in the detection method, a decrease in OPA1, an increase in HRG, or an increase in ARHG6 is detected.

16. A method for obtaining information on treatment efficacy, which uses a decrease or increase in blood protein detected by the detection method according to claim 14 or 15 as an indicator for determining the efficacy correlated with the Birmingham Vasculitis Activity Score (BVAS) of remission induction treatment for MPA and / or GPA.

17. In a blood specimen of a patient with MPA and / or GPA among ANCA-associated vasculitis patients undergoing remission induction treatment, the following (1): (1) A decrease in any protein selected from OPA1 and AACT; And the following (2): (2) An increase in any protein selected from HRG, ARHG6, PCYOX, ALS, and ITIH1; A detection method for detecting a decrease or increase in two or more kinds of middle proteins selected therefrom.

18. The detection method according to claim 17, wherein the ANCA-associated vasculitis patient who is the blood specimen provider is an MPA patient, and the detection target is a combination of an increase in HRG and an increase in ITIH1.

19. In the detection method, the ANCA-associated vasculitis patient who is the blood specimen provider is a GPA patient, and the detection target is a combination of increases and decreases in the following two kinds of blood proteins: A combination of a decrease in OPA1 and a decrease in AACT; a combination of a decrease in OPA1 and an increase in PCYOX; a combination of a decrease in OPA1 and an increase in ARHG6; a combination of a decrease in AACT and an increase in PCYOX; a combination of a decrease in AACT and an increase in ITIH1; a combination of an increase in HRG and an increase in PCYOX; a combination of an increase in ARHG6 and an increase in PCYOX; a combination of a decrease in AACT and an increase in HRG; a combination of an increase in HRG and an increase in ARHG6; a combination of an increase in ARHG6 and an increase in ALS; a combination of an increase in PCYOX and an increase in ALS; a combination of an increase in PCYOX and an increase in ITIH1; or a combination of a decrease in AACT and an increase in ALS; The detection method according to claim 17.

20. In the detection method, the ANCA-associated vasculitis patient who is the blood specimen provider is an MPA patient or a GPA patient, and the detection target is a combination of a decrease in OPA1 and an increase in PCYOX. The detection method according to claim 17.

21. Using the decrease or increase in blood proteins detected by the detection method according to any one of claims 17 - 20 as an index for the effectiveness judgment correlated with the Birmingham Vasculitis Activity Score (BVAS) of remission induction treatment for MPA and / or GPA. A method for obtaining information regarding treatment efficacy.

22. In the blood specimens of patients with MPA and / or GPA nephritis among ANCA-associated vasculitis patients undergoing remission induction treatment, the following (1): (1) A decrease in OPA1; And the following (2): (2) An increase in any protein selected from HRG, ARHG6, PCYOX, ALS, and ITIH1; A detection method for detecting a decrease or increase in one kind of blood protein selected therefrom.

23. In the detection method, detecting a decrease in OPA1, an increase in HRG, or an increase in ARHG6. The detection method according to claim 22.

24. Using the decrease or increase in blood proteins detected by the detection method according to claim 22 or 23 as an index for the effectiveness judgment of remission induction treatment in cases with MPA and / or GPA nephritis. A method for obtaining information regarding treatment efficacy.

25. In the blood specimens of patients with MPA and / or GPA nephritis among ANCA-associated vasculitis patients undergoing remission induction treatment, the following (1): (1) A decrease in OPA1; And the following (2): (2) An increase in any protein selected from HRG, ARHG6, PCYOX, ALS, and ITIH1; A detection method for detecting a decrease or increase in two or more blood proteins selected from

26. In the detection method, the ANCA-associated vasculitis patient who is the blood sample provider is an MPA patient, and the detection target is a combination of an increase in HRG and an increase in ITIH1. The detection method according to claim 25.

27. In the detection method, the ANCA-associated vasculitis patient who is the blood sample provider is a GPA patient, and the detection target is a combination of increases and decreases in the following two blood proteins: A combination of a decrease in OPA1 and an increase in PCYOX; a combination of a decrease in OPA1 and an increase in ARHG6; a combination of an increase in HRG and an increase in PCYOX; a combination of an increase in ARHG6 and an increase in PCYOX; a combination of an increase in HRG and an increase in ARHG6; a combination of an increase in ARHG6 and an increase in ALS; a combination of an increase in PCYOX and an increase in ALS; or a combination of an increase in PCYOX and an increase in ITIH1; The detection method according to claim 25.

28. In the detection method, the ANCA-associated vasculitis patient who is the blood sample provider is an MPA patient or a GPA patient, and the detection target is a combination of a decrease in OPA1 and an increase in PCYOX. The detection method according to claim 25.

29. A method for obtaining information on treatment effects, wherein a decrease or increase in blood proteins detected by the detection method according to any one of claims 25 to 28 is used as an indicator for judging the effectiveness of remission induction treatment for MPA and / or GPA.

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