Diagnostic or prognostic factors for relapsing-remitting multiple sclerosis

Abstract

The invention provides a method of detecting or predicting a relapse of multiple sclerosis in an individual having a form of multiple sclerosis, comprising: (a) providing a blood sample of the individual; (b) testing the blood sample to determine a protein activity or protein level, wherein the protein is Factor VIII, von Willebrand Factor, or Protein C; and (c) detecting or predicting a relapse of multiple sclerosis in the individual if the protein activity or protein level is elevated compared to the protein activity or protein level in an individual not having the form of multiple sclerosis and the patient's own baseline value. The invention also provides a method of treating an individual having multiple sclerosis who is experiencing a relapse or is predicted to experience a relapse, comprising treating the individual by administering a dose of a steroid or an anticoagulant compound effective to reduce symptoms of multiple sclerosis.

Description

[0001] This application is a divisional application of Chinese patent application No. 201780040017.1 (PCT / US2017 / 040445), filed on June 30, 2017, entitled "Diagnostic or predictive factors for relapsing-remitting multiple sclerosis". Technical Field

[0002] The disclosure of this application pertains to the fields of medicine and pharmaceuticals, and more specifically to the field of multiple sclerosis. Background Technology

[0003] Multiple sclerosis, or MS, is an autoimmune disease that affects the central nervous system. MS is a disease of unknown cause, with a prolonged course involving many remissions and relapses. Some people may live with MS for many years without experiencing severe symptoms. Others may lose their abilities quickly. It is unclear why the course of the disease varies so much. However, most people with MS experience periodic relapses, also known as flare-ups, exacerbations, or attacks. These can be mild or severe. Symptoms can include muscle weakness, visual disturbances, balance problems, memory loss, and / or loss of bowel or bladder control.

[0004] Currently, medications used to treat multiple sclerosis can be divided into two groups: those for symptom management and those for altering the course of multiple sclerosis. Medications for symptom management include steroids, such as glucocorticoids.

[0005] However, there are currently no known methods for predicting or diagnosing whether a patient with multiple sclerosis is about to experience a relapse. If a patient does experience a relapse, there are no known methods for predicting or diagnosing the likelihood of recovery from the relapse with standard symptom treatment. Such prediction or diagnosis would help patients and doctors monitor the progression of the relapse and prevent it from becoming a severe relapse. Summary of the Invention

[0006] Various implementations include methods for diagnosing susceptibility to relapse of acute severe multiple sclerosis (MS) in an individual, including obtaining a sample from the individual, analyzing the sample to determine the presence or absence of one or more biomarkers associated with acute severe MS relative to healthy subjects and / or the individual's baseline level, and diagnosing susceptibility to relapse of acute severe MS in the individual based on the presence of one or more biomarkers. In another implementation, the one or more biomarkers include elevated factor VIII coagulation activity. In another implementation, the one or more biomarkers include elevated von Willebrand factor (VWF) antigen levels. In another implementation, the presence of one or more biomarkers is associated with an increased risk of disability progression. In yet another implementation, the individual's multiple sclerosis is in remission.

[0007] Other embodiments include methods for determining the risk of relapse of multiple sclerosis (MS) in an individual suffering from a form of MS, including obtaining a blood sample from the individual, testing the blood sample to determine protein activity and / or levels, wherein said protein is factor VIII, von Willebrand factor, or protein C; and determining the risk of relapse of MS in the individual if the protein activity and / or level is elevated relative to a baseline of a subject and / or individual not suffering from said form of MS. In another embodiment, said form of MS is relapsing-remitting MS. In another embodiment, the multiple sclerosis in the individual is in remission. In another embodiment, testing the blood sample to determine protein activity or protein levels is performed concurrently with other blood tests, such as partial thromboplastin time (PTT) testing, international normalized ratio (INR) testing, and erythrocyte sedimentation rate (ESR) testing. In another embodiment, blood sample testing is performed at least monthly during the treatment and / or monitoring phases of MS. In another embodiment, elevated factor VIII activity indicates increased weakness and / or sensory impairment. In another embodiment, an individual has elevated factor VIII activity or level when factor VIII level is equal to or greater than 160. In another embodiment, an individual has elevated factor VIII activity or level when factor VIII level is greater than 191. In another embodiment, an individual has elevated factor VIII activity or level when factor VIII level is greater than 200. In another embodiment, an individual has elevated von Willebrand factor level when von Willebrand factor activity is greater than 215. In another embodiment, an individual has elevated von Willebrand factor level when von Willebrand factor level is greater than 214. In another embodiment, the method is used for patients at greater risk of severe relapse. In another embodiment, the method is used for patients at risk of disability due to MS.

[0008] Other embodiments include methods for treating an individual, including detecting and / or predicting relapse of multiple sclerosis (MS) in the individual, and treating the individual by administering a therapeutically effective dose of a steroid and / or anticoagulant compound that effectively relieves MS symptoms. In another embodiment, detecting and / or predicting relapse of MS includes measuring the presence of elevated levels of one or more biomarkers associated with acute severe MS relative to healthy subjects. In yet another embodiment, the method further includes administering disease-modifying treatments and / or agents. In another embodiment, the anticoagulant compound is enoxaparin (LOVENOX), rivaroxaban (XARELTO), dabigatran (PRADAXA), or apixaban (ELIQUIS). In another embodiment, the steroid is a corticosteroid. In another embodiment, the steroid is dexamethasone, prednisone, methylprednisolone, or adrenocorticotropic hormone (ACTHAR). In another embodiment, the anticoagulant compound is Xarelto. In another embodiment, the anticoagulant compound is a heparin derivative. In another embodiment, the anticoagulant compound is Lovenox, Enoxaperin, or heparin. In yet another embodiment, the method includes administering sodium methylprednisolone.

[0009] Various implementations include methods for home and / or hospital diagnosis of relapse of multiple sclerosis (MS) in individuals suffering from one form of MS, including providing a home and / or hospital test kit for factor VIII protein activity or level, providing a blood sample from the patient, testing the factor VIII protein activity or level in the individual's blood sample using the home and / or hospital test kit, and diagnosing relapse of MS in the individual based on a factor VIII protein level or activity that is twice the level and / or baseline value of factor VIII protein activity or activity in individuals not suffering from said form of MS. In another implementation, said form of MS is relapsing-remitting MS. In another implementation, the need for physician evaluation is determined based on the blood sample test results. In another implementation, the need for physician evaluation is determined if the factor VIII protein level or activity is greater than 160. In another implementation, recovery from MS relapse is determined based on the blood sample test results.

[0010] Other features and advantages of the invention will become clear from the following detailed description, taken in conjunction with the accompanying drawings illustrating various embodiments of the invention. Attached Figure Description

[0011] Figure 1According to the implementation scheme described in this paper, an acute relapse of multiple sclerosis (MS) with slurred speech and arm weakness was depicted. The subjects were women in their 70s with a confirmed diagnosis of MS and were not receiving treatment to change the disease.

[0012] Figure 2 Based on the implementation scheme described in this paper, an acute relapse of gait ataxia and facial paralysis with newly enhanced brainstem lesions was depicted. Subjects were women in their 50s with a confirmed diagnosis of MS and were not receiving disease-modifying treatment after receiving standard methylprednisolone sodium succinate therapy.

[0013] Figure 3 According to the implementation method described in this article, an acute, refractory relapse presenting with leg weakness and sensory loss, which has never been completely eliminated despite prolonged steroid treatment, was depicted. The subjects were women in their 50s undergoing various treatments for their condition.

[0014] Figure 4 According to the implementation scheme described in this paper, acute relapses with improved leg weakness and little improvement were observed. Subjects were men in their 50s with a confirmed diagnosis who were not receiving treatment for disease-altering conditions or had newly enhanced thoracic spinal cord lesions.

[0015] Figure 5 According to the implementation scheme described in this article, an acute recurrence of vertigo and leg weakness with presentation and diagnosis was depicted. Subjects were over 60 years of age and had a history of recurrent leg weakness. Males. Specifically, subjects were not receiving treatment to change their condition when diagnosed with vertigo, and were taking... It relapsed afterward.

[0016] Figure 6 Based on the implementation plan described in this paper, an acute relapse with blurred vision and near-hemiplegia was depicted. The subjects were in their 30s and were currently taking medication. Women.

[0017] Figure 7 Based on the implementation scheme described in this paper, an acute relapse with inability to sit was depicted. Subjects were women in their 50s who were receiving interferon therapy. Improvement with continuous, intermittent high-dose steroids and physical therapy returned to the previous baseline. Factor VIII activity and von Willebrand factor (vWF) antigen normalization were found to be consistent with neurological improvements; high-dose steroid treatment was used for a much longer regimen than recommended by the standard treatment algorithm.

[0018] Figure 8According to the implementation plan described in this paper, an acute severe relapse was depicted in subjects aged 60 years and older. Subjects were women with a confirmed diagnosis of MS who were receiving treatment including interferon during a series of severe acute relapses. Different treatments were administered. Patients responded to prolonged high-dose steroids, as reflected in factor VIII and vWF normalization during relapse and clinical improvement. However, without continued steroids and further hospitalization, this improvement could not be maintained, and the Disability Status Grade (EDSS) progressed from 6 on day 1 to EDSS9 on day 2447.

[0019] Figure 9 According to the implementation plan described in this paper, an acute relapse was depicted in a subject in their 40s. The subject was a woman who was unable to stand and was receiving interferon therapy. Clinical improvement was achieved using extended steroid and physical therapy, as reflected by factor VIII activity and VWF antigen normalization, as well as the switch to Gilenya and pulsatile steroids.

[0020] Figure 10 According to the implementation plan described in this paper, an acute relapse and near-hemiplegia with enhancing thoracic myelopathy was depicted in a subject aged 40 years and older. The subject was currently taking... Women with this condition often experience a prolonged and incomplete recovery process. Subsequent relapses are less severe, characterized by dizziness and gait instability. The EDSS score is 5.5 to 9 before and after the first acute relapse, gradually increasing to 6.5 and worsening to 7.5 during subsequent relapses.

[0021] Detailed Explanation

[0022] All references, publications, and patents cited herein are incorporated herein by reference as if they were all listed. Unless otherwise specified, the technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. Hornyak et al., Introduction to Nanoscience and Nanotechnology, CRC Press (2008); Singleton et al., Dictionary of Microbiology and Molecular Biology, 3rd ed., J. Wiley & Sons (New York, NY 2001); March, Advanced Organic Chemistry Reactions, Mechanisms and Structure, 7th ed., J. Wiley & Sons (New York, NY 2013); and Sambrook and Russell, Molecular Cloning: A Laboratory Manual, 4th ed., ColdSpring Harbor Laboratory Press (Cold Spring Harbor, NY 2012) provide general guidance to those skilled in the art regarding many of the terms used in this application. Those skilled in the art will recognize that many methods and materials similar or equivalent to those described herein can be used in the practice of this invention. In fact, the invention is by no means limited to the methods and materials described herein.

[0023] Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0024] Unless otherwise specified, the following terms used in this application, including those in the specification and claims, have the definitions given below.

[0025] As used herein, the term “multiple sclerosis” or “MS” refers to an autoimmune disease affecting the central nervous system. MS is a disease of unknown etiology with a prolonged course involving multiple remissions and relapses. In some implementations, individuals with multiple sclerosis experience a variety of symptoms, including, but not limited to, diplopia, blindness in one eye, muscle weakness, sensory difficulties, or coordination difficulties. Several forms of multiple sclerosis are known, and the term “multiple sclerosis” or “MS” as used herein implies inclusion of all of these forms. Some common forms of MS are benign multiple sclerosis (benign MS), relapsing-remitting multiple sclerosis (RRMS), secondary progressive multiple sclerosis (SPMS), primary progressive multiple sclerosis (PPMS), and progressive-relapsing multiple sclerosis (PRMS). In relapsing forms of MS, such as, but not limited to, symptoms of relapsing-remitting and progressive-relapsing multiple sclerosis may occur as separate disease episodes referred to as relapse, flare-ups, acute exacerbations, worsening, or sudden onset.

[0026] The term “baseline” or “baseline value” is used in accordance with the various embodiments described herein. As used herein, the term refers to a specific control value for a particular individual under examination or treatment of a disease, such that, for example, when a patient shows signs of recovery or has some symptoms of the disease, a blood value of the patient can be established by a doctor examining the patient, and thus form a baseline or baseline value for said patient or individual, which can subsequently serve as a control value for said same patient or individual in the future.

[0027] As used herein, the terms “relapse,” “onset,” “acute change,” “worsening,” or “sudden onset” refer to an increase in the severity of the disease or any of its signs or symptoms. In some embodiments, a relapse lasts at least 24 hours. In some embodiments, a relapse may be associated with inflammation or demyelination in the brain or spinal cord. In some embodiments, a worsening lasts from days to weeks or months. In some embodiments, a relapse occurs after a period of days, weeks, or months from a previous relapse.

[0028] The term "treatment period" refers to the length of time during which an individual is undergoing treatment for a disease. Similarly, the term "monitoring period" refers to the length of time during which an individual is being monitored for disease progression or recovery. During the treatment or monitoring period, an individual may be under continuous or intermittent supervision by healthcare professionals.

[0029] As used herein, the terms “treatment” and “treating” refer to achieving the desired pharmacological and / or physiological effects. These effects may be preventative in terms of complete or partial prevention of the disease or its symptoms and / or therapeutic in terms of partial or complete cure of the disease and / or adverse effects attributable to the disease. As used herein, “treatment” encompasses any treatment of diseases in mammals (particularly humans) and includes: (a) preventing the occurrence of the disease in subjects who are susceptible to the disease but have not yet been diagnosed with it; (b) suppressing the disease, i.e., stopping its development; and (c) alleviating the disease, i.e., causing the disease to regress.

[0030] In various embodiments, the pharmaceutical compositions according to the invention, for example comprising anticoagulant compounds and / or steroids, can be formulated for delivery via any route of administration. "Route of administration" can refer to any route of administration known in the art, including but not limited to aerosol, nasal, oral, transmucosal, transdermal, or enteral. "Enteric" refers to routes of administration typically associated with injection, including intraorbital, infusion, intra-arterial, intracapsular, intracardiac, intradermal, intramuscular, intraperitoneal, intrapulmonary, intraspinal, intrasternal, intrasheath, intrauterine, intravenous, subarachnoid, subcapsular, subcutaneous, transmucosal, or transtracheal routes. Via enteral routes, the composition can be in the form of a solution or suspension for infusion or injection, or as a lyophilized powder.

[0031] The pharmaceutical compositions according to the invention may also contain any pharmaceutically acceptable carrier. As used herein, “pharmaceutically acceptable carrier” refers to a pharmaceutically acceptable material, composition, or medium relating to carrying or transporting a target compound from one tissue, organ, or part of the body to another tissue, organ, or part of the body. For example, a carrier may be a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, or a combination thereof. Each component of the carrier must be “pharmaceutically acceptable” because it must be compatible with the other components of the formulation. It must also be suitable for contact with any tissue or organ it may come into contact with, meaning it must not carry the risk of toxicity, irritation, allergic reactions, immunogenicity, or any other complications that outweigh its therapeutic benefit.

[0032] The pharmaceutical compositions according to the invention can also be encapsulated, tableted, or prepared in emulsions or syrups for oral administration. Pharmaceutically acceptable solid or liquid carriers may be added to enhance or stabilize the compositions, or to facilitate their preparation. Liquid carriers include syrups, peanut oil, olive oil, glycerin, saline, alcohols, and water. Solid carriers include starch, lactose, calcium sulfate, dihydrate, kaolin, magnesium stearate or stearic acid, talc, pectin, gum arabic, agar, or gelatin. The carrier may also include sustained-release materials, such as glyceryl monostearate or glyceryl distearate, alone or with waxes.

[0033] Pharmaceutical formulations are prepared using conventional pharmaceutical techniques, which, for tablets, involve grinding, mixing, granulation, and compression when necessary; or for hard gelatin capsules, involve grinding, mixing, and filling. When a liquid carrier is used, the formulation will be a syrup, elixir, emulsion, or aqueous or non-aqueous suspension. Such liquid formulations can be administered directly orally (po) or filled into soft gelatin capsules.

[0034] The pharmaceutical compositions according to the invention can be delivered in a therapeutically effective amount. A precise therapeutically effective amount is the concentration of the composition that will produce the most effective result in terms of therapeutic efficacy in a given subject. This concentration will vary depending on various factors, including, but not limited to, the characteristics of the therapeutic compound (including activity, pharmacokinetics, pharmacodynamics, and bioavailability), the physiological condition of the subject (including age, sex, disease type and stage, overall physical condition, responsiveness to a given dose, and type of drug treatment), the nature of one or more pharmaceutically acceptable carriers in the formulation, and the route of administration. Those skilled in the art of clinical and pharmacology will be able to determine the therapeutically effective amount through routine experiments, for example, by monitoring the subject's response to administration of the compound and thus adjusting the dosage.

[0035] As described herein, the inventors have developed a technique for diagnosing or predicting relapses in individuals suffering from a form of multiple sclerosis, according to various embodiments described herein. As further disclosed herein, clinical observations support that a disproportionate number of patients with refractory relapsed multiple sclerosis will have transiently abnormally elevated levels of Factor VIII activity and elevated vWF antigen levels in their blood during the onset and progression of their relapses. Furthermore, personalized, high-dose, and sustained steroid treatment tends to improve clinical function, consistent with the standardization of abnormally elevated Factor VIII activity and vWF antigen levels.

[0036] In another implementation, high levels of vwF antigen, vWF activity, and / or factor VIII activity drive the severity of MS relapse and can be measured peripherally, and treatment strategies that reduce these values ​​improve clinical outcomes.

[0037] In various embodiments, a method for detecting or predicting relapse of multiple sclerosis in an individual suffering from a form of multiple sclerosis is disclosed herein, comprising: (a) providing a blood sample of the individual; (b) testing the blood sample to determine protein activity or protein level, wherein the protein is factor VIII, von Willebrand factor, or protein C; and (c) detecting relapse of multiple sclerosis in the individual if the protein activity or protein level is elevated compared to the protein activity or protein level in an individual not suffering from said form of multiple sclerosis or as a control, the patient's own lowest baseline value. In some of these embodiments, said form of multiple sclerosis is relapsing-remitting multiple sclerosis, with or without secondary progression. In some embodiments, the multiple sclerosis in the individual is in remission. In some embodiments, the blood sample is simultaneously tested with other blood tests to determine protein activity or protein level, said other blood tests such as partial thromboplastin time (PTT) test, international normalized ratio (INR) test, and erythrocyte sedimentation rate (ESR) test. In some of these embodiments, blood tests are performed at least monthly during the treatment and / or monitoring phases of multiple sclerosis. In some embodiments, elevated factor VIII activity indicates increased weakness and / or sensory impairment. In some embodiments, an individual may have elevated factor VIII activity or level when factor VIII levels are equal to or greater than 150, or more than twice the individual's baseline value. In some embodiments, an individual may have elevated factor VIII activity or level when factor VIII levels are equal to or greater than 160, or more than twice the individual's baseline value. In some embodiments, an individual may have elevated factor VIII activity or level when factor VIII levels are equal to or greater than 180, or more than twice the individual's baseline value. In other embodiments, an individual may have elevated factor VIII activity or level when factor VIII levels are equal to or greater than 191, or more than twice the individual's baseline value. In other embodiments, an individual may have elevated factor VIII activity or level when factor VIII levels are equal to or greater than 200, or more than twice the individual's baseline value. In some implementations, an individual may have elevated von Willebrand factor activity when von Willebrand factor activity is greater than 215, or more than twice the individual's baseline value. In some implementations, an individual may have elevated von Willebrand factor levels when von Willebrand factor levels are greater than 214, or more than twice the individual's baseline value. In some implementations, the method for detecting or predicting multiple sclerosis relapse is used in patients at greater risk of severe relapse. In some implementations, the method is used in patients at risk of disability due to multiple sclerosis relapse.

[0038] In another embodiment, factor VIII activity and / or von Willebrand factor antigen levels are examined daily, according to the various embodiments described herein. In another embodiment, factor VIII activity and / or von Willebrand factor antigen levels are examined weekly. Factor VIII activity and / or von Willebrand factor antigen levels are examined monthly. Factor VIII activity and / or von Willebrand factor antigen levels are examined at random intervals.

[0039] In various embodiments, a method for treating an individual with multiple sclerosis who is experiencing or is predicted to experience a relapse is disclosed herein, the method comprising: (a) detecting or predicting a relapse of multiple sclerosis in the individual as described herein; and (b) treating the individual by administering a dose of a steroid compound that is effective in alleviating symptoms of multiple sclerosis.

[0040] In another embodiment, the present invention provides a method for treating multiple sclerosis and / or relapsing multiple sclerosis with secondary progression by detecting relapses of multiple sclerosis and administering a therapeutically effective dose of sodium methylprednisolone.

[0041] In various embodiments, this document discloses a method for home and / or inpatient diagnosis of relapse of multiple sclerosis in an individual suffering from one form of multiple sclerosis, the method comprising: (a) providing a test kit for factor VIII protein activity or level; (b) providing a blood sample from the patient; (c) testing the factor VIII protein activity or level in the individual's blood sample using the test kit; and (d) diagnosing a relapse of multiple sclerosis in the individual based on an elevated level or activity of factor VIII protein compared to the level or activity of factor VIII protein in an individual not suffering from said form of multiple sclerosis. In some of these embodiments, said form of multiple sclerosis is relapsing-remitting multiple sclerosis. In some embodiments, the need for physician evaluation is determined based on the blood sample test results. In some embodiments, the need for physician evaluation is determined if the level or activity of factor VIII protein is greater than 150, or if it is greater than or equal to twice the patient's usual baseline value. In some embodiments, recovery from multiple sclerosis relapse is determined based on the blood sample test results.

[0042] In various embodiments, a method is disclosed herein for determining the responsiveness of a patient experiencing relapses of multiple sclerosis to a drug, the method comprising: (a) providing a blood sample from the patient; (b) testing the blood sample to determine the activity or level of a protein, wherein said protein is factor VIII, von Willebrand factor, and / or protein C; and (c) determining that the patient is responsive to the drug if the protein activity or level is not increased or decreased compared to the protein activity or level of an individual not suffering from multiple sclerosis. In one of these embodiments, the patient has previously been tested to have elevated levels or activity of one or more proteins, said proteins being factor VIII, von Willebrand factor, and / or protein C.

[0043] In various embodiments, a method for determining the effectiveness of multiple sclerosis treatment is disclosed herein, the method comprising: (a) providing a blood sample from an individual undergoing treatment; (b) testing the blood sample to determine the activity or level of a protein, wherein said protein is factor VIII, von Willebrand factor, and / or protein C; and (c) determining that the treatment is effective if the protein activity or level is reduced compared to the individual's protein activity or level before the start of treatment. In some of these embodiments, if the treatment is determined to be ineffective, the individual may be provided with a modified therapy or treatment.

[0044] In various embodiments, a method for selecting subjects for clinical trials or studies is disclosed herein, the method comprising: (a) detecting relapses in multiple sclerosis in a group of subjects using the method described herein; and (b) selecting subjects whose blood samples show elevated protein activity or levels for clinical trials or studies, wherein the protein is factor VIII, von Willebrand factor, and / or protein C.

[0045] Various embodiments include a method for treating multiple sclerosis, the method comprising administering an effective amount of (i) an anticoagulant compound and (ii) a steroid co-administered to a patient requiring such treatment. Some of these embodiments may further include agents that modify the disease. In some of these embodiments, the anticoagulant compound may be enoxaparin (e.g., ), Rivaroxaban (for example, ), Dabigatran (e.g., ) or Apixaban (e.g., In some embodiments, the steroid may be a corticosteroid. In one embodiment, the corticosteroid may be dexamethasone, prednisone, methylprednisolone, or adrenocorticotropic hormone (e.g., In another embodiment, the steroid is sodium methylprednisolone. In one embodiment, the methods described herein can be used for cross-comparison of the efficacy of improved disease-modifying agents. In another embodiment, the present invention provides a method for treating multiple sclerosis, the method comprising administering an effective amount of a heparin derivative to a patient requiring such treatment, said heparin derivative including, but not limited to, Lovenox, Enoxaperin, and heparin.

[0046] Other implementation methods include methods for reducing the number or severity of multiple sclerosis relapses, said methods comprising administering an effective amount of (i) an anticoagulant compound and (ii) a steroid to a patient requiring such treatment. In some of these implementation methods, the anticoagulant compound may be enoxaparin (e.g., ), Rivaroxaban (for example, ), Dabigatran (e.g., ) or Apixaban (e.g., In some embodiments, the steroid may be a corticosteroid. In another embodiment, the steroid is sodium methylprednisolone. In yet another embodiment, the corticosteroid may be dexamethasone, prednisone, methylprednisolone, or adrenocorticotropic hormone (e.g., ).

[0047] In another implementation, the patient is a patient with elevated factor VIII activity who requires treatment; elevated factor VIII activity in an individual is considered to be twice the individual's baseline value.

[0048] In one implementation, factor VIII activity is considered normal when it is between 56 and 160, or between 56 and 191, or between 56 and 200. In some implementations, elevated factor VIII activity levels can serve as a warning sign of MS. In some implementations, the patient may benefit from one or more doses of dexamethasone.

[0049] In one implementation, von Willebrand factor activity (also known as ristocetin cofactor or RCF) is considered normal between 51 and 215. An increase in this number, above 215, can serve as a warning sign of MS. In some implementations, the patient may benefit from one or more doses of dexamethasone.

[0050] In one implementation, von Willebrand factor levels (antigen) are considered normal between 52 and 214. If the level is above 214, factor VIII activity is elevated. In some implementations, this can serve as a warning against MS. In some implementations, the patient may benefit from one or more doses of dexamethasone.

[0051] In various implementations, dexamethasone is administered to the patient intravenously (IV) or orally. In another implementation, methylprednisolone sodium succinate is administered to the patient at a dose of 500 mg to 1000 mg daily for 5 to 10 days, or intermittently. In another implementation, the drug dose is given after laboratory and clinical examinations. In one implementation, the IV dose of dexamethasone ranges from 50 mg to 100 mg daily for 3–5 days. In another implementation, laboratory tests for factor VIII and Von Willebrand factor are subsequently repeated. If the results indicate elevated levels of these proteins and the patient remains frail, dexamethasone treatment is repeated. If the patient feels better, but test results still show elevated levels, the dexamethasone dose is reduced or the intervals are lengthened until test results are standardized and the patient shows significant improvement. In some implementations, these “low-dose” dexamethasone pulse therapies are given to the patient weekly or monthly until the patient returns to a stable state and is free of MS symptoms. In some implementations, high doses of dexamethasone may be administered to the patient if they are hospitalized and have a severe form of exacerbation. In one implementation, a high dose of dexamethasone refers to an intravenous administration of 4 mg of dexamethasone every 6 hours for one or more days.

[0052] In one implementation, dexamethasone is used to treat patients with refractory relapse or elevated factor VIII or Von Willebrand factor activity. In one implementation, these patients improve within weeks or months of treatment.

[0053] The present invention also relates to a kit for determining the activity or level of factor VIII, VWf antigen, and / or protein C. The kit can be used to implement the method for diagnosing relapsed multiple sclerosis in individuals according to the present invention. The kit is an assembly of materials or components comprising at least one composition of the present invention. Therefore, in some embodiments, the kit contains a composition comprising the measurement of the activity or level of factor VIII, VWf antigen, and / or protein C, as described above.

[0054] The exact properties of the components configured in the kit of the present invention depend on its intended purpose. For example, some embodiments are configured for the treatment of multiple sclerosis. In one embodiment, the kit is specifically configured for the treatment of mammalian subjects. In another embodiment, the kit is specifically configured for the treatment of human subjects. In many more embodiments, the kit is configured for veterinary applications, treating subjects such as, but not limited to, farm animals, domestic animals, and laboratory animals.

[0055] The kit may include instructions for use. Instructions for use typically include a tangible expression of the techniques used to achieve the desired outcome (such as diagnosing relapse of multiple sclerosis in an individual) by using the kit's components. Optionally, the kit may also contain other useful components, such as diluents, buffers, pharmaceutically acceptable carriers, syringes, catheters, dressing devices, pipettes or measuring tools, bandage materials, or other useful personal items, as will be readily apparent to those skilled in the art.

[0056] Materials or components assembled in the kit can be stored in any convenient and suitable manner to maintain their operability and usability for use by the practitioner. For example, components may be in dissolved, dehydrated, or lyophilized form; they may be provided at room temperature, refrigerated, or frozen temperatures. The components are typically contained in suitable packaging materials. As used herein, the phrase "packaging material" refers to one or more physical structures for containing the contents of the kit (such as the compositions of the present invention). Packaging materials are constructed using known methods, preferably to provide a sterile, uncontaminated environment. The packaging materials used in the kit are those commonly used in the medical field. As used herein, the term "packaging" refers to a suitable solid matrix or material, such as glass, plastic, paper, foil, etc., capable of containing individual kit components. Thus, for example, packaging may be a glass vial containing a suitable amount of the compositions of the present invention for diagnosing relapses of multiple sclerosis. Packaging materials typically have an external label indicating the contents and / or purpose and / or components of the kit.

[0057] Embodiments of this disclosure are further described in the following examples. These examples are merely illustrative and are in no way intended to limit the scope of the claimed invention. Detailed Implementation

[0058] Example 1

[0059] Factor VIII activity

[0060] Factor VIII is expressed in the blood-brain barrier. It is a marker for brain endothelial cells and for the integrity of the blood-brain barrier. Previous studies have shown that thrombin is activated in multiple sclerosis plaques and that thrombin inhibition may be useful for recovery from multiple sclerosis exacerbations in animal models. This process also involves cell signaling, direct fibrin deposition effects, and microglial effects. In one embodiment, this paper discloses that elevated factor VIII activity may predict an appropriate subgroup of MS patients who may benefit from thrombin inhibition during recovery from multiple sclerosis exacerbations.

[0061] In some implementations, factor VIII activity is not consistently high in individuals with a high Extended Disability Status Scale (EDSS). In one implementation, fluctuations may occur parallel to the patient's disease course. Factor VIII activity of 160 or higher is associated with approximately 99% of multiple sclerosis exacerbations, manifesting as symptoms such as acute, sudden onset of limb weakness, sensory loss, or progressive, persistent loss of physical function and vision. In some implementations, fluctuations in increased factor VIII activity may indicate a treatable period of multiple sclerosis exacerbation.

[0062] It should be noted that not all clinical deterioration and not all deterioration detected by magnetic resonance imaging (MRI) is associated with increased factor VIII activity. However, in one implementation, patients with more severe deterioration are more likely to have increased factor VIII activity that may persist for several months. In one implementation, this is seen through symptoms such as gait problems, increased limb stiffness, or possible spinal cord fluctuations.

[0063] In one implementation, when treated with one or more doses of steroids, the elevated factor VIII activity during exacerbations returns to normal. In another implementation, randomized factor VIII activity testing may be correlated with the extent of multiple sclerosis or multiple sclerosis treatment.

[0064] Example 2

[0065] Association between Factor VIII activity and deterioration

[0066] The inventors have established an association between increased factor VIII activity over time and the worsening of MS. In one embodiment, the invention provides that increased activity is associated with slow-to-recovery relapses in multiple sclerosis. In one embodiment, increased activity is associated with the worsening of spinal multiple sclerosis. In another embodiment, a patient is diagnosed with elevated factor VIII activity and is treated with... When treated with steroids, factor VIII activity returns to normal.

[0067] The various methods and techniques described above provide multiple ways of carrying out the present invention. It will be understood, of course, that not all of the stated objectives or advantages are necessarily achieved according to any particular embodiment described herein. Therefore, for example, those skilled in the art will recognize that the methods can be carried out in a manner that achieves or optimizes one or more advantages taught herein, rather than necessarily achieving other objectives or advantages that may be taught or proposed herein. Various advantageous or disadvantageous alternatives are mentioned herein. It will be understood that some preferred embodiments specifically include one, another, or several advantageous features, while others specifically exclude one, another, or several disadvantageous features, while still others specifically reduce existing disadvantageous features by including one, another, or several advantageous features.

[0068] Furthermore, those skilled in the art will recognize the applicability of various features from different embodiments. Similarly, the various elements, features, and steps discussed above, as well as other known equivalents for each such element, feature, or step, can be mixed and matched by those skilled in the art to perform the methods according to the principles described herein. Among the various elements, features, and steps, some will be deliberately included and some will be deliberately excluded in different embodiments.

[0069] Although the invention has been disclosed in certain embodiments and examples, those skilled in the art will understand that embodiments of the invention extend beyond the specifically disclosed embodiments to other alternative embodiments and / or uses, modifications and equivalents thereof.

[0070] Numerous modifications and alternatives have been disclosed in embodiments of the invention. Many more modifications and alternatives will be apparent to those skilled in the art. These modifications are not limiting, but rather selections of components relating to the compositions of the invention and the diseases and other clinical conditions for which they can be diagnosed, prognosed, or treated. Various embodiments of the invention may specifically include or exclude any of these modifications or elements.

[0071] In some embodiments, the figures used to describe and claim certain embodiments of the invention, representing amounts of components, properties (such as concentrations), reaction conditions, etc., are understood to be modified in some cases by the term "about". Therefore, in some embodiments, the numerical parameters listed in the written description and appended claims are approximations that can be varied depending on the desired properties sought to be obtained through a particular embodiment. In some embodiments, numerical parameters should be interpreted based on the significant figures stated and by applying conventional rounding techniques. Although the ranges of numbers and parameters listing a broad range of some embodiments of the invention are approximations, the values ​​listed in specific embodiments of the invention are stated as precisely as possible. The numerical values ​​presented in some embodiments of the invention may contain some errors necessarily caused by the standard deviation found in the respective test measurements.

[0072] In some embodiments, the terms “a,” “an,” and “the,” and similar designations used in the description of particular embodiments of the invention (particularly in some of the following claims) may be interpreted to cover both singular and plural forms. Descriptions of numerical ranges herein are intended only as a shorthand method for individually referring to each separate value falling within the range. Each individual value is incorporated into the specification as if it were described separately herein, unless otherwise indicated herein. All methods described herein may be performed in any suitable order unless otherwise indicated or otherwise obviously contradicted. Any use of illustrative language (e.g., “as”) provided with respect to certain embodiments herein is intended only to better illustrate the invention and is not a limitation on the scope of the invention as otherwise claimed. No language in the specification should be construed as indicating that any unclaimed element is necessary for the implementation of the invention.

[0073] The grouping of alternative elements or embodiments of the invention disclosed herein is not to be construed as limiting. Each member of a group may be mentioned and claimed individually or in any combination with other members of groups or other elements found herein. For convenience and / or patentability reasons, one or more members of a group may be included in or excluded from one group. Where any such inclusion or deletion occurs, it is assumed that the specification herein contains the group so modified, and therefore satisfies the written description of all Markush groups used in the appended claims.

[0074] Preferred embodiments of the invention are described herein, including the best mode known to the inventors for carrying out the invention. Changes to these preferred embodiments will become apparent to those skilled in the art upon reading the preceding description. It is understood that those skilled in the art can use these changes as appropriate, and that the invention can be practiced according to other embodiments specifically described herein. Therefore, many embodiments of the invention include all changes and equivalents to the subject matter described in the appended claims as permitted by applicable law. Furthermore, the invention includes any combination of the foregoing elements in all its possible variations, unless otherwise indicated herein or otherwise clearly contradicted.

[0075] Furthermore, various references to patents and printed publications are made throughout the specification. Each of the above-cited references and printed publications is included separately in this document as cited.

[0076] Finally, it is understood that the embodiments of the invention disclosed herein are an illustration of the principles of the invention. Other modifications may be used within the scope of the invention. Therefore, for example, but not limited to, alternative configurations of the invention may be used in accordance with the teachings herein. Thus, embodiments of the invention are not limited to those precisely shown and described.

Claims

1. Use of a composition for determining the protein activity and / or level of factor VIII antigen in the preparation of a kit for diagnosing susceptibility to relapse in relapsing-remitting multiple sclerosis in an individual, said kit comprising an instruction manual, wherein said instruction manual includes information regarding the following steps: Obtain an individual's blood sample; The blood samples were analyzed to determine the protein activity and / or level of factor VIII antigen; and If protein activity and / or levels are elevated relative to baseline in subjects without MS and / or in the individuals, then the risk of MS relapse in the individual is determined.

2. The use of claim 1, wherein the multiple sclerosis in the individual is in remission.

3. The use of claim 1, wherein the specification includes information for determining the blood sample test for protein activity or protein level to be performed simultaneously with other blood tests.

4. The use of claim 3, wherein the other blood test includes partial thromboplastin time test, international normalized ratio test, and erythrocyte sedimentation rate test.

5. The use of claim 3 or 4, wherein the specification includes information that blood sample testing is performed at least monthly during the treatment and / or monitoring period of MS.

6. The use of claim 1, wherein the specification includes information that elevated factor VIII activity indicates increased weakness and / or sensory impairment.

7. The use of claim 1, wherein the specification includes information that an individual has elevated factor VIII activity or level when factor VIII level is equal to or greater than 160.

8. The use of claim 1, wherein the specification includes information that when the factor VIII level is greater than 191, the individual has elevated factor VIII activity or level.

9. The use of claim 1, wherein the specification includes information that an individual has elevated factor VIII activity or level when the factor VIII level is greater than 200.

10. The use of claim 1, wherein the specification includes information indicating that the kit is used in patients at greater risk of relapse.

11. The use of claim 1, wherein the kit is for an individual at risk of disability due to MS relapse.

12. The use of claim 1, wherein the kit is used for home and / or hospitalized diagnosis of relapse of relapsing-remitting multiple sclerosis in an individual, and wherein the protein is factor VIII, and the diagnosis of relapse of multiple sclerosis in an individual is based on an elevated level or activity of factor VIII protein compared to the activity or level of factor VIII protein in an individual without MS.

13. Use of a combination of steroids and anticoagulants in the preparation of a medicament for treating relapse of relapsing-remitting multiple sclerosis in an individual, wherein the individual has elevated factor VIII antigen levels and / or activity relative to a subject who has not previously had relapsing-remitting multiple sclerosis or the individual’s baseline.

14. The use of claim 13, wherein the anticoagulant compound is enoxaparin, rivaroxaban, dabigatran, or epipixaban.

15. The use of claim 13, wherein the steroid is a corticosteroid.

16. The use of claim 13, wherein the steroid is dexamethasone, prednisone, methylprednisolone, or adrenocorticotropic hormone.

17. The use of claim 13, wherein the anticoagulant compound is Xarelto.

18. The use of claim 13, wherein the anticoagulant compound is a heparin derivative.

19. The use of claim 13, wherein the anticoagulant compound is Lovenox, Enoxaperin, or heparin.

20. The use of claim 13, including the application of sodium methylprednisolone.

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