Fetuin-a for treating or preventing pathological inflammations

Abstract

The present invention relates to Fetuin-A for use in a method for treating or preventing a pathological inflammation in a patient, wherein the patient is preferably characterized by having a blood serum level of Fetuin-A below a non-pathological blood serum level, and / or a blood serum level of tumor necrosis factor alpha (TNF-α) above the average blood serum level found in the healthy population.

Description

[0001] Fetuin-A for Treating or Preventing Pathological Inflammations

[0002] The present invention refers to the use of Fetuin-A (alpha-2-HS-glycoprotein) in the treatment of inflammations. Thus, the present invention relates to Fetuin-A for use in a method for treating or preventing a pathological inflammation in a patient, wherein the patient is preferably characterized by having a blood serum level of Fetuin-A below a non-pathological blood serum level, and / or a blood serum level of tumor necrosis factor alpha (TNF-a) above the average blood serum level found in the healthy population.

[0003] Overwhelming immunological reactions are a severe risk for patients. For instance, immunological response to lipopolysaccharide (LPS) occurring from Gram-negative bacteria can even cause death. Exposure to low doses of LPS can already cause severe symptoms. Likewise, sepsis and hypoxia can lead to undesirable and sometimes overwhelming immune responses. Thus, there is a desire to control patients’ immune systems and maintain it at a desirable balance.

[0004] Inflammation (from Latin: inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants (Ferrero-Miliani L, et al.: Chronic inflammation: importance of NOD2 and NALP3 in interleukin-1 beta generation. ClinExpImmunol 147(2) 2007, 227; Chen, LD et al.: Inflammatory responses and inflammation-associated diseases in organs. OncotargetlmpactJ LLC. 9(6), 2017, 7204) and is a protective response involving immune cells, blood vessels, and molecular mediators. The function of inflammation is to eliminate the initial cause of cell injury, clear out necrotic cells and tissues damaged from the original insult and the inflammatory process, and initiate tissue repair. The five cardinal signs are heat, pain, redness, swelling, and loss of function. Inflammation is a generic response, and therefore it is considered as a mechanism of innate immunity, as compared to adaptive immunity, which is specific for each pathogen. (Abbas AB, Lichtman AH (2009). Ch.2 Innate Immunity. In Saunders (Elsevier) (ed.). Basic Immunology. Functions and disorders of the immune system (3rd ed.). ISBN 978-1-4160-4688-2). Too little inflammation could lead to progressive tissue destruction by the harmful stimulus (e.g., bacteria) and compromise the survival of the organism. In contrast, too much inflammation, in the form of chronic inflammation, is associated with various diseases, such as hay fever, periodontal disease, atherosclerosis, and osteoarthritis.

[0005] Inflammation can be classified as either acute or chronic. Acute inflammation is typically understood as the initial response of the body to harmful stimuli and is achieved by the increased movement of plasma and leukocytes (in particular granulocytes) from the blood into the injured tissues. A series of biochemical events propagates and matures the inflammatory response, involving the local vascular system, the immune system, and various cells within the injured tissue. Prolonged inflammation, known as chronic inflammation, leads to a progressive shift in the type of cells present at the site of inflammation, such as mononuclear cells, and is characterized by simultaneous destruction and healing of the tissue from the inflammatory process. Inflammation has also been classified as Type 1 and Type 2 based on the type of cytokines and helper T cells (Th1 and Th2) involved (Berger A (August 2000). "Th1 and Th2 responses: what are they?". BMJ. 321 (7258): 424).

[0006] T helper cells (Th cells) interact with various cytokines. There is a cross regulation between T helper cells of type 1 (Th1 cells) and T helper cells of type 2 (Th2 cells) and vice versa. Th1 cells are known to secrete interferon-gamma (IFN-y) and interleukins (ILs) IL-2 and, in newer nomenclature, IL-12. This may lead to a dominant cellular response. Th1 cells may influence Th2 cells by IFN-y and, in newer nomenclature, IL-12. Th2 cells are known to secrete IL-4, IL-5, IL-6 and IL-10, and, in newer nomenclature, IL-13. This may lead to a dominant humoral response. Th2 cells may influence Th1 cells by IL-4 and, in newer nomenclature, IL-10. In older nomenclature, Th cells may base on cloned T cells. In newer nomenclature, Th cells may base on unseparated Peripheral Blood Mononuclear Cells (PBMCs).

[0007] Inflammation, in particular an overwhelming inflammatory reaction, may significantly influence cytokine secretion that may be influences and controlled by other inherent components. Substantial evidence exists for the detrimental effect of pro- inflammatory cytokines on the cardiovascular system (Schernthaner C, Lichtenauer M, Wernly B, Paar V, Pistulli R, Rohm I, et al.: Multi-biomarker analysis in patients with acute myocardial infarction. Eur J Clin Invest. 2017; 47(9): 638-48). During inflammation, proinflammatory cytokines, such as IL-113. and IL-6, decrease the synthesis of Fetuin-A in the liver. In several body fluids, fluctuations in the levels of C-reactive protein (CRP), tumor necrosis factor alpha (TNF-a), interleukins, S100 proteins, metalloproteinases, angiogenin’s, etc. are observed. Since a different task is carried out by each of these biomarkers, it has been proposed that IBD induces multifarious responses which in turn, may affect the levels of different compounds via feedback mechanisms, consumption, or reprioritization of synthesis. The activation of the innate immune system, even by relatively innocuous stimuli, stimulates the release of several proinflam matory cytokines like TNF that can injure of kill the host (Ombrellino M. et al.: Fetuin-A attenuates TNF synthesis and inflammatory response to carrageenan Shock 15 (2001 ), 181 ).

[0008] While inflammation is reasonable and helps the body under many circumstances, in other conditions, overwhelming inflammatory reactions are detrimental and thus undesired. Pathological inflammation can be acute or chronic pathological inflammation. Such undesired and / or detrimental is a pathological inflammation. There is a large variety of severe pathological conditions that are often associated with pathological inflammation such as, e.g., Parkinson’s Disease, Cirrhosis, Ankylosing Spondylitis, Antiphospholipid Antibody Syndrome, Autoimmune Encephalitis, Chronic Recurrent Multifocal Osteomyelitis, Gout, Henoch-Schoenlein Purpura, Juvenile Dermatomyositis, Juvenile Idiopathic Arthritis, Juvenile Lupus (SLE), Juvenile Scleroderma, Juvenile Vasculitis, Kawasaki Disease, Lupus (Systemic Lupus Erythematosus), Mixed Connective Tissue Disease, Myositis, Poststreptococcal Inflammatory Syndromes, Psoriatic Arthritis, Reactive Arthritis, Rheumatoid Arthritis, Scleroderma, Sjogren's Syndrome, Spondyloarthritis I Spondyloarthropathy, Systemic Juvenile Idiopathic Arthritis, Undifferentiated / mixed Connective Tissue Disease, Uveitis, Vasculitis (from different origins), inflammatory bowel disease, and / or other related diseases.

[0009] Accordingly, it is of high interest to have means on hand that regulate inflammations such as by ameliorating inflammations to non-pathological levels.

[0010] There are several anti-inflammatory compounds (also: anti-inflammatorica, antiphlogistic drugs, or antiphlogistica) in the art. For instance, several non-steroidal anti-inflammatory drugs (NSAIDs). such as, e.g., aspirin, ibuprofen, and naproxen, typically inhibiting cyclooxygenase (COX). However, many pathological immunogenic conditions are not sufficiently or even essentially responding to such compounds. There are acquired resistances and inherent resistances.

[0011] Furthermore, the treatment or prevention by an NSAID I COX inhibitor is often not strong enough to achieve a significant amelioration of pathological inflammations, in particular when these have become chronic pathological inflammations, NSAIDs I COX inhibitors often bear undesired side effects or loose functionality.

[0012] For severe forms of pathological inflammations, often corticosteroids such as cortisone are administered to the patient. In particular when this is continued for a longer time and potentially even as sole treatment, the patient suffers from severe side effects.

[0013] Accordingly, there is still an unmet need for further treatment options for treating and / or preventing pathological inflammation in a patient.

[0014] Surprisingly, it has been found that Fetuin-A can be used independent from the blood serum level as prophylactic and / or therapeutic agent for the treatment of inflammation and its related diseases. Fetuin-A can be used in a method for treating of preventing acute or chronic inflammations, optionally independent from the current level of Fetuin-A in plasma. Fetuin-A is identified as an efficient immune regulator. Surprisingly Fetuin-A can be used for the treatment of acute and chronic inflammations.

[0015] An aspect of the present invention relates to Fetuin-A for use in a method for treating or preventing a pathological inflammation in a patient.

[0016] In other words, the present invention also relates to a method for treating or preventing a pathological inflammation in a patient, wherein the patient is administered with a sufficient amount of Fetuin-A. Inflammations may include acute and chronic inflammations. The present invention refers to Fetuin-A for use in a method for treating or preventing acute or chronic inflammations, independent from the current level of Fetuin-A in plasma / serum.

[0017] Surprisingly, it was found that Fetuin-A may treat and / or prevent inflammation.

[0018] Attenuating pro-inflammatory cytokines was observed. Positive effects of Fetuin-A in lipopolysaccharide-induces (LPS-induced) lung injury were surprisingly found by restoring the lung damage by preventing the immune infiltration, restoring the lung function by reducing the airway resistance. Furthermore, positive effects of Fetuin-A were found in hypoxia-induced lung injury by restoring the lung damage by preventing the immune infiltration and lung alveolar collapse.

[0019] In a preferred embodiment, the patient is characterized by having a blood serum level of Fetuin-A below a non-pathological blood serum level, and / or a blood serum level of tumor necrosis factor alpha (TNF-a) above the average blood serum level found in the healthy population.

[0020] The present invention relates to Fetuin-A for use in a method for treating or preventing a pathological inflammation in a patient, wherein the patient is characterized by having

[0021] (a) a blood serum level of Fetuin-A below a non-pathological blood serum level, and / or

[0022] (b) a blood serum level of tumor necrosis factor alpha (TNF-a) above the average blood serum level found in the healthy population.

[0023] An aspect of the present invention relates to Fetuin-A for use in a method for treating or preventing a pathological inflammation in a patient, wherein the patient is characterized by having

[0024] (a) a blood serum level of Fetuin-A below a non-pathological blood serum level, and

[0025] (b) a blood serum level of tumor necrosis factor alpha (TNF-a) above the average blood serum level found in the healthy population.

[0026] In the context of the present invention, Fetuin-A may be understood in the broadest sense as generally understood in the art. In the context of the present invention, the terms “Fetuin-A”, “Fetuin A”, “alpha2-HS glycoprotein”, “a2-HS glycoprotein”, “AHSG”, “Ahsg”, “a2-HS”, “A2HS”, “AHS” and “HSGA” may be understood interchangeably.

[0027] Tumor necrosis factor alpha (TNF-a) may also be designated as “TNF”, “TNF-alpha”, “TNF alpha”, “tumor necrosis factor-alpha”, “tumor necrosis factor”, “tumor necrosis factor”, “cachexin”, “cachectin”, DIF, TNFA, TNFSF2, or TNLGI F. TNF-a may be understood as an adipokine and as a cytokine. TNF-a may comprise the soluble form and the transmembrane form thereof. Preferably, TNF-a in the context of the present invention refers to the soluble form of TNF-a, which may be soluble in patient’s blood serum. When considering the blood plasma level, the whole TNF-a is considered, including potential glycosylations.

[0028] TNF-a may also include recombinant forms thereof, as far as the patient is under treatment therewith.

[0029] Alternatively or additionally, the patient is characterized by having a TNF-a level in lung tissue that is above the average lung tissue level found in the healthy population.

[0030] Additionally, the patient may optionally be characterized by having a blood serum level of the Interferon-alpha (IFN-a) level above the average blood serum level found in the healthy population.

[0031] Interferon-alpha (IFN-a) may also be designated as “Interferon alfa” (IIIPAC name), “IFN-alpha”; “leucocyte-IFN”, type I interferon”, or “HulFN-alpha-Le”.

[0032] IFN-a may be any subtype thereof such as IFNA1 , IFNA2, IFNA4, IFNA5, IFNA6, IFNA7, IFNA8, IFNA10, IFNA13, IFNA14, IFNA16, IFNA17, and / or IFNA21 , or may be a mixture of two or more or even all thereof. Regarding the blood plasma level, the whole content of IFN-a is considered, thus, the sum of all subtypes thereof. When considering the blood plasma level, the whole IFN-a is considered, including potential glycosylations.

[0033] IFN-a may also include recombinant forms thereof, as far as the patient is under treatment therewith, including interferon alfacon-1 , and synthetically modified forms of IFN-a (e.g. PEGylated forms of IFN-a such as, e.g., PEGylated interferon alfa-2a and / or PEGylated interferon alfa-2b), wherein in case of synthetically modified forms, merely the content of the polypeptide is considered.

[0034] It will be understood that Fetuin-A as well as any other component mentioned herein such as, e.g., an optionally used further anti-inflammatory compound also embraces a pharmaceutically acceptable salt thereof. Such pharmaceutically acceptable salt may for instance comprise a counter ion such as, e.g., sodium, potassium, chloride, ammonium, sulfate, acetate, phosphate, etc.

[0035] The person skilled in the art knows Fetuin-A. Fetuin-A may be of any species. Preferably, Fetuin-A is mammalian or bovine Fetuin-A. Preferably, Fetuin-A is human, mouse, rat, or bovine Fetuin-A. Preferably, Fetuin-A is human Fetuin-A.

[0036] Fetuin-A as used herein may be suitable for being used in a medical / therapeutic context. Fetuin-A may be, but does not necessarily be isolated Fetuin-A. It may optionally be isolated as described in EP Appl. No. 23173323.9. Fetuin-A may also be commercially obtained. It may be obtained from isolation from blood or blood fractions such as plasma or may be obtained by genetic engineering means such as (heterologous) expression. In a preferred embodiment, Fetuin-A may be isolated from human plasma. This may be beneficial in some contexts to obtain optimal compatibility. This may provide foptimal compatibility. Since plasma fractions vary widely in composition, various purification methods for Fetuin-A from human biological fluids may be of interest to make the most effective and complete use of available resources. Fetuin-A may, for instance, be isolated from human plasma Cohn fraction IV such as, e.g., by using a chromatographic method. Likewise, recombinant sources can be used.

[0037] As used herein, “isolating” may be understood interchangeably with “purifying” in the broadest sense as increasing the content of the isolated Fetuin-A in a composition. It does not necessarily be pure. However, preferably, the product of the method comprises at least 25% (w / w), based on the total protein weight, of Fetuin-A. More preferably, the product of the process comprises at least 50% (w / w), even more preferably at least 70% (w / w), even more preferably at least 80% (w / w), in particular at least 90% (w / w), based on the total protein weight, of Fetuin-A.

[0038] Fetuin-A has multiple different functions in the body. Besides being bone stabilizing protein, Fetuin-A also known to involve various other functions such regulation of immune response during the inflammation. Fetuin-A is a heterodimeric plasma glycoprotein containing an A-chain of 282 amino acids and a B-chain of 27 amino acid residues linked by a single inter-disulfide bond. Fetuin-A binds with a plethora of receptors and exhibits multifaceted physiological and pathological functions. It is involved in the regulation of calcium metabolism, osteogenesis, and the insulin signaling pathway. It also acts as an ectopic calcification inhibitor, protease inhibitor, inflammatory mediator, anti-inflammatory partner, atherogenic factor, and adipogenic factor, among other several additional functions. Fetuin-A has also been demonstrated to play an interesting role in the pathogenesis of several disorders (Abede E.C. et al.: The structure, biosynthesis, and biological roles of fetuin-A: A review. Front Cell Dev Biol, 2022).

[0039] Fetuin-A is a negative acute-phase protein with pro- and anti-inflammatory effects on the immune system (Wang H., Sama A. E. (2012): Anti-inflammatory role of fetuin-A in injury and infection. Curr Mol Med 12(5): 625-633). Inhibitory effects on IL and TNF secretion had been found in vivo and in vitro in some contexts (Dziegielewska K. M., Andersen N. A., Saunders N. R. (1998): Modification of macrophage response to lipopolysaccharide by fetuin. Immunol Lett 60(1 ): 31-35; Ombrellino M., Wang H., Yang H., Zhang M., Vishnubhakat J., Frazier A., Scher L. A., Friedman S. G., Tracey K. J. (2001 ): Fetuin, a negative acute phase protein, attenuates TNF synthesis and the innate inflammatory response to carrageenan. Shock 15(3): 181-185). Fetuin-A also has a function as a regulator of the inflammatory response during the course of a severe inflammatory response such as sepsis (Wang H., Sama A. E. (2012): Anti-inflammatory role of fetuin-A in injury and infection. Curr Mol Med 12(5): 625-633). Proinflam matory effects have been reported by Hennige et al. 2008 in a mouse experiment and an in vitro experiment with human monocytic THP-1 cells, a cell line in derivation from an acute monocyte leukaemia. Fetuin-A may be associated with atherosclerosis. Fetuin-A has been shown to carry out various immunologic tasks, including regulation of macrophage- related lipopolysaccharide-triggered opsonization, TNF-a and transforming growth factor beta (TGF-|3) levels. Decreased circulating Fetuin-A levels constrains the activities of several anti-inflammatory mediators, thereby aggravating the inflammatory response. Fetuin-A is one of the inhibitors of calcification in soft tissue and vascular tree (Cakir, H. et al.: Lower Serum Fetuin-A Levels are Associated with a Higher Ten-Year Mortality Risk in Patients with ST-Elevation Myocardial Infarction Arq Bras Cardiol, 11 , 2022, 14).

[0040] Surprisingly, in view of the experimental findings, it was found that Fetuin-A may be used as a beneficial antagonist in type 1 inflammations. Proliferating helper T cells that develop into effector T cells differentiate into two major subtypes of cells known as Th1 and Th2 cells (also known as Type 1 and Type 2 helper T cells (Th), respectively). Th1 helper cells lead to an increased cell-mediated response (primarily by macrophages and cytotoxic T cells), typically against intracellular bacteria and protozoa. They may be triggered by the polarizing cytokine IL-12 and their effector cytokines are IFN-y and IL-2. The main effector cells of Th1 immunity may be macrophages as well as CD8 T cells, IgG B cells, and IFN-y CD4 T cells. The key Th1 transcription factors may be STAT4 and T-bet. IFN-y secreted by CD4 T cells may activate macrophages to phagocytose and digest intracellular bacteria and protozoa. In addition, IFN-y may activate iNOS (inducible nitric oxide synthase) to produce nitric oxide free radicals to directly kill intracellular bacteria and protozoa. Th1 overactivation against autoantigens will cause Type IV or delayed-type hypersensitivity reaction. Tuberculin reaction and Type 1 diabetes belong to this category of autoimmunity (Zhu J, Paul WE (September 2008). "CD4 T cells: fates, functions, and faults". Blood. 112 (5): 1557. doi:10.1182 / blood-2008-05-078154).

[0041] Fetuin-A may suppress the IFN-y synthesis and inhibit in parallel the merpins. Therefore, Fetuin-A is the best therapeutic approach in the treatment of type 1 inflammations. Especially in Multisystem Inflammatory Syndrome in Adults (MIS-A) Fetuin-A is helpful. Multisystem inflammatory syndrome (MIS) is a rare but severe condition initially recognized in children and adolescents (MIS-C) infected with SARS-CoV-2, the virus that causes COVID-19. Like in children, adults who have been infected with SARS-CoV-2 can develop MIS (MIS-A) days to weeks after getting sick with COVID-19. MIS-A is a condition where inflammation occurs in different internal and external body parts like the heart, gastrointestinal tract, skin, or brain. MIS-A is less common than MIS-C. Compared with MIS-C, MIS-A can also be more difficult to distinguish from acute COVID-19. However, like children with MIS-C, adults with MIS-A appear to recover quickly from the most dangerous heart- related complications.

[0042] As used herein, “non-pathological” in the context of blood serum levels may be understood as a blood serum levels of the respective compound that is considered healthy in the art, preferably in a medicinal context.

[0043] As used herein, a blood serum level of Fetuin-A below a non-pathological blood serum level may be a decrease to any extend. In a preferred embodiment, such serum level of Fetuin-A is decreased by at least 1 % by weight, preferably by at least 5% by weight, more preferably by at least 10% by weight, in particular by at least 20% by weight or by at least 50% by weight, referred to the lowest blood serum level considered as non-pathological (i.e. , being a normal range in healthy patients).

[0044] In view of the teaching in scientific publications, the lowest non-pathological blood serum level of Fetuin-A may be 300 pg / mL.

[0045] In view of the teaching in scientific publications, the range serum level of Fetuin-A that is considered as being in the healthy range may be in the range of 300 to 1000 pg / mL. For instance, Abebe et al. (Frontiers in Cell and Developmental Biology, 2022, DOI 10.3389 / fcell.2022.945287) the normal range of Fetuin-A serum levels is 300 to 1000 pg / mL. Such ranges are also confirmed by Li et al. PLoS One, 2011 , 6(2):e16945.

[0046] This is also in line with other prior art documents. Manolakis et al. (World Journal of Gastroenterology, 2017, 23(3):437-446) teach that a normal range of blood serum level of Fetuin-A is approximately 710 pg / mL. Minas et al. (Journal of Chronic Obstructive Pulmonary Disease, 2013, 10:28-34) teaches a control group having an Fetuin-A serum level of approximately 487 pg / mL. These ranges are in the range considered as non-pathological, i.e., in a healthy range. A range far out the normal levels (below 140 mg / mL) was found in a pathological population of coronary heart disease patients as shown in Zissimopoulos et al. (Hel J Nucl Med., 2015, 18, Suppl 1 :147).

[0047] As used herein, a blood serum level of tumor necrosis factor alpha (TNF-a) above the average blood serum level found in the healthy population may be an increase to any extend. In a preferred embodiment, such blood serum level of TNF-a is increased by at least 1 % by weight, preferably by at least 5% by weight, more preferably by at least 10% by weight, in particular by at least 20% by weight or by at least 50% by weight or by at least 75% by weight or by at least 2-fold by weight or by at least 3-fold by weight, referred to the average blood serum level found in the healthy population. It was reported that the level of healthy patients may be in the range of approximately 75 pg / mL (Damas et al., Critical Care Medicine, 1989, 17(10):975- 978.

[0048] As used herein, a blood serum level of interferon-alpha (IFN-a) above the average blood serum level found in the healthy population may be an increase to any extend. In a preferred embodiment, such blood serum level of IFN-a is increased by at least 1 % by weight, preferably by at least 5% by weight, more preferably by at least 10% by weight, in particular by at least 20% by weight or by at least 50% by weight or by at least 75% by weight or by at least 2-fold by weight or by at least 3-fold by weight, referred to the average blood serum level found in the healthy population.

[0049] The average blood serum level found in the healthy population may be considered as being in the range of 42 pg / mL. Contoli et al. (Frontiers in Immunology, 2021 , 12:1 -10, Article 648004) teach a level in healthy patients of 24 to 87 pg / mL with an average in the range of 42 pg / mL.

[0050] As used in the context of the present invention, the term “patient” may be understood in the broadest sense as a subject the Fetuin-A is administered to, irrespective, whether it is a human or an animal and whether clinical symptoms occur or do not occur. Preferably, the patient is a human patient.

[0051] The Fetuin-A (optionally forming part of a pharmaceutical composition) may be administered to the patient by any means.

[0052] In a preferred embodiment, Fetuin-A (optionally forming part of a pharmaceutical composition) is administered via the respiratory tract, preferably via intranasal administration, is injected, preferably injected intravenously (i.v.), intraperitoneally (i.p.), intradermally (i.d.), intraarterially (i.a.), intramuscularly (i.m.), and / or subcutaneously (s.c.), topically, or orally (also perorally, p.o.)

[0053] In a preferred embodiment, the Fetuin-A (optionally forming part of a pharmaceutical composition) is administered via the respiratory tract, in particular via intranasal administration. This may be achieved by any means such as by administering the patient with an aerosol, which droplets contains Fetuin-A. Fetuin-A (optionally forming part of a pharmaceutical composition) may also be injected into the tissue or into a blood vessel via a syringe or a drip. Alternatively, it may also be injected intraperitoneally, or it may be administered orally, nasally, topically or subcutaneously. Exemplarily, the Fetuin-A may be injected intravenously (i.v.), intraperitoneally (i.p.), intradermally (i.d.), intraarterially (i.a.), intramuscularly (i.m.), and / or subcutaneously (s.c.). Alternatively, the Fetuin-A may be taken up orally, e.g., as a powder, a tablet, a pill, a capsule, a chewable capsule, syrup, juice, gel, liquid or paste. Alternatively, Fetuin-A may be taken up nasally (intra nasal) (e.g., as spray or aerosol), percutaneously (e.g., as cream, spray or ointment and / or via a coated plaster) and / or by inhalation (e.g., inhalation of an aerosol or of a spray). It will be understood that the Fetuin-A may be administered locally or systemically.

[0054] Preventing a patient may be understood in the broadest sense as a prophylactic administration of Fetuin-A (optionally forming part of a pharmaceutical composition) to a patient who has or is at risk of developing a pathologic inflammation, independent on whether there are clinical symptoms or not.

[0055] Treating a patient may be understood in the broadest sense as administration of Fetuin-A (optionally forming part of a pharmaceutical composition) to a patient who bears a pathologic inflammation, independent on whether there are clinical symptoms or not.

[0056] Inflammation may occur in virtually each tissue of a patient’s body. In principle, Fetuin-A may be used for treatment of inflammations in any tissue. In a preferred embodiment, the pathological inflammation involves inflammation of lung tissue, in particular is associated with respiratory insufficiency.

[0057] In a preferred embodiment, the pathological inflammation is associated with hypoxia. In a preferred embodiment, the pathological inflammation is associated with hypoxia in the lung.

[0058] In a preferred embodiment, the inflammation is triggered by lipopolysaccharide (LPS). Optionally, LPS may originate from one or more species of Gram-negative bacteria. In a preferred embodiment, the pathological inflammation is triggered by LPS and is at least party located in the lung. In a preferred embodiment, the pathological inflammation is associated with pneumonia. In a preferred embodiment, the pathological inflammation is a chronic pathological inflammation. As generally understood, chronic inflammation is understood as slow, long-term inflammation lasting for prolonged periods. A chronic pathological inflammation typically persists for at least two weeks. In a preferred embodiment, the chronic pathological inflammation persists for at least one month, for at least six months, or for at least one year.

[0059] In a preferred embodiment, the pathological inflammation is at in a late phase of an inflammation. Thus, a downregulation terminating the inflammation may not be sufficiently induced by known means. In a preferred embodiment, the chronic pathological inflammation persisted for at least one month, for at least six months, or for at least one year, from the onset of the inflammation to the treatment.

[0060] Pathological inflammation may or may not be associated with Fetuin-A deficiency. If present, Fetuin-A deficiency may be independent from the cause of the inflammation. Patients suffering from acute or chronic inflammations may be treated or prophylactically treated with the pharmaceutical composition comprising Fetuin-A.

[0061] In a preferred embodiment, the patient is repeatedly administered with Fetuin-A for at least one month, at least two months, or at least three months.

[0062] In a preferred embodiment, the patient bears a chronic pathological inflammation and is repeatedly administered with Fetuin-A for at least one month, at least two months, or at least three months.

[0063] Such administration may follow any administration scheme. The patient may be administered with Fetuin-A once per day, once per week, every two week (biweekly), every three weeks, every month, every two months, or less often than every two months.

[0064] In a preferred embodiment, the patient is repeatedly administered with Fetuin-A by not more often than once per week for a period of at least one, at least two or at least three months. In a preferred embodiment, the patient is repeatedly administered with Fetuin-A by injections of Fetuin-A in a dose range of 1 to 1000 pg / kg body weight at each injection.

[0065] In a preferred embodiment, the patient is injected not more often than once per week for a period of at least one, at least two, or at least three months.

[0066] In a preferred embodiment, the patient is repeatedly administered with Fetuin-A by injections of Fetuin-A in a dose range of 1 to 1000 pg / kg body weight at each injection, wherein the patient is injected no more frequently than every two weeks for at least three months.

[0067] In an alternative preferred embodiment, the pathological inflammation is an acute pathological inflammation.

[0068] Then, the patient may optionally be administered with a bolus dose administration of Fetuin-A. Administration may preferably injection such as by means of a syringe or a drip. Acute pathological inflammation may for instance be or may be associated with sepsis.

[0069] The prevention or treatment of the present invention may be of particular interest for patients who suffer from an inflammation, which does not therapeutically respond to other anti-inflammatory treatments such as other anti-inflammatory compounds.

[0070] In a preferred embodiment, the patient does not therapeutically respond to cyclooxygenase (COX) inhibitors, in particular does not therapeutically respond to non-steroidal anti-inflammatory drugs (NSAIDs), or is a patient with a contraindication for COX inhibitors.

[0071] In a preferred embodiment, the patient is characterized in that:

[0072] (a) it does not therapeutically respond on the current anti-inflammatory drugs;

[0073] (b) the level of Fetuin-A in the blood of the patient is either below or above or at the normal level.

[0074] In a preferred embodiment, the patient is characterized in that:

[0075] (a) no or little response on the current anti-inflammatory drugs; and (b) the level of Fetuin-A in the blood of the patient is either below or above or at the normal level.

[0076] As used herein, the term “does not therapeutically respond” may be understood as not reasonably reacting on such compound to a degree that is therapeutically useful.

[0077] Preferably, an anti-inflammatory compound that does not therapeutically respond does not decrease one or more inflammatory biomarkers to a reasonable degree, preferably does not decrease one or more inflammatory biomarkers by at least 10%, at least 25%, or at least 50%, in the treated areas of the patient’s body (when administered to said areas in therapeutically reasonable doses, preferably according to the user instructions) compared to the levels before treatment with said anti-inflammatory compound.

[0078] In the context of the present invention, the term “anti-inflammatory compound” may be understood in the broadest sense as any compound that is therapeutically suitable for treating or preventing an inflammation. In a preferred embodiment, an anti-inflammatory compound is selected from the group consisting of:

[0079] (a) a non-steroidal anti-inflammatory drug (NSAID), preferably a salicylate (e.g., acetylsalicylic acid), dolobid, salicylic acid, disalcid), a propionic acid derivative (e.g., ibuprofen, dexibuprofen, naproxen, fenoprofen, ketoprofen, dexketoprofen, flurbiprofen, oxaprozin, loxoprofen, pelubiprofen, zaltoprofen, fenbufen, tiaprofenic acid), an acetic acid derivative (e.g., indomethacin, acemetacin, tolmetin, sulindac, etodolac, ketorolac, diclofenac, fenclofenac, aceclofenac, bromfenac, fentiazac, nabumetone), an enolic acid (oxicam) derivative (e.g., piroxicam, meloxicam, tenoxicam, droxicam, lornoxicam, isoxicam, phenylbutazone), an anthranilic acid derivatives (fenamates)), mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid, etofenamate, a selective COX-2 inhibitor (Coxib) (e.g., celecoxib, rofecoxib, valdecoxib, parecoxib, lumiracoxib TGA cancelled registration, etoricoxib, firocoxib), a sulfonanilide (e.g., nimesulide), clonixin, licofelone, or H- harpagide;

[0080] (b) an antileukotriene, preferably ablukast, iralukast, masilukast, montelukast, pobilukast, pranlukast, tipelukast, tomelukast, verlukast, zafirlukast, or Zileuton; (c) an immune selective anti-inflammatory derivative (ImSAID), preferably antibodies binding to at least one pro-inflammatory agent and thereby inactivating the agent, such as anti-TNF-a antibodies, or antibodies binding to at leas one receptor of a pro-inflammatory agent and thereby inactivating the receptor;

[0081] (d) a corticosteroid, preferably cortisol, cortisone, or aldosterone, in particular cortisone;

[0082] (e) an anti-inflammatory compound different from (a) to (d), preferably eugenol, eucalyptol, menthone, or menthol.

[0083] It will be understood that two or more of the above compounds may be combined with each other. It will be further understood that not all compounds are usable for each any administration. For instance, menthol will typically be administered topically and not systemically.

[0084] As generally used herein, inflammatory biomarkers are generally known by the person skilled in the art. For instance, an inflammatory biomarker is selected from the group consisting of:

[0085] (a) one or more interleukins, in particular interleukin-1 (IL-1 ), interleukin-2 (IL-2), interleukin-6 (IL-6), interleukin-8 (IL-8), and / or interleukin-18 (IL-18);

[0086] (b) tumor necrosis factor-alpha (TNF-a);

[0087] (c) C-reactive protein (CRP);

[0088] (d) one or more eicosanoids, in particular one or more prostaglandins (PGLs) and / or one or more leukotrienes; and

[0089] (e) a combination of two or more thereof.

[0090] As generally used herein, an inflammation may preferably be associated in an increased level of one or more of such inflammatory biomarkers. As used herein, an increase may, for instance, be an increase by at least 10%, by at least 25% or by at least 50%, in comparison to a sample from the same tissue of a comparable healthy organism of the same species.

[0091] For example, a COX inhibitor that does not therapeutically respond does not decrease the targeted prostaglandin levels to a reasonable degree, preferably does not reduce the targeted prostaglandin levels by at least 10%, at least 25%, or at least 50%, in the treated areas of the patient’s body (when administered to said areas in therapeutically reasonable doses, preferably according to the user instructions) compared to the levels before treatment with said COX inhibitor. For example, an NSAID that does not therapeutically respond does not decrease the pain level to a recognizable degree. For example, an NSAID that does not therapeutically respond does not decrease the pain level to a bearable level.

[0092] In a preferred embodiment, the patient does not therapeutically respond to antiinflammatory drugs except corticosteroids.

[0093] The pathological inflammation may have any molecular cause and may be associated with any inflammatory biomarkers or other compounds. It was surprisingly found that Fetuin-A is an inhibitor of meprin (in particular, meprin a and [3). Thus, it allows treating and preventing pathological inflammation is associated with an elevated level of meprin alpha and / or meprin beta in the inflammatory site and / or systemically in the patient’s blood plasma.

[0094] In a preferred embodiment, the pathological inflammation is associated with an elevated level of meprin alpha and / or meprin beta in the inflammatory site and / or systemically in the patient’s blood plasma.

[0095] As used herein, meprin may be understood in the broadest sense as generally understood in the art. Meprin may be meprin A (EC 3.4.24.18, also: endopeptidase-2, meprin-a, meprin, N-benzoyl-L-tyrosyl-p-aminobenzoic acid hydrolase, PABA-peptide hydrolase, PPH). Meprin is a metalloprotease. Meprin may be meprin a, meprin (3, or a mixture thereof.

[0096] Early after 1980 Erwin Sterchi and Jidith Bond invention of metalloprotease from renal tissue later popularly known as Meprins got huge scientific attention for their various physiological roles (Beynon, R.J., Shannon, J.D. and Bond, J.S. 1981. Purification and characterization of a metallo-endoproteinase from mouse kidney. Biochem. J. 199, 591-598; Sterchi, E.E., Green, J.R. and Lentze, M.J. 1982. Non- pancreatic hydrolysis of N-benzoyl-L-tyrosyl-p-aminobenzoic acid (PABA-peptide) in the human small intestine. ClinSci. 62, 557-560). Meprin a and [3 are encoded by two different gene from different chromosomes (Gorbea, C.M., Marchand, P., Jiang, W., Copeland, N.G., Gilbert, D.J., Jenkins, N.A.a, Bond, J.S. 1993 Cloning, expression, and chromosomal localization of the mouse meprin [3 subunit. J.Biol.Chem. 268, 21035-21043; Jiang, W., Sadler, P.M., Jenkins, N.A., Gilbert, D.J., Copeland, N. G. and Bond, J.S. (1993) Tissue-specific expression and chromosomal localization of the a subunit of mouse meprin A. J.Biol.Chem. 268, 10380-10385). Meprin a and [3 belongs to zing-dependent metallo-protease of astacin family and the metzicin superfamily (Stocker, W. and Zwilling, R. (1995) Astacin. Methods Enzymol. 248, 305-325). Therefore, they are phylogenetically related to matrix metalloproteinases (MMPs) and ADAMs. Highly glycosylated and complex multi domain meprins expressed as zymogens. Functional activation of merpins achieved by the removal of N-terminal propeptides by substrate specific serine proteases (Kruse, M.N., Becker, C., Lottaz, D., Kohler, D., Yiallouros, I., Kreil, H.W., Sterchi, E.E. and Stocker, W. 2004 Human meprin a and [3 homo-oligomers: cleavage of basement membrane proteins and sensitivity to metalloprotease inhibitors. Biochem.J. 378,383-389; Becker, C., Kruse, M.N., Slotty, K.A., Kohler, D., Harris, J.R., Rosmann, S., Sterchi, E.E. and Stocker, W. 2003 Differences in the activation mechanism between the a and [3 subunits of human meprin. Biol-Chem. 384, 825-831 ). Once activated meprins execute various functions. Both enzymes functions as C and N-procollagen proteinases and induce collagen maturation and assembly (Biasin V, Marsh LM, Egemnazarov B, Wilhelm J, Ghanim B et.al. 2014). Meprin (3, a novel mediator of vascular remodelling underlying pulmonary hypertension. J. Pathol. May;233(1 ):7-17; Prox J, Arnold P, Becker-Pauly C.2015 Meprin a and meprin [3: Procollagen proteinases in health and disease. MatrixBiol. 2015 May-Jul;44-46:7-13). Ch ronic IBD, such as CD (Crohn’s disease) and UC (ulcerative colitis) are chronic inflammations of the gastrointestinal tract, characterized by a diffuse leucocyte infiltration of the intestinal mucosa and a deregulation of the mucosal immune system (Neuman, M.G. 2007 Immune dysfunction in inflammatory bowel disease. Transl.Res.149, 173-186). Genetic analysis studies have demonstrated that IBD is associated with meprins (Banerjee, S., Oneda, B., Yap, L. M., Jewell, D.P., Matters, G.L., Fitzpatrick, L.R., Seibold, F., Sterchi, E.E., Ahmad, T., Lottaz, D. and Bond, J. S. 2009 MEP1A allele for meprin A metalloprotease is a susceptibility gene for inflammatory bowel disease. Mucosallmmunol. 2, 220-231 ; Banerjee, S., Jin, G., Bradley, S.G., Matters, G.L., Gailey, R.D., Crisman, J.M., Bond, J.S. 2011 Balance of meprin A and B in mice affects the progression of experimental inflammatory bowel disease. Am. J. Physiol. Gastroinstest.LiverPhysiol. 300, G273-G282). Experimental data clearly demonstrate that meprins modulate the immune environment by processing and activating proinflam matory cytokines such as interleukins (IL-1 (3, IL-18), transforming growth factor a (TGF-a), tumour necrosis factor-a (TNF-a) and there by promoting inflammation (Jefferson, T., auf dem Keller, U., Bellac, C., Metz, V.V., Broder, C., Hedrich, J., Ohler, A., Maier, W., Magdolen, V., Sterchi, E. et al. 2012 The substrate degradome of meprin metalloproteases reveals an unexpected proteolytic link between meprin [3 and ADAM10. Cell. Mol. LifeSci. ; McGovern, D.P., Gardet, A., Torkvist, L., Goyette, P., Essers, J., Taylor, K.D., Neale, B.M., Ong, R.T., Lagace, C., Li, C. et al. 2010 Genome-wide association identifies multiple ulcerative colitis susceptibility loci. Nat.Genet. 42, 332-337; Herzog, C., Haun, R. S., Kaushal, V., Mayeux, P. R., Shah, S.V. and Kaushal, G.P. 2009 Meprin A and meprin a generate biologically functional IL-1 [3 from pro-IL-1 [3. Biochem. Biophys. Res. Commun. 379, 904-908; Herzog, C., Kaushal, G.P. and Haun, R.S. 2005 Generation of biologically active interleukin-1 [3 by meprin B. Cytokine 31 , 394-403). Further studies demonstrate that meprin [3 mediates intestinal leucocyte infiltration in accordance with its ability to cleave adhesion molecules and components of extracellular matrix (Crisman, J. M., Zhang, B., Norman, L.P. and Bond, J.S. 2004 Deletion of the mouse meprin [3 metalloprotease gene diminishes the ability of leukocytes to disseminate through extracellular matrix. J. Immunol. 172, 4510-4519; Kruse, M. N., Becker, C., Lottaz, D., Kohler, D., Yiallouros, I., Kreil, H.W., Sterchi, EE., Stocker, W. 2004 Human meprin a and [3 homo-oligomers: cleavage of basement membrane proteins and sensitivity to metalloprotease inhibitors. Biochem.. J. 378, 383-389; Ambort, D., Brellier, F., Becker-Pauly, C., Stocker, W., Andrejevic-Blant, S., Chiquet, M., Sterchi, E.E. 2009 Specific processing of tenascin-C by the metalloprotease meprin beta neutralizes its inhibition of cell spreading. MatrixBiol. 29, 31-42; Oneda, B., Lods, N., Lottaz, D., Becker-Pauly, C., Stocker, W., Pippin, J., Huguenin, M., Ambort, D., Marti, H.P., Sterchi, E.E. 2008 Metalloprotease meprin [3 in rat kidney: glomerular localization and differential expression in glomerulonephritis. PloS ONE 3,e2278).

[0097] In vivo studies demonstrate that mice were protected in the absence of meprin-a while mice with normal levels of meprin-a suffer with acute renal failure (Mathew, R., Futterweit, S., Valderrama, E., Tarectecan, A.A., Bylander, J.E., Bond, J.S., Trachtman, H. 005 Meprin-a in chronic diabetic nephropathy: interaction with the renin-angiotensin axis. Am. J. Physiol. RenalPhysiol. 289, F911-F921 ; DeGuzman, J.B., Speiser, P.W. and Trachtman, H. 2004 Urinary meprin-a: a potential marker of diabetic nephropathy. J.Pediatr.Endocrinol.Metab. 17, 1663-1666; Trachtman, H., Valderrama, E., Dietrich, J.M. and Bond, J.S. 1995 The role of meprin A in the pathogenesis of acute renal failure. Biochem.Biophys.Res.Commun. 208,498-505). It has been identified that during ischaemia / reperfusion (IR) injury and cisplatin- induced AKI (acute kidney injury) in rodents, meprin a and meprin [3 undergo redistribution from apical brush-border membranes of the proximal tubule to the basolateral tubular basement membrane and thus initiated IR leads to initiation of inflammation and rapid tissue damage. (Oneda, B., Lods, N., Lottaz, D., Becker- Pauly, C., Stocker, W., Pippin, J., Huguenin, M., Ambort, D., Marti, H.P. and Sterchi, E.E. 2008 Metalloprotease meprin [3 in rat kidney: glomerular localization and differential expression in glomerulonephritis. PloS ONE 3, e2278; Bylander, J., Li, Q., Ramesh, G., Zhang, B., Reeves, W.B. and Bond, J.S. 2008 Targeted disruption of the meprin metalloproteinase [3 gene protects against renal ischemia-reperfusion injury in mice. Am.J. Physiol. Renal. Physiol. 294, F480-F490; Herzog, C., Seth, R., Shah, S.V. and Kaushal, G.P. 2007 Role of meprin A in renal tubular epithelial cell injury. Kidneylnt. 71 , 1009-1018; Schrier, R.W., Wang, W., Poole, B. and Mitra, A. 2004 Acute renal failure: definitions, diagnosis, pathogenesis, and therapy. J. Clin. Invest. 114, 5-14).

[0098] Activated merpins need to neutralize in order to restore the normal physiology of tissues or organs otherwise deleterious effects can be seen as mentioned earlier. Jana Hedrich colleagues have identified Fetuin A as endogenous and biological inhibitor of meprin a and [3 (Hedrich J, Lottaz D, Meyer K, Yiallouros I, Jahnen- Dechent W, Stocker W, Becker-Pauly C. Fetuin-A and cystatin C are endogenous inhibitors of human meprin metalloproteases. Biochemistry. 2010 Oct 5;49(39):8599-607). Fetuin A exhibits inhibitory constant (Ki) for merpin a 4.2 x 10’5M, while for meprin-[3 Ki 1.5 x 10’6M. Further, in silico protein-protein interaction studies have demonstrated the how meprins interact with Fetuin A (Dholey Y, Chaudhuri A, Sen Chakraborty S, An integrated in silico approach to understand protein-protein interactions: human meprin-[3 with fetuin-A. J. Biomol. Struct.Dyn. 2020 Apr;38(7):2080-2092).

[0099] It is also postulated that meprin activated and secreted TNF-a has tight link with Fetuin A. TNF-a has binding sites within the Fetuin A gene and consequently, binding of TNF-a to Fetuin A gene, reduces the expression of Fetuin A. (Manolakis AC, Christodoulidis G, Kapsoritakis AN, Georgoulias P, Tiaka EK, Oikonomou K, Valotassiou VJ, Potamianos SP, a2-Heremans-schmid glycoprotein (fetuin A) downregulation and its utility in inflammatory bowel disease. World J Gastroenterol.

[0100] 2017 Jan 21 ;23(3):437-446)

[0101] The Current invention reflects to an identified mechanisms on how inflammation and related disease can be controlled by controlling the expression of proinflammatory cytokines (TNF-a and other) through meprin a and [3 regulators. Current intervention identifies Fetuin A as natural and biological inhibitors of meprin a and [3 and thereby preventing or inhibiting the inflammation. Fetuin A is an immune regulator (Indications)

[0102] Meprin proteins gets activated during infection and inflammation, which in turn actives the production of TNF-a. It is of utmost important to keep the TNF-a levels under control otherwise deleterious effects will be manifested (tissue injury and necrosis).

[0103] Meprin may control expression of proinflammatory cytokines (Tumour necrosis factor alpha (TNF-a) and others.). TNF-a is one of the cytokines plays major role in inflammation as proinflammatory cytokine. It is often of interest to keep the TNF-a levels under control otherwise deleterious effects will be manifested such as tissue injury, undesired apoptosis and / or necrosis. Thus, in a preferred embodiment, the present invention may comprise controlling expression of proinflammatory cytokines (TNF-a and others). This may be achieved by controlling meprin a and / or [3 regulators by Fetuin-A. The present intervention identifies Fetuin-A as natural and biological inhibitors of meprin a and [3 and thereby preventing or inhibiting the inflammation. Fetuin-A is believed to down regulate the production of TNF-a by directly regulating the one or more meprin proteins. Meprin proteins may be activated during infection and inflammation and which in turn actives the production of TNF-a.

[0104] In a preferred embodiment, the pathological inflammation is associated with Parkinson’s Disease, Cirrhosis, Ankylosing Spondylitis, Antiphospholipid Antibody Syndrome, Autoimmune Encephalitis, Chronic Recurrent Multifocal Osteomyelitis, Gout, Henoch-Schoenlein Purpura, Juvenile Dermatomyositis, Juvenile Idiopathic Arthritis, Juvenile Lupus (SLE), Juvenile Scleroderma, Juvenile Vasculitis, Kawasaki Disease, Lupus (Systemic Lupus Erythematosus), Mixed Connective Tissue Disease, Myositis, Poststreptococcal Inflammatory Syndromes, Psoriatic Arthritis, Reactive Arthritis, Rheumatoid Arthritis, Scleroderma, Sjogren’s Syndrome, Spondyloarthritis I Spondyloarthropathy, Systemic Juvenile Idiopathic Arthritis, Undifferentiated / mixed Connective Tissue Disease, Uveitis, Vasculitis (from different origins), inflammatory bowel disease, and / or one or more other related diseases.

[0105] Thus, the present invention also refers to Fetuin-A (or a pharmaceutical composition comprising such) is used in a method for treating or preventing a patient suffering from Parkinson’s Disease, Cirrhosis, Ankylosing Spondylitis, Antiphospholipid Antibody Syndrome, Autoimmune Encephalitis, Chronic Recurrent Multifocal Osteomyelitis, Gout, Henoch-Schoenlein Purpura, Juvenile Dermatomyositis, Juvenile Idiopathic Arthritis, Juvenile Lupus (SLE), Juvenile Scleroderma, Juvenile Vasculitis, Kawasaki Disease, Lupus (Systemic Lupus Erythematosus), Mixed Connective Tissue Disease, Myositis, Poststreptococcal Inflammatory Syndromes, Psoriatic Arthritis, Reactive Arthritis, Rheumatoid Arthritis, Scleroderma, Sjogren’s Syndrome, Spondyloarthritis I Spondyloarthropathy, Systemic Juvenile Idiopathic Arthritis, Undifferentiated / mixed Connective Tissue Disease, Uveitis, Vasculitis (from different origins), inflammatory bowel disease, and / or other related diseases.

[0106] In a preferred embodiment, the pathological inflammation, which is preferably a chronic pathological inflammation, is associated with a least one of the following diseases characterized in that the disease is:

[0107] (a) a chronic neurological disorder, in particular selected from the group consisting of Parkinson’s Disease, Multiple Sclerosis, and neurocognitive disorder due to prion disease such as Creutzfeldt-Jakob disease, variant Creutzfeldt-Jakob disease, or other forms of spongiform encephalitis;

[0108] (b) a rheumatoid disease and / or inflammatory arthritis, in particular selected from the group consisting of Juvenile Dermatomyositis, Juvenile Idiopathic Arthritis, gout, Scleroderma such as Juvenile Scleroderma, Vasculitis such as Juvenile Vasculitis Rheumatoid Arthritis, Psoriatic Arthropathy such as Psoriatic Arthritis, Spondyloarthritis / Spondyloarthropathy, Adult-Onset Still’s Disease, Scleroderma, and Juvenile Idiopathic arthritis;

[0109] (c) a chronic inflammatory disease of the gastrointestinal tract, in particular Morbus Crohn, Colitis Ulcerosa, and Inflammatory Bowel Disease; and / or

[0110] (d) an autoimmune and / or autoinflammatory disorder in particular selected from the group consisting of Ankylosing Spondylitis, Antiphospholipid Antibody Syndrome, Autoimmune Encephalitis Chronic Recurrent Multifocal Osteomyelitis, Henoch-Schoenlein Purpura, Juvenile Lupus, Lupus such as juvenile and / or systemic Lupus such as Lupus Erythematosus, Mixed Connective Tissue Disease, and Sjdgren’s-Syndrome, and / or

[0111] (e) other inflammatory disease selected from the group consisting of Kawasaki Disease, Myositis, Poststreptococcal Inflammatory Syndromes, Reactive Arthritis, Systemic Juvenile Idiopathic Arthritis, Cirrhosis, Undifferentiated / mixed Connective Tissue Disease, and Uveitis.

[0112] Thus, the present invention also refers to Fetuin-A (or a pharmaceutical composition comprising such) is used in a method for treating or preventing a patient suffering from one or more of the aforementioned diseases.

[0113] The prevention or treatment of the present invention is not limited to the compensation of a Fetuin-A deficiency. Likewise, patients who bear non- pathological or even increased levels of Fetuin-A may benefit from administration of Fetuin-A.

[0114] In a preferred embodiment, the patient is administered with a predetermined Fetuin-A dose independent from the current level of Fetuin-A in plasma.

[0115] Thus, it is not required that the level of Fetuin-A is determined before. It will be understood that the blood serum level may also be determined in blood, serum, or another blood fraction.

[0116] Administered doses of Fetuin-A may be essentially equal or may be different in various injections. In a preferred embodiment, Fetuin-A is administered at essentially equal doses at least two times, at least three times or at least five times.

[0117] It will be understood that the term “essentially equal” means not significantly deviating from each other. Preferably, the term “essentially equal” may be understood as not deviating by more than 10% from each other.

[0118] In a preferred embodiment, the patient is characterized by having (a) a blood serum level of Fetuin-A below 300 pg / mL, preferably below 290 pg / mL, more preferably below 250 pg / mL, in particular blow 200 pg / mL; and / or

[0119] (b) a blood serum level of TNF-a above 42 pg / mL, preferably above 75 pg / mL, more preferably above 90 pg / mL, even more preferably above 100 pg / mL or above 110 pg / mL or above 130 pg / mL or above 150 pg / mL, or above 170 pg / mL.

[0120] Thus, Fetuin-A may be used for the treatment of patients with a proven Fetuin-A deficiency. Additionally or alternatively, Fetuin-A may be used for the treatment of patients having a proven excess of TNF-a.

[0121] Optionally, these patients may additionally have a proven excess of IFN-a and / or one or more other (pro)inflammatory mediators or biomarkers.

[0122] Alternatively or additionally, the patient is characterized by having a TNF-a level in lung tissue that is increased by at least 1 % by weight, preferably by at least 5% by weight, more preferably by at least 10% by weight, in particular by at least 20% by weight or by at least 50% by weight or by at least 75% by weight or by at least 2- fold by weight or by at least 3-fold by weight, referred to the average lung tissue level found in the healthy population.

[0123] Alternatively or additionally, the patient is characterized by having a blood serum level of INF-a above 42 pg / mL, preferably above 43 pg / mL, more preferably above 45 pg / mL, even more preferably above 50 pg / mL or above 60 pg / mL or above 70 pg / mL or above 80 pg / mL or above 90 pg / mL.

[0124] Fetuin-A as used herein may form part of composition with one or more further pharmaceutically acceptable components. Such composition may preferably also be suitable for being used in a medical / therapeutic context. Such composition may, for example, comprise one or more solvents, one or more further components present in blood, one or more polypeptides, one or more pharmaceutically acceptable salts, and / or other pharmaceutically acceptable components.

[0125] In a preferred embodiment, the Fetuin-A forms part of composition with one or more further pharmaceutically acceptable components. In one embodiment, the composition may comprise one or more further ingredients such as a as liquid carrier (e.g., a buffer). Optionally, the composition may be a pharmaceutical composition. Moreover, the invention comprises pharmaceutical compositions comprising a protein preparation comprising Fetuin-A as described above and at least one pharmaceutically acceptable carrier for use in treatment or prophylaxis in patients suffering from Fetuin-A deficiency.

[0126] In a preferred embodiment, the Fetuin-A forms part of a pharmaceutical composition comprising Fetuin-A and at least one pharmaceutically acceptable carrier.

[0127] Accordingly, the present invention also relates to a pharmaceutical composition comprising Fetuin-A and at least one pharmaceutically acceptable carrier for use in a method for treating or preventing a pathological inflammation in a patient.

[0128] In other words, the present invention thus also relates to a method for treating or preventing a pathological inflammation in a patient, wherein the patient is administered with a sufficient amount of a pharmaceutical composition comprising Fetuin-A and at least one pharmaceutically acceptable carrier.

[0129] It will be understood that the embodiments and definitions as laid out in the context of Fetuin-A for use above mutatis mutandis apply to the pharmaceutical composition for use.

[0130] As used herein, the terms “pharmaceutical composition” and “pharmaceutical formulation” may be understood interchangeably. As used herein, the terms “pharmaceutically acceptable carrier”, “pharmaceutically acceptable excipient”, “carrier” and “excipient” may be understood interchangeably in the broadest sense as any substance that may support or at least not prevent the pharmacological acceptance of the Fetuin-A. Such pharmaceutical composition may be ready to use and may preferably be a liquid formulation, in particular an injection portion.

[0131] In a preferred embodiment, Fetuin-A forms part of an injectable pharmaceutical composition.

[0132] A pharmaceutical composition may also be a dosage unit. Thus, the present invention also relates to a dosage unit of the pharmaceutical composition usable in the context of the treatment or prevention of the present invention. Exemplarily, the present invention may refer to a single dose container or to a multiple dosage form.

[0133] A pharmaceutically acceptable carrier may exemplarily be selected from the list consisting of an aqueous buffer, saline, water, dimethyl sulfoxide (DMSO), ethanol, vegetable oil, paraffin oil, or combinations of two or more thereof. Furthermore, the pharmaceutically acceptable carrier may optionally contain one or more detergent(s), one or more foaming agent(s) (e.g., sodium lauryl sulfate (SLS), sodium dodecyl sulfate (SDS)), one or more coloring agent(s) (e.g., food coloring), one or more vitamin(s), one or more salt(s) (e.g., sodium, potassium, calcium, zinc salts), one or more humectant(s) (e.g., sorbitol, glycerol, mannitol, propylene glycol, polydextrose), one or more enzyme(s), one or more preserving agent(s) (e.g., benzoic acid, methylparaben, one or more antioxidant(s), one or more herbal and plant extract(s), one or more stabilizing agent(s), one or more chelating agents (e.g., ethylenediaminetetraacetic acid (EDTA), and / or one or more uptake mediator(s) (e.g., polyethylene imine (PEI), a cell-penetrating peptide, a protein transduction domain (PTD), an antimicrobial peptide, etc.).

[0134] The present invention also relates to a dosage unit of the pharmaceutical composition usable in the context of the treatment or prevention of the present invention. Exemplarily, the present invention may refer to a single dose container or to a multiple dosage form.

[0135] The composition of the present invention is also suitable for being used in a medical / therapeutic context. The present invention also relates to for use as a medicament.

[0136] Optionally, the patient is further administered with one or more further antiinflammatory compounds. In a preferred embodiment, the patient is further administered with one or more corticosteroids. Such corticosteroid may be any corticosteroids that bears anti-inflammatory activity. In a preferred embodiment, the patient is further administered with cortisone. The patient may optionally further administered with one or more NSAIDs. As used throughout the present invention “further administered” does not necessarily mean that the compound is administered in the same composition with Fetuin-A.

[0137] The further anti-inflammatory compound may be administered prior to, concomitantly with, or after administration of Fetuin-A. In a preferred embodiment, the further anti-inflammatory compound is administered in such way that a therapeutically active concentration of Fetuin-A is concomitantly achieved with a therapeutically active concentration of the further anti-inflammatory compound. In a preferred embodiment, the further anti-inflammatory compound is administered not more than one week prior to, at the same day or not more than one week after the administration of Fetuin-A. In a preferred embodiment, the further anti-inflammatory compound is administered not more than one day prior to, at the same day or not more than one day after the administration of Fetuin-A. In a preferred embodiment, the further anti-inflammatory compound is administered not more than one hour prior to or not more than one hour after the administration of Fetuin-A.

[0138] The further anti-inflammatory compound may be administered in the same route or a different route than Fetuin-A. For instance, it is also possible that one active agent is administered systemically and the other is locally such as topically administered.

[0139] In a preferred embodiment, Fetuin-A is administered together with a further antiinflammatory compound, wherein both are combined in the same pharmaceutical composition.

[0140] Thus, a further aspect of the present invention relates to a pharmaceutical composition comprising:

[0141] (A) Fetuin-A;

[0142] (B) one or more further anti-inflammatory compounds; and

[0143] (C) one or more pharmaceutically acceptable carriers.

[0144] It will be understood that the embodiments and definitions as laid out in the context of Fetuin-A for use above mutatis mutandis apply to the pharmaceutical composition.

[0145] It will further be understood that the pharmaceutical composition comprising (A) Fetuin-A;

[0146] (B) one or more further anti-inflammatory compounds; and

[0147] (C) one or more pharmaceutically acceptable carriers may be used in a method for treating or preventing a pathological inflammation in a patient.

[0148] In the context of the pharmaceutical composition, a further anti-inflammatory compound is different from Fetuin-A. In the context of the present invention, a further anti-inflammatory compound may be defined as above.

[0149] In another preferred embodiment, the patient is not administered with cortisone, in particular not administered with any corticosteroid. Then, in a preferred embodiment, Fetuin-A may be the sole active ingredient with which the patient is administered.

[0150] The following examples and figures are intended to provide illustrative embodiments of the present invention described and claimed herein. These examples are not intended to provide any limitation on the scope of the invented subject-matter. The following figures, examples and claims further illustrate the invention.

[0151] Figures

[0152] Figure 1 shows the effects of Fetuin-A in LPS-induced lung dysfunction on airway resistance. Herein, the diamonds represent the control group of untreated mice, squares represent mice treated with LPS (1 mg / kg in vehicle, intratracheal), triangles represent mice treated with LPS (1 mg / kg, intratracheal) + prophylactic Fetuin-A (1 mg / kg, intranasal), and crosses represent mice treated with LPS (1 mg / kg, intratracheal) + therapeutic Fetuin-A (1 mg / kg, intranasal). The percent baseline airway resistance (% resistance) is based on assessing phosphate buffered saline (PBS) aerosol set as 100%. Herein, an asterix (*) indicates a p < 0.01 versus control group and a doubled cross indicates a p < 0.01 versus mice treated with LPS (1 mg / kg in vehicle, intratracheal).

[0153] Figure 2 shows the effects of Fetuin-A in LPS-induced lung dysfunction on cytokine levels such as (A) tumor necrosis factor alpha (TNF-a, given in pg / 100 pg total lung lysate), (B) interleukin 6 (IL-6, given in pg / 15 pg total lung lysate), (C) interleukin 17 (IL-17, given in units / 100 pg total lung lysate), and (D) interleukin 13 (IL-13, given in pg / 5 pg total lung lysate). Ctrl: mice of the control group (untreated), LPS+Veh: mice treated with LPS (1 mg / kg in vehicle, intratracheal), LPS+Pro: mice treated with LPS (1 mg / kg, intratracheal) + prophylactic Fetuin-A (1 mg / kg, intranasal), and LPS+Ther: mice treated with LPS (1 mg / kg, intratracheal) + therapeutic Fetuin-A (1 mg / kg, intranasal).

[0154] Figure 3 shows the effects of Fetuin-A in LPS-induced lung dysfunction on the tissue level in (A) mice of the control group (untreated), (B) mice treated with LPS (1 mg / kg in vehicle, intratracheal), (C) mice treated with LPS (1 mg / kg, intratracheal) + prophylactic Fetuin-A (1 mg / kg, intranasal), and (D) mice treated with LPS (1 mg / kg, intratracheal) + therapeutic Fetuin-A (1 mg / kg, intranasal). Herein, “A” indicates an alveolar and “V” indicates a vessel. The arrowhead in (B) shows the increased inflammation in lung parenchymal region and the arrowhead in (D) shows the reduced inflammation in lung parenchymal region.

[0155] Figure 4 shows the effects of Fetuin-A on hypoxic stress. Herein, Western blots of the hypoxic stress biomarkers (A) HIF-a and (C) Nrf2 are show. Furthermore, the levels of (B) HIF-a and (D) Nrf2 as determined by densiometric ratios are shown for untreated mice (control), mice treated with CoCl2 (80 mg / kg, in drinking water) (C0CI2+), and mice treated with CoCl2 (80 mg / kg, in drinking water) + Fetuin-A (1 mg / kg, intranasal) (C0CI2+ Fetuin-A).

[0156] Figure 5 shows the effects of Fetuin-A in hypoxic stress on cytokine levels such as (A) tumor necrosis factor alpha (TNF-a, given in pg / 100 pg total lung lysate), (B) interleukin 17 (IL-17, given in pg / 100 pg total lung lysate), (C) interleukin 6 (IL-6, given in units / 5 pg total lung lysate), and (D) interleukin 13 (IL-13, given in pg / 5 pg total lung lysate). This is shown for untreated mice (control), mice treated with C0CI2 (80 mg / kg, in drinking water) (C0CI2), and mice treated with C0CI2 (80 mg / kg, in drinking water) + Fetuin-A (1 mg / kg, intranasal) (C0CI2+ Fetuin-A).

[0157] Figure 6 shows the effects of Fetuin-A in hypoxic stress on the tissue level in (A) untreated mice (control), (B) mice treated with CoCl2 (80 mg / kg, in drinking water) (C0CI2), and (C) mice treated with CoCl2 (80 mg / kg, in drinking water) + Fetuin-A (1 mg / kg, intranasal) (C0CI2+ Fetuin-A). In (B), the arrowhead 1 shows the increased inflammation in the peribronchial space, and the arrowhead 2 shows the alveolar collapse. In (C), the arrowhead indicates reduced inflammation with Fetuin-A treatment.

[0158] Examples

[0159] Example 1 : Effect of Fetuin-A in lipopolysaccharide-induced (LPS-induced) acute lung injury in murine model.

[0160] Material and Methods

[0161] Study animals: 6-7 weeks old, healthy male C57bl / 6 mice. It is reasonable assumed that the blood serum levels were at a normal range at the onset of the experiment.

[0162] Reagents and kits:

[0163] Mouse TNF-a DuoSet ELISA (Supplier Cat.No.: DY410-05)

[0164] Mouse IL-6 DuoSet ELISA (Supplier Cat.No.: DY406-05)

[0165] Mouse IL-17 DuoSet ELISA (Supplier Cat.No.: DY421 )

[0166] Mouse IL-13 DuoSet ELISA (Supplier Cat.No.: DY413)

[0167] Study groups: Animals were housed for 7 days before start of the experiments to get acclimatize in the animal house. All experimentally used mice were randomized into three groups: control group, LPS vehicle group, LPS + prophylactic Fetuin-A treatment group (animals were treated with Fetuin-A (1 mg / kg) two days before LPS challenge once a day) and LPS + therapeutic Fetuin-A treatment group (animals were treated with Fetuin-A (1 mg / kg) one day after LPS challenge). On day four, all animals were subjected to lung function (airway hyper-responsiveness / airway resistance) test using mechanical ventilator. The brief description of study outline is depicted below.

[0168] Groups of the study (each five mice per group (n = 5)):

[0169] Group 1 : Control (untreated mice)

[0170] Group 2: LPS (1 mg / kg, intratracheal)

[0171] Group 3: LPS (1 mg / kg, intratracheal) + prophylactic Fetuin-A (1 mg / kg, intranasal) Group 4: LPS (1 mg / kg, intratracheal) + therapeutic Fetuin-A (1 mg / kg, intranasal)

[0172] Table 1. Study outline of LPS study

[0173] Measurement of Airway hyper-responsiveness (AHR):

[0174] AHR was measured as airway resistance in anesthetize using an invasive airway mechanic instrument that had mechanical ventilator (FlexiVent, SciReq, Canada). This machine uses mouse ventilator to measure respiratory mechanics and all process were controlled by computer. Briefly, mice were anesthetized using xylazine and thiopentone. Then these mice were tracheotomized, then cannulated and further cannula was connected to the Y tube of FlexiVent. Then PBS / different concentrations of methacholine were aerosolized using ultrasonic nebulizer. The machine can calculate various parameters like airway resistance, lung compliance, lung elastance with or without methacholine. In general, methacholine is used to measure lung function as it is a non-specific airway constrictor agent. In general, disease mice would have difficulty in breathing even with lower concentrations of Methacholine compared to healthy mice. Airway resistance was measured against increasing concentrations of methacholine (Meh). The results were expressed assuming PBS aerosol values as 100% with increasing dose of methacholine. Thus, if the mice are having lung dysfunction, those mice will have higher airway resistance even with lower concentrations of Methacholine.

[0175] Assessment of lung injury and inflammation:

[0176] To assess the LPS induced lung injury, animals were sacrificed using cervical dislocation method. Upon sacrifice, lung tissues were collected and divided into two parts one for the histological examination and second one for evaluation of inflammatory cytokines. In the current study, various pro-inflammatory cytokines were assessed (as mentioned in the Table 3 below) as per the specific ELISA Kit user manual instructions. For the histopathological assessment, Periodic acid- Schiff’s (PAS) staining and H & E staining were used.

[0177] In line with knowledge in the art, the blood serum level of Fetuin-A was considered to decrease below a non-pathological blood serum level due to LPS administration, while the blood serum level of tumor necrosis factor alpha (TNF-a) was considered above the average blood serum level due to inflammation.

[0178] Results

[0179] Both prophylactic and therapeutic doses of Fetuin-A treatment significantly attenuated the LPS induced lung dysfunction compared to LPS vehicle treated animals as shown in Figure 1 . All the pro-inflammatory cytokines under investigation (TNF-a, IL-6, IL-13 and IL-17) were also reduced significantly as visible from Figure 2. Histopathological examination clearly shows the parenchymal inflammation mostly with infiltrating neutrophils in the lungs of LPS vehicle treated animals while there is significant reduced parenchymal inflammation on both Fetuin-A treatment groups (see Figure 3).

[0180] The experimental results demonstrate the positive effects of Fetuin-A in LPS- induced lung injury by restoring the lung damage by preventing the immune infiltration, restoring the lung function by reducing the airway resistance and attenuating pro-inflammatory cytokines. Therefore, it demonstrated that Fetuin-A is suitable to treat inflammatory diseases.

[0181] Example 2: Effect of Fetuin-A on hypoxia murine model

[0182] Material and Methods

[0183] Study animals: 6-7 weeks old, male C57bl / 6 mice.

[0184] Reagents and kits:

[0185] Mouse TNF-a DuoSet ELISA (Supplier Cat.No.: DY410-05)

[0186] Mouse IL-6 DuoSet ELISA (Supplier Cat.No.: DY406-05) Mouse IL-17 DuoSet ELISA (Supplier Cat.No.: DY421 )

[0187] Mouse IL-13 DuoSet ELISA (Supplier Cat.No.: DY413)

[0188] HIF1a Antibody (28b) (Supplier Cat.No.: sc-13515)

[0189] Rec Anti-HIF-1 an antibody (Supplier Cat.No.: ab 179483)

[0190] Anti-Nrf2 antibody (Supplier Cat.No.: ab31163)

[0191] Study groups: Animals were housed for 7 days before start of the experiments to get acclimatize in the animal house. All experimental animals were randomized into three groups: control group of untreated mice, cobalt chloride (C0CI2) vehicle group (C0CI2 was given via drinking water for the entire study duration), CoCl2+therapeutic Fetuin-A treatment group (animals were treated with Fetuin-A (1 mg / kg each) on day 8, 10 and 12 after C0CL2 challenge). On day fourteen, all animals were subjected to lung function (airway hyper-responsiveness / airway resistance) test using mechanical ventilator and sacrificed under euthanasia. The brief description of study outline is depicted below.

[0192] Groups of the study:

[0193] Group 1 : Control (untreated mice, n = 2)

[0194] Group 2: CoCl2 (80 mg / kg, in drinking water, n = 3)

[0195] Group 3: C0CI2 (80 mg / kg, in drinking water + Fetuin-A (1 mg / kg, intranasal) (n = 3)

[0196] Table 2. Study outline of C0CI2 study

[0197] Measurement of Airway hyper-responsiveness (AHR) and assessment of lung injury and inflammation were conducted as described in Experiment 1 above. A Western blot was conducted by standard means known in the art (see list above in Example 2: Reagents and kits).

[0198] In line with knowledge in the art, the blood serum level of Fetuin-A was considered to decrease below a non-pathological blood serum level due to LPS administration, while the blood serum level of tumor necrosis factor alpha (TNF-a) was considered above the average blood serum level due to inflammation.

[0199] Results

[0200] Western blot analysis of hypoxia stress related proteins HIF-a and Nrf2 were significantly upregulated in C0CI2 animals demonstrating the hypoxic stress while these proteins were brought to significantly reduced levels by Fetuin-A as shown in Figure 4. All the pro-inflammatory cytokines under investigation (TNF-a, IL-6, IL-13, and IL-17) were also reduced significantly with Fetuin-A treatment as shown in Figure 5.

[0201] Histopathological examination clearly shows the peribronchial inflammation and alveolar collapse in the lungs of CoCl2-treated animals while improvements were achieved with Fetuin-A treatment (see Figure 6).

[0202] The results demonstrate the positive effects of Fetuin-A in hypoxia induced lung injury by restoring the lung damage by preventing the immune infiltration and lung alveolar collapse. Attenuating pro-inflammatory cytokines were observed similar to effects seen in the LPS models. Therefore, this model also demonstrated that Fetuin-A can be used to treat and / or prevent inflammation.

Claims

Claims1. Fetuin-A for use in a method for treating or preventing a pathological inflammation in a patient, wherein the patient is characterized by having(a) a blood serum level of Fetuin-A below a non-pathological blood serum level, and(b) a blood serum level of tumor necrosis factor alpha (TNF-a) above the average blood serum level found in the healthy population.

2. The Fetuin-A for use according to claim 1 , wherein the Fetuin-A is administered via the respiratory tract, preferably via intranasal administration, is injected, preferably injected intravenously (i.v.), intraperitoneally (i.p.), intradermally (i.d.), intraarterially (i.a.), intramuscularly (i.m.), and / or subcutaneously (s.c.), topically, or orally.

3. The Fetuin-A for use according to any one of claims 1 or 2, wherein the pathological inflammation involves inflammation of lung tissue, in particular is associated with respiratory insufficiency.

4. The Fetuin-A for use according to any one of claims 1 to 3, wherein the pathological inflammation is associated with hypoxia.

5. The Fetuin-A for use according to any one of claims 1 to 4, wherein the inflammation is triggered by lipopolysaccharide (LPS) and / or is associated with pneumonia.

6. The Fetuin-A for use according to any one of claims 1 to 5, wherein the pathological inflammation is a chronic pathological inflammation, preferably wherein the chronic pathological inflammation persists for at least one month, for at least six months, or for at least one year, preferably wherein patient is repeatedly administered with Fetuin-A for at least one month, at least two months, or at least three months.

7. The Fetuin-A for use according to any one of claims 1 to 6, wherein patient is repeatedly administered with Fetuin-A by injections of Fetuin-A in a dose range of 1 to 1000 pg / kg body weight at each injection.

8. The Fetuin-A for use according to any one of claims 1 to 7, wherein the pathological inflammation is an acute pathological inflammation.

9. The Fetuin-A for use according to any one of claims 1 to 8, wherein the patient does not therapeutically respond to cyclooxygenase (COX) inhibitors, in particular does not therapeutically respond to non-steroidal anti-inflammatory drugs (NSAIDs), or is a patient with a contraindication for COX inhibitors; in particular wherein the patient does not therapeutically respond to antiinflammatory drugs except corticosteroids.

10. The Fetuin-A for use according to any one of claims 1 to 9, wherein the pathological inflammation is associated with an elevated level of meprin alpha and / or meprin beta in the inflammatory site and / or systemically in the patient’s blood plasma.

11. The Fetuin-A for use according to any one of claims 1 to 10, wherein the pathological inflammation, which is preferably a chronic pathological inflammation, is associated with a least one of the following diseases characterized in that the disease is:(a) a chronic neurological disorder, in particular selected from the group consisting of Parkinson’s Disease, Multiple Sclerosis, and neurocognitive disorder due to prion disease such as Creutzfeldt- Jakob disease, variant Creutzfeldt-Jakob disease, or other forms of spongiform encephalitis;(b) a rheumatoid disease and / or inflammatory arthritis, in particular selected from the group consisting of Juvenile Dermatomyositis, gout, Scleroderma such as Juvenile Scleroderma, Vasculitis such as Juvenile Vasculitis, Rheumatoid Arthritis, Psoriatic Arthropathy suchas Psoriatic Arthritis, Spondylarthritis / Spondyloarthropathy, Adult- Onset Still's Disease, Scleroderma, and Juvenile Idiopathic Arthritis;(c) a chronic inflammatory disease of the gastrointestinal tract, in particular Morbus Crohn, Colitis Ulcerosa, and Inflammatory Bowel Disease; and / or(d) an autoimmune and / or autoinflammatory disorder in particular selected from the group consisting of Ankylosing Spondylitis, Antiphospholipid Antibody Syndrome, Autoimmune Encephalitis, Chronic Recurrent Multifocal Osteomyelitis, Henoch-Schoenlein Purpura, Juvenile Lupus, Lupus such as juvenile and / or systemic Lupus such as Lupus Erythematosus, Mixed Connective Tissue Disease, and Sjogren's Syndrome, and / or(e) other inflammatory disease selected from the group consisting of Kawasaki Disease, Myositis, Poststreptococcal Inflammatory Syndromes, Reactive Arthritis, Systemic Juvenile Idiopathic Arthritis, Cirrhosis, Undifferentiated / mixed Connective Tissue Disease, and Uveitis.

12. The Fetuin-A for use according to any one of claims 1 to 11 , wherein the patient is administered with a predetermined Fetuin-A dose independent from the current level of Fetuin-A in plasma, in particular wherein Fetuin-A is administered at essentially equal doses at least two times, at least three times or at least five times.

13. The Fetuin-A for use according to any one of claims 1 to 12, wherein the patient is characterized by having(a) a blood serum level of Fetuin-A below 300 pg / mL, preferably below 290 pg / mL, more preferably below 250 pg / mL, in particular blow 200 pg / mL; and / or(b) a blood serum level of TNF-a above 42 pg / mL, preferably above 75 pg / mL, more preferably above 90 pg / mL, even more preferably above 100 pg / mL or above 110 pg / mL or above 130 pg / mL or above 150 pg / mL, or above 170 pg / mL.

14. The Fetuin-A for use according to any one of claims 1 to 13, wherein the patient is further administered with one or more corticosteroids, in particular cortisone.

15. The Fetuin-A for use according to any one of claims 1 to 14, wherein the Fetuin-A forms part of a pharmaceutical composition comprising Fetuin-A and at least one pharmaceutically acceptable carrier, in particular wherein it forms part of an injectable pharmaceutical composition.

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