WO2012076194A1 - Combination preparations comprising a cytokine antagonist and corticosteroid - Google Patents

Abstract

The invention relates to pharmaceutical compositions for a combination therapy comprising a cytokine antagonist and a corticosteroid. Illnesses such as osteoarthritis, tendon diseases and/or degenerative illnesses of the spinal column can be treated by means of the combination therapy.

Description

 "Combination Preparations with Cvtokine Antagonist and Corticosteroid"

The present invention relates to pharmaceutical compositions for combination therapy with a cytokine antagonist and a corticosteroid. The combination therapy may treat diseases such as osteoarthritis (including inflammatory forms of osteoarthritis), tendon disorders and / or degenerative spinal disorders, preferably with local treatment.

Osteoarthritis refers to a "joint wear and tear" that exceeds the age-customary level, it is associated with loss of cartilage in the affected joint, resulting in pain and functional deterioration caused by an excess of stress, congenital or traumatic causes, such as malalignment of the joints, or Bone deformity due to bone disease, such as osteoporosis, may also result from other conditions such as joint inflammation or may be accompanied by congestion associated with overgrowth.

Basically, all joints can be affected by arthritic changes. In Germany, the disease is most often located in the knee joint. Osteoarthritis is one of the most common consultations in a general medical practice. About 10% of the population in western countries suffers from osteoarthritis. If one calculates the osteoarthritis disorders of the small vertebral joints and the degenerative ones Disk Diseases, even about 15% -20% of the population are affected. The risk of developing osteoarthritis increases with age. About two-thirds of people over 65 are affected by the disease, but not all sufferers also suffer from the symptoms.

For the treatment of osteoarthritis, some forms of therapy are already known. These include conservative (e.g., drug) therapies as well as surgical procedures to the replacement of the full joint with a prosthesis. In order to avoid such extensive and irreversible interventions, an effective drug treatment is generally preferable in order to delay the time of a complete joint replacement as much as possible.

However, many drug treatments also have disadvantages. On the one hand, this is due to the side effects of the drugs themselves, but their effectiveness is sometimes limited.

An often used medicinal agent for the treatment of osteoarthritis is cortisone and related corticosteroids. However, these are usually administered systemically locally as an injection into the affected joint. However, this shows that the positive effect of corticosteroids decreases after just one week. This is clinically proven through randomized trials and clinical experience.

Another drug that can be used to treat osteoarthritis is the endogenous protein IL-1 Ra or an isoform or fragment thereof that has similar activity, interleukin-1 receptor antagonist (IL-1 Ra) binds to the same receptors on the cell surface, such as interleukin-1 (IL-1), but does not elicit the signal cascade normally caused by IL-1 binding. By binding to the IL-1 receptor, IL-1Ra blocks the binding of IL-1, thus preventing its signal transduction and thus the pro-inflammatory effect of IL-1 on the target cells.

The treatment of patients with endogenous serum in which IL-1 Ra has been enriched and among other factors is known in the art. The IL-1 Ra thus used is also called Orthokin. Surprisingly, a recombinant IL-1 Ra fragment, anakinra, had no effect on the treatment of osteoarthritis compared to placebo treatment. Anakinra is a truncated to the amino acids 26-177 and terminal L-methionylated isoform of the human interleukin-1 receptor antagonist and has a sequence length of 153 amino acids. The production takes place for example by Escherichia coli strains with recombinant methods. The invention therefore an object of the invention to provide a drug osteoarthritis treatment, which has a better efficacy and in particular has a good long-term efficacy. Surprisingly, it has now been found that the efficacy, in particular the long-term efficacy, of corticosteroids such as cortisone in osteoarthritis, inflammatory forms of osteoarthritis and degenerative spinal disease can be significantly and synergistically improved by the additional administration of a cytokine antagonist such as Orthokin and Anakinra. This is particularly evident in the local administration of the therapeutic agents directly into the joint to be treated. This is particularly surprising in view of the fact that this beneficial effect occurs with additional administration of both natural IL-1 Ra and orthokin, as well as recombinant IL-1 Ra such as anakinra, although anakinra alone has been shown to have no effect in the treatment of arthrosis and degenerative Spinal diseases shows. The present invention opens up the possibility of making the recombinant IL-1 Ra suitable for the treatment of osteoarthritis and spinal disorders, since this alone is not suitable for the treatment of these diseases. A similar, surprisingly good efficacy and high safety of the combination of these agents has also been found for autoimmune diseases such as atopic dermatitis and circular hair loss, in particular the anti-inflammatory effect plays a role.

A possible explanation for this fact is that the cytokine antagonists have an anabolic effect and can abrogate or even reverse the harmful catabolic effects of the corticosteroid known in the affected joints. Therefore, in the treatment of, for example, osteoarthritis in addition to the cytokine antagonists, the corticosteroids may alternatively or additionally be combined with anabolic growth factors to achieve a similar or even potentiating effect. The invention thus makes it possible to develop a corticosteroid which does not have the known harmful effects in osteoarthritis, which may consist of enhancing cartilage destruction, by combining it with a cytokine antagonist.

Thus, in a first aspect, the present invention provides a pharmaceutical composition comprising a corticosteroid together with a cytokine antagonist and optionally a growth factor, wherein the cytokine antagonist is the naturally occurring or recombinant interleukin antagonist IL-1Ra protein in particular orthokin or anakinra, and wherein the pharmaceutical composition is suitable for local administration. Likewise, the therapeutics can also be administered in two different pharmaceutical compositions simultaneously or in chronological order. Corresponding In a second and a third aspect of the invention, there is provided a pharmaceutical composition comprising a cytokine antagonist and optionally a growth factor for use in a combination therapy together with a corticosteroid and a pharmaceutical composition containing a corticosteroid for use in a combination therapy together with a cytokine. Antagonists and optionally provided a growth factor. In both the second and third aspects of the invention, the cytokine antagonist is the naturally occurring or recombinant interleukin antagonist IL-1Ra protein, especially orthokin or anakinra, and the pharmaceutical composition is suitable for local administration.

In a fourth aspect of the invention, there is provided a kit comprising a pharmaceutical composition containing a cytokine antagonist and optionally a growth factor, and a pharmaceutical composition containing a corticosteroid. The cytokine antagonist is the naturally occurring or recombinant interleukin antagonist IL-1Ra protein, especially orthokine or anakinra, and the pharmaceutical compositions are suitable for local administration.

Moreover, in a fifth aspect, the invention relates to the use of a cytokine antagonist and optionally a growth factor for the manufacture of a pharmaceutical composition for use in a combination therapy together with a corticosteroid, and in a sixth aspect the use of a corticosteroid for the preparation of a pharmaceutical composition for use in a combination therapy together with a cytokine antagonist and optionally a growth factor. In both the fifth and sixth aspects of the invention, the cytokine antagonist is the naturally occurring or recombinant interleukin antagonist IL-1Ra protein, especially orthokine or anakinra, and the pharmaceutical composition is suitable for local administration. Further embodiments of the invention are given in the following detailed description and in the claims.

The invention is based on the surprising discovery that the treatment of diseases of the joints and the spine such as osteoarthritis / arthritis, arthritis, inflammatory forms of osteoarthritis and degenerative spinal disease, as well as in autoimmune diseases using corticosteroids by the additional administration of a cytokine antagonist and optionally a growth factor can be significantly improved. In particular, for the treatment with the recombinant IL-1 Ra anakinra only by the combination with a corticosteroid efficacy, which is much higher than the sole effect of corticosteroids or the anakinra in combination with a corticosteroid in the first place to one makes effective agent in the treatment of these diseases. In the case of the natural IL-1 Ra Orthokin, a significant improvement in the effectiveness is observed, especially in inflammatory or inflammatory processes of osteoarthritis or inflammation of the vertebral joints or the nerve root. Thus, the invention is directed to the combination therapy of such diseases by means of a corticosteroid together with a cytokine antagonist such as Anakinra or Orthokin and optionally a growth factor.

These different active ingredients can be administered simultaneously - in the same formulation or in different formulations - or else sequentially. The pharmaceutical compositions according to the invention which contain only one of the two different active ingredients, as well as the kit according to the invention, can therefore be intended, on the one hand, for a simultaneous administration and, on the other hand, for a sequential administration of the cytokine antagonist and the corticosteroid. However, simultaneous administration is preferred, especially in only one formulation. Thus, for example, the two pharmaceutical compositions of the kit of the invention may be appropriately mixed before administration to the patient and then administered as a formulation. In a sequential administration of the cytokine antagonist and the corticosteroid, the various drugs are preferably administered within a period of one week, preferably within 5 days, 3 days, one day, or within 12 hours.

According to the invention, the cytokine antagonist can also be combined with a growth factor. Optionally, another cytokine antagonist is contained in the pharmaceutical composition or kit according to the invention.

The cytokine antagonist used in the invention may be any substance or mixture of substances that reduces or inhibits at least one, preferably substantially all, of the biological activities of one or more cytokines in the body of the patient. The antagonistic effect can be done directly by the antagonist or indirectly, for example by activation or inhibition of other signaling pathways, which in turn act on the biological activity of the cytokine. Preferably, the biological activity of the cytokine is inhibited by blocking its interaction with one or more of the receptors to which it is capable of binding. This can be achieved, for example, by competitive binding of the antagonist to the corresponding receptor or by binding of the antagonist to the cytokine itself. Preferably, the cytokine antagonist inhibits the action of the cytokine IL-1. The cytokine antagonist may be, for example, a protein, a peptide, a nucleic acid, a lipid or an organic compound. Also, the cytokine antagonist may consist of a mixture of two or more cytokine antagonists as described herein. In particular, the cytokine antagonist may be a naturally occurring peptide or protein or even a recombinantly produced peptide or protein. In addition, the cytokine antagonist may be or contain an antibody or an antigen-binding fragment of an antibody, particularly an antibody or antibody fragment capable of binding the particular cytokine or cytokine receptor. Examples of suitable cytokine antagonists are interleukin antagonists, in particular IL-1 antagonists such as IL-1 Ra, tumor necrosis factor (TNF) antagonists, in particular a TNF-o antagonist such as an anti-TNF-a antibody, interferon Antagonists, and chemokine antagonists. Particularly preferred is naturally occurring or recombinant IL-1 Ra protein, preferably human IL-1 Ra. IL-1 Ra preferably comprises or consists preferably of the amino acid sequence of an isoform or a homologue of human IL-1 Ra according to SEQ ID NOs: 1, 2, 3, 4 or 5, an isoform of equine IL-1 Ra according to SEQ ID NOs : 6 or 7, or an isoform of canine IL-1 Ra according to SEQ ID NO: 8. Preferably, the pharmaceutical composition or the kit according to the invention comprises such a cytokine antagonist in addition to the naturally occurring or recombinant IL-1 Ra protein.

In addition, according to the invention, fragments or derivatives of IL-1Ra can be used as cytokine antagonists as long as they can perform the desired function, that is, reduce or inhibit one or more biological functions of IL-1. Fragments of IL-1 Ra preferably comprise at least 20, more preferably at least 40, 60, 80, or at least 100 amino acids of a natural IL-1 Ra sequence. Preferably, the fragments are naturally occurring secreted fragments of IL-1 Ra. In one embodiment, the IL-1 Ra comprises amino acids 26 to 177 of human IL-1 Ra, preferably amino acids 26 to 177 of the sequence of SEQ ID NO: 1. Derivatives of IL-1 Ra are preferably homologous to natural IL-1 Ra and preferably have a homology or identity to natural IL-1 Ra of at least 60%, more preferably at least 70%, 75%, 80%, 85%, 90%, 95% and most preferably at least 98% over a range of at least 20 contiguous amino acids, preferably at least 40, 60, 80 or at least 100 contiguous amino acids, most preferably the entire length of IL-1 Ra. Particularly preferred are the IL-1 Ra, also called orthokin, which can be isolated from natural biological samples, such as blood, and the IL-1 Ra fragment with the amino acids 26 to 177 of human IL-1 Ra, also called anakinra. The recovery of orthokine is described inter alia in the patent applications WO 00/46249 A1 and WO 03/080122 A1. Anakinra and other IL-1 antagonists that can be used in this invention are described, inter alia, in patent application EP 0 343 684 A1. When obtaining IL-1 Ra from natural biological samples such as blood, such as in Orthokin, the IL-1 Ra solution obtained preferably also contains growth factors, which may also be responsible for the surprising effectiveness of the combination of active substances according to the invention. Therefore, according to the invention, the cytokine antagonist may also be present in combination with one or more growth factors or replaced by one or more growth factors. The growth factor according to the invention preferably has an anabolic effect. Examples of suitable growth factors are TGF-β, IGF, BMP, HGF and VEGF. Also included are analogues, derivatives and fragments of these growth factors, as long as they have the desired effect, ie in particular their effect as a growth factor.

The corticosteroid used in the invention may be any naturally occurring or synthetically produced corticosteroid. In particular, it may be a glucocorticoid, a mineralocorticoid or an androgen, with glucocorticoids preferably being used. Likewise, a mixture of two or more corticosteroids may be used as described herein. Examples of glucocorticoids are cortisone, hydrocortisone, prednisone, prednisolone, cloprednol, deflazacort, fluocortin, triamcinolone, dexamethasone, methylprednisolone, fluprednisolone, clocortolone, clobetasone, alclomethasone, flumethasone, fluopredniden, fluorandrenolone, betamethasone, beclomethasone, fluocortolone, mometasone, fluticasone, Halomethasone, fluocinolone, diflobarone, desoximethasone, fluocinonide, amcinonide, halcinonide, diflucortolone, clobetasol and paramethasone. Examples of mineralocorticoids are aldosterone, desoxycorticosterone and fludrocortisone, and examples of androgens are dehydroepiandrosterone (DHEA) and estrogens. The corticosteroid can be used as a free compound or in the form of a salt, ester or prodrug. In preferred embodiments, the corticosteroid used is triamcinolone, cortisone, hydrocortisone, prednisolone or prednisone. The corticosteroid is preferably crystalloid.

In preferred embodiments, the pharmaceutical compositions or kit of the invention are for use in the treatment of joint diseases such as osteoarthritis, arthritis, arthritis and inflammatory cartilage loss, tendon disease, degenerative

Spinal diseases and also autoimmune diseases. The osteoarthritis to be treated may be due to overwork, congenital or traumatic causes, or the result of another condition such as inflammation. The osteoarthritis to be treated is preferably an activated osteoarthritis or an inflammatory osteoarthritis. The pharmaceutical compositions of the invention may be used for the treatment of osteoarthritis and arthritis are used on any joint, such as knee joint, hip joint, ankle, shoulder joint, vertebral joints, finger joints, elbow joint, toe joints, temporomandibular joint and wrist. The arthritis to be treated may be an infection-related arthritis such as bacterial arthritis or a noninfection-related arthritis such as rheumatoid arthritis, psoriatic arthritis or gouty arthritis. Alternatively, the pharmaceutical composition of the invention and / or the kit of the invention may also be for use in the treatment of a disease other than one or more of said diseases (such as rheumatoid arthritis). The degenerative spinal disease to be treated may be, for example, a herniated disc. Autoimmune diseases include, among others, autoimmune diseases of the joints such as ankylosing spondylitis, rheumatoid arthritis and systemic lupus erythematosus, as well as other autoimmune diseases such as atopic dermatitis and alopecia areata (circular hair loss).

The pharmaceutical compositions of the invention or the kit according to the invention are preferably intended for local administration. Therefore, they are in preferred embodiments for injection, in particular for injection into the body region to be treated, in particular in the affected joint, to the affected nerve root or in the affected disc, or determined in the local environment thereof. The pharmaceutical composition is thus intended in particular for intraarticular and / or periradicular injection. Alternatively, the pharmaceutical compositions of the invention may be formulated for topical administration, particularly as a cream or gel, or for systemic administration, especially oral administration in the form of tablets, capsules or lozenges. The mode of administration depends inter alia on the disease to be treated. In local osteoarthritis or degenerative spinal disease, therefore, local administration of the pharmaceutical compositions of the invention is preferred. In preferred embodiments, the pharmaceutical compositions of the invention or the kit of the invention are intended or suitable only for administration other than systemic administration.

The pharmaceutical compositions according to the invention are in each case suitably formulated in a manner known to the person skilled in the art for the various administration routes. Thus, a suitable for injection pharmaceutical composition is preferably present as a solution or dispersion or in dry form, for example as a powder or lyophilisate, which must be dissolved prior to injection in a suitable solvent such as water. The pharmaceutical compositions of the invention contain the cytokine antagonist and / or the corticosteroid in therapeutically effective amounts. The cytokine antagonist is therefore preferably in a concentration of 0.5 to 150 mg / dose is present in the cytokine antagonist-containing pharmaceutical compositions, but may also be present in significantly lower concentrations such as 1 ng / dose or more, for example between 1 and 1000 ng / dose. These low dose levels may be used particularly in combination with growth factors and / or natural IL-1 Ra preparations such as orthokin compositions. The higher dose concentrations are preferred, for example, in recombinantly produced cytokine antagonists such as anakinra. The corticosteroid is preferably present at a concentration of from 1 to 80 mg / dose, more preferably from 5 to 40 mg / dose in the corticosteroid-containing pharmaceutical compositions. In addition, the pharmaceutical compositions of the invention may further contain one or more excipients and / or one or more excipients.

The pharmaceutical compositions of the invention may also be intended for the treatment of patients already receiving another treatment for the relevant disease, i. have been subjected to, for example, osteoarthritis, arthritis, and / or degenerative spinal disease, especially if this other treatment has not been successful or the disease symptoms have at least partially returned despite initially successful treatment. In preferred embodiments, this other treatment is a therapy with a cytokine antagonist such as Anakinra or Orthokin but without a corticosteroid, or a therapy with a corticosteroid, especially a glucocorticoid as described above, but without a cytokine antagonist. Patients according to the invention may be humans as well as animals suffering from any of the diseases described herein. Thus, the pharmaceutical compositions of the invention may be useful for the treatment of a human and / or an animal such as a dog, a cat, a horse, a cow, a pig, a goat, a camel or the like.

In another embodiment of the invention, the pharmaceutical compositions of the invention are intended for use in combination therapy with exosomes. Exosomes are small, lipid-membrane-enveloped vesicles found in the extracellular space of, for example, the human body. They are formed by cells by cleavage from the cellular plasma membrane and secreted. Normally, these exosomes also contain proteins taken from their cell of origin.

The exosomes may be contained directly in the pharmaceutical composition of the present invention or may be administered simultaneously or sequentially in a separate composition. Preferably, the exosomes are obtained from a blood sample. The exosomes are preferably autologous or allogenic with respect to the patient to be treated. Methods for obtaining and administering exosomes are described, for example, in patent application WO 2006/007529 A2. Thus, a preferred embodiment provides that the pharmaceutical compositions of the invention are for a treatment in which exosomes are first recovered from a patient's blood sample and subsequently re-administered to that patient together with a cytokine antagonist and a corticosteroid.

In the event that the combination therapy involves exosomes obtained from a blood sample of a patient, it is sometimes preferable to perform a centrifugation step of at least 100,000 g in order to concentrate the exosomes, since such high relative centrifugal accelerations are particularly are suitable for concentrating exosomes. This is true of the first, second, third, fourth, fifth and / or sixth aspects of the present invention (a pharmaceutical composition containing a corticosteroid together with a cytokine antagonist, a pharmaceutical composition containing a cytokine antagonist for use in a combination therapy together with a corticosteroid A pharmaceutical composition containing a corticosteroid for use in a combination therapy together with a cytokine antagonist, kit and / or uses of a cytokine antagonist or corticosteroid, respectively). Preferably, such a centrifugation step is carried out in the treatment of diseases in which an increased concentration of exosomes makes sense, preferably in the treatment of rheumatoid arthritis. More preferably, such a centrifugation step is generally performed in the event that the combination therapy involves exosomes derived from a blood sample of a patient. The centrifugation step with at least 100,000 g is preferably carried out for at least 30 minutes, in particular at least 60 minutes, since the concentration is then particularly effective.

In the following some examples for the disclosure of the invention are presented.

Below are several case studies of patients with advanced osteoarthritis. These were treated with a combination therapy with a cytokine antagonist (e.g., recombinant IL-1 Ra recombinant or IL-1 Ra derived from autologous blood samples) and a corticosteroid.

Abbreviations:

right

Ii left bds on both sides

 IRO internal rotation

 ARO external rotation

 VAS visual analog scale for pain sensation (0 to 10)

 WOMAC patient questionnaire on osteoarthritis

 CRP c-reactive protein, a blood-detectable marker of inflammation

 OSG thigh joint

Case I: A., 69 years

 Diagnosis: coxarthrosis re, grade III-IV in radiograph; Hip pain with limp for about 3 years, patient still does not want a hip replacement; clinical limp, IRO / ARO re hip 5/0/5, incidental Lyme disease known;

 Therapy: 5x weekly injections of 1 mg anakinra with 10 mg triamcinolone were given.

 Result: At the end of treatment (after the 5th session) the Schonhinken had disappeared. IRO / ARO right now 10/0/15; VAS improved from 8 to 3; 70% pain reduction (personal assessment of the patient according to the current degree of pain (here 30%) compared to the pain before the treatment (100%), the pain reduction is the difference between present pain and pain before the treatment (100% - 30% = 70%)). After 3 months of control unchanged improvement compared to the status at the end of therapy.

Case II: R., 54 years, female

 Diagnosis: clinically and radiologically rhizarthrosis re moderate with severe pain (VAS 6) with functional impairment when gripping objects. Cortisone injections in the past without success.

Therapy: A 5-time injections treatment for the right thumb joint of 0.5 mg anakinra in combination with 1 mg triamcinolone (at the 1st, 3rd and 5th sessions) was performed.

 Result: At the end of the therapy freedom from pain, 100% improvement; VAS now 0; Right hand function normal; 3 months after the end of treatment, the result remained very good.

Case III: W., 49 years, male

 Diagnosis: Clinically and radiologically moderate knee arthrosis bds grade II-III for many years. Hyaluronic acid injections and injections of cortisone in the knee in the past without success

 Therapy: A 6-course anakinra treatment with 10 mg triamcinolone was made at the 1, 3, and 5 sessions.

Result: 100% improvement in pain at the end of therapy, right knee, left knee 70% improvement in pain Case IV: T., 45 years, male, musician

 Diagnosis: Radiological and Clinical Inpingement Ii Shoulder for about 2 years; previous cortisone injections without success; Abduction reduced by about 15 degrees

Therapy: An injection of 50 mg Anakinra with 10 mg Triam plus one control was made. The injection of anakinra and 10 mg of triam was mixed in a syringe and mounted sterile.

 Result: In the subsequent control one week after the treatment complete freedom from pain (100%), function normal. Because of the good therapy success no further treatments were planned. Follow-up checks were unremarkable.

Case V: K., 45 years, male

 Diagnosis: Clinically and radiologically medial knee osteoarthritis re grade IV and retropatellar for many years; From the outside, the attempt to have a remodeling osteotomy or a knee replacement on the right was recommended. However, the patient wanted a conservative therapeutic trial. In the past, injections of hyaluronic acid and cortisone (triamcinolone) had no clinical success.

 Therapy: A 10-course anakinra treatment (100 mg per session) with parallel administration of 10 mg triamcinolone (total treatment dose 50 mg) twice weekly was performed.

 Result: At the end of therapy 65% pain reduction after 3 months.

Case VI: M., 50 years, male

 Diagnosis: Clinical and radiological (MRI) internal nerve damage right knee III with marked deterioration of function and pain medial right knee. OP was recommended, patient would like to not surgical alternative.

 Therapy: A single injection of 10 mg triamcinolone and 1 mg anakinra was made.

 Result: One month after injection 80% pain improvement, patient does not want surgery any more, but re-injection, because it helped very well. At follow-up 6 months after therapy, no OP request remains, patient pain free.

Case VII: G., 42 years, male

 Diagnosis: Clinically and radiologically lumbar facet arthrosis for many years, secondary to diverticulum. Inpatient treatment with cortisone injections into the lumbar facets without success.

Therapy: 6 therapy sessions twice weekly with injections of 6 mg anakinra into the lumbar facet were made. An additional 3 mg of triamcinolone was administered at the first injection, and only 6 mg anakinra were administered in follow-up treatments 2-6. Result: 60% pain improvement, VAS improved from 7 before treatment to 3 after treatment. Controls unchanged after 5 months.

In a treatment with anakinra and cortisone, a case series (number of patients: N = 12) was statistically evaluated. The pain level was previously defined as 100. The pain level afterward was 30, 0, 30, 0, 35, 0, 40, 60, 40, 50, 80 and 50 for the individual patients.

Result:

average pain reduction: 71, 5% after approx. 3 months (before therapy 100% pain, end of treatment 28.5% pain), standard deviation: SD = 22, p <0.001.

Orthokin and cortisone therapy for osteoarthritis:

 Number of patients: N = 129, average follow-up period: 3 months, average pain reduction: 71% (i.e., reduction from 100% pain before treatment to 29% after treatment), strikingly rapid onset of action.

Case VIII: T., 56 years, female

 Diagnosis: Clinically radiologically there is medial and retropatellar gonarthrosis Ii, grade IV. A total of knee replacement has already been planned on the left;

 Therapy: 3 injection of exosomes combined with anakinra and 10 mg triamcinolone in the left knee (2x weekly) while avoiding knee surgery.

Result: At the time of the third injection 100% pain improvement, significant improvement in function. The operative appointment was canceled and the patient was still pain-free 5 months after the end of therapy.

Case IX: L, 57 years, male

 Diagnosis: severe shoulder pain II for 6 months (VAS 8); since then significantly disturbed sleep. The patient has been unable to sleep for the past 6 months, which is why he is disturbed by general well-being. Numerous injections of cortisone into the left shoulder were unsuccessful. A surgery for the left shoulder was agreed. Here an attempt should be made to avoid the operation. Radiographic and clinical signs of partial rotator cuff rupture and subacromial tightness with complete left shoulder stiffness; Discomfort left arm with weakness of force of hand and forearm left, grade 4.

 Therapy: The injections were applied dorsally and laterally in the left shoulder. 2 ml Orthokin were administered with 10 mg Anakinra and 10 mg Triamcinolone via a syringe in the left shoulder. Therapy was performed on 4 consecutive days.

Result: Already on the second day of treatment, the patient reported an extreme pain improvement with a pain reduction of 90%. VAS had dropped from 8 to 1, the shoulder was up free and normally mobile. The patient was able to sleep through the first 6 months. The patient was thus greatly improved in his general well-being. Continuation of therapy until treatment day 4. Furthermore, there was a clear improvement as on treatment day 2, at the follow-up 6 months after treatment, there was an unchanged positive finding. The operation was canceled, mobility was free, the patient can easily lift suitcases and books above shoulder level again.

Case X: F., 45 years, female

Diagnosis: Complete right shoulder stiffness for approx. 8 months. All previous therapies were without success, an operation was planned. Patient wanted attempt of renewed conservative treatment. The night sleep was not possible for several weeks. Shoulder pain starting on the left side, main findings but right shoulder, there VAS 9 with severe acute attacks up to 10, as a result reduced general condition. Therapy: Treatment of the right shoulder from a combination of 2 ml Orthokin administered separately together with another syringe from a combination of 150 mg Anakinra and 5 mg Triamcinolone on 6 consecutive days.

Result: From the 5th day 85% pain improvement. Nocturnal sleep was possible since the second treatment, thereby significantly improved general condition. VAS at the end of treatment at 1st follow-up 8 months after treatment continued to show a very good unaltered result; OP was canceled.

Case X: p. 25 years, male

 Diagnosis: Severe juvenile rheumatoid arthritis for approx. 15 years.

Treatment with 25 mg Enbrel 2 times a week, 10 mg methotrexate, 5 mg decortin and naproxen 2x1 a day. Massive synovitis and pain both OSG and both shoulders. Abduction of both shoulders before treatment 60 degrees. Laboratory CRP value: 5.35 (to 0.5 mg is normal); Leukocytosis.

 Therapy: Blood was drawn for preparation of exosomes in a 6 ml syringe (Orthokin syringe). Thereafter, incubation at 37 degrees for 24 h, wherein when filling the syringe with blood previously 1 mg Anankinra (IL-1 Ra) and 2 mg prednisolone were applied to the syringe. After various centrifugation steps (up to 100,000 g), the mixture was then applied to the patient's OSGe and shoulders.

Result: Significant swelling of the joints after 3 days. Clinical and laboratory control after 9 days: 80% improvement in pain, normal OSG, no swelling. CRP value now at 1, 93. Improvement also in other affected joints that were not injected locally. Overall quality of life improved significantly. The control after 3 months shows a stable situation. VAS before treatment 9, since the first week after injection VAS 3. Patient very satisfied, work can resume.

Claims

claims 1 . A pharmaceutical composition comprising a corticosteroid together with a cytokine antagonist and optionally a growth factor for the treatment of osteoarthritis, wherein the cytokine antagonist is the naturally occurring or recombinant interleukin antagonist IL-1 Ra protein, in particular Orthokin or Anakinra, and wherein the pharmaceutical Composition suitable for local administration. 2. A pharmaceutical composition containing a cytokine antagonist and optionally a growth factor for treating osteoarthritis in a combination therapy together with a corticosteroid, wherein the cytokine antagonist is the naturally occurring or recombinant interleukin antagonist IL-1 Ra protein, in particular Orthokin or Anakinra, and wherein the pharmaceutical composition is suitable for local administration. A pharmaceutical composition containing a corticosteroid for the treatment of osteoarthritis in a combination therapy together with a cytokine antagonist and optionally a growth factor, wherein the cytokine antagonist is the naturally occurring or recombinant interleukin antagonist IL-1 Ra protein, in particular Orthokin or Anakinra, and wherein the pharmaceutical composition is suitable for local administration. A kit comprising a pharmaceutical composition containing a cytokine antagonist and optionally a growth factor and a pharmaceutical composition containing a corticosteroid for the treatment of osteoarthritis, wherein the cytokine antagonist is the naturally occurring or recombinant interleukin antagonist IL-1 Ra protein, in particular Orthokin or Anakinra, and wherein the pharmaceutical compositions are suitable for local administration. A pharmaceutical composition according to claim 2 or 3 or a kit according to claim 4, wherein the pharmaceutical composition (s) is / are intended for simultaneous or sequential administration of the cytokine antagonist or growth factor and corticosteroid. 6. Pharmaceutical composition or kit according to one of claims 1 to 5, comprising a further cytokine antagonist selected from the group consisting of interleukin antagonists, in particular IL-1 antagonists such as IL-1 Ra, tumor necrosis factor (TNF) antagonists, in particular a TNF-a antagonist such as an anti-TNF-a antibody, interferon antagonists and chemokine antagonists. A pharmaceutical composition or kit according to any one of claims 1, 2 and 4 to 6, wherein the cytokine antagonist is present at a concentration of 0.5 to 150 mg / dose in the cytokine antagonist-containing pharmaceutical composition. 8. A pharmaceutical composition or kit according to any one of claims 1 to 7, wherein the corticosteroid  (a) a glucocorticoid such as cortisone, hydrocortisone, prednisone, prednisolone, cloprednol, deflazacort, fluocortin, triamcinolone, dexamethasone, methylprednisolone, fluprednisolone, clocortolone, clobetasone, alclomethasone, flumethasone, fluopredniden, fluorandrenolone, betamethasone, beclomethasone, fluocortolone , Mometasone, fluticasone, halomethasone, fluocinolone, diflorasone, desoximethasone, fluocinonide, amino-nide, halcinonide, diflucortolone, clobetasol, paramethasone;  (b) a mineralocorticoid such as aldosterone, desoxycorticosterone and fludrocortisone; or  (c) an androgen such as dehydroepiandrosterone (DHEA) and estrogens;  or a salt, ester or prodrug thereof. The pharmaceutical composition or kit according to any one of claims 1 and 3 to 8, wherein the corticosteroid is present at a concentration of 1 to 80 mg / dose in the corticosteroid-containing pharmaceutical composition. The pharmaceutical composition or kit of any one of claims 1 to 9, wherein the growth factor is selected from the group consisting of TGF-β, IGF, BMP, HGF and VEGF. 1 1. A pharmaceutical composition or kit according to any one of the preceding claims, wherein the osteoarthritis is an activated osteoarthritis or an inflammatory osteoarthritis. 12. A pharmaceutical composition or kit according to any one of claims 1 to 1 1, wherein the local administration is selected from the group consisting of injection into the affected body region, in particular in the affected joint the affected nerve root or in the affected disc, or in the local environment thereof; intra-articular injection; and topical administration. The pharmaceutical composition or kit according to any one of claims 1 to 12, wherein the pharmaceutical composition (s) further contain (s) a carrier and / or an excipient. A pharmaceutical composition or kit according to any one of claims 1 to 13 for use in combination therapy with exosomes. A pharmaceutical composition or kit according to claim 14, wherein the exosomes are obtained from a blood sample. 16. A pharmaceutical composition or kit according to claim 14 or 15, wherein the exosomes are autologous or allogenic with respect to the patient to be treated. Use of a cytokine antagonist and optionally a growth factor for the manufacture of a pharmaceutical composition for use in a combination therapy together with a corticosteroid, wherein the cytokine antagonist is the naturally occurring or recombinant interleukin antagonist IL-1 Ra protein, in particular Orthokin or Anakinra, and wherein the pharmaceutical composition is suitable for local administration. Use of a corticosteroid for the preparation of a pharmaceutical composition for use in a combination therapy together with a cytokine antagonist and optionally a growth factor, wherein the cytokine antagonist is the naturally occurring or recombinant interleukin antagonist IL-1Ra protein, especially Orthokin or Anakinra, and wherein the pharmaceutical composition is suitable for local administration.