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Common Principles of Treatment of Systemic Vasculitis

Irina Alexandrovna Zborovskaya – , director of the Federal Budgetary State Institution (FBSI) “Research and development institute of clinical and experimental rheumatology” of the RAMS, cathedral professor of hospital therapy with the course of clinical rheumatology of the doctors improvement faculty of Volgograd state medical university, doctor of medical sciences. Some stages in the treatment of systemic vasculitis are typically singled out. They are the following:
  1. Remission induction that is rapid control of immune response.
  2. Prolonged immunosuppressive therapy (not less than 0,5 – 2 years). The doses which are sufficient for achieving clinical and laboratory remission should be administered. Rapid control of immune response in an exacerbation of the disease.
  3. Achievement of steady, complete remission of vasculitis, determination of the extent of organ involvement, treatment, rehabilitation.
Most western researchers emphasize the necessity of following a certain order in treating vasculitis. 1. Remission induction in combination with a short course of aggressive therapy (e.g. cyclophosphane, plasmapheresis). 2. Maintenance of remission. 3. Treatment of vasculitis in an exacerbation of the disease. The objective of the first stage foresees taking control of immune inflammation until ischemic, necrotic changes in organs and tissues develop. This objective can be achieved using the following:
  • use of large doses of glucocorticoids as a monotherapy or in combination with immunosuppressive agents, mainly of cytotoxic action as well as pulse therapy;
  • administration of intravenous immunoglobulin;
  • use of extracorporal methods of treatment (for example, plasmapheresis).
Treatment of microcirculatory abnormalities with drugs which influence rheological properties of the blood such as heparin, fraxiparin, or aggregation of platelets, such as pentoxyphyllin is typically performed at this stage. Pentoxyphyllin also suppresses synthesis of basic proinflammatory cytokines. In case of development of peripheral gangrene of soft tissues of the extremities, nodular periarteriitis (NP) and obliterating thromboangiitis vasoprostan or synthetic analogs of prostacyclin in combination with glucocorticoids and cyclophosphane are indicated. If there are any signs of replication of hepatitis B or C virus, especially in case of classic nodular periarteriitis and essential cryoglobulinemic purpura, IF- a drugs in combination with plasmapheresis are typically administered. In infected ulcers and skin necrosis broad spectrum antibiotics are used. The choice of drugs and the dosage at the 1st stage of the disease depends on the extent of the pathologic process, extent of functional abnormalities, patient’s age and intercurrent infections. The second stage of treatment of systemic vasculitis envisages prolonged maintenance therapy with glucocorticoids and immunosuppressive agents in the doses which are sufficient for achieving clinical and laboratory remission of vasculitis. At this stage the treatment is aimed at achieving complete remission of vasculitis, rapid control of vasculitis attack, prevention of possible complications or gastrointestinal involvement. At this stage of treatment drugs which affect the main links of pathogenesis of systemic vasculitis, such as disaggregants, aminoquinoline, calcium antagonists, serotonin blockers, etc. are administered. In some cases surgical intervention is indicated, especially if great vessels are impaired or complications of the pathological process develop. The main objective of this stage is achieving complete remission of vasculitis. If vasculitis persists for 3 months, at the third stage of treating systemic vasculitis glucocorticoid and cytostatic therapy is typically withdrawn. The extent of organ and system involvement as well as the extent of the disorder of their functions, methods of treating these abnormalities and evaluation of the quality of life of patients should be considered. The duration of this stage varies greatly. In most cases it depends on effectiveness of treatment and the time when the treatment was initiated. It also depends on the extent of functional abnormalities of organs and systems. The evaluation criteria of steady remission of vasculitis have not been developed yet. However, in an exacerbation of the disease aggressive therapy may be required. In this case glucocorticoids are usually the choice. 1. Glucocorticoids. Over 40 years glucocorticoids have been considered as the most powerful anti-inflammatory drugs which are used in the treatment of various diseases. Mechanisms of anti-inflammatory and immunomodulatory action of glucocorticoids
  • Regulation of secretion of Th-1 and Th-2- cytokines. Suppression of Th-1-type immune response.
  • Reduction of the amount of leukocytes entering the area of inflammation due to decreased expression of ELAM-1 and ICAM-1 adhesive molecules on the surface of endothelial cells.
  • Inhibition of gene transcription of anti-inflammatory IL-1, IL-8, FHO-α cytokines.
  • Changes of the functional activity of leukocytes and endothelial cells.
  • Suppression of phospholipase-A2 and cyclooxygenase-2 functional activity.
  • Inhibition of synthesis and effects of inflammatory mediators.
  • Suppression of activation, proliferation and synthesis of antibodies by B- lymphocytes.
  • Stimulation of apoptosis of T- and B-lymphocytes.
  • Suppression of IL-1-induced chemotaxis of neutrophils and production of superoxide radicals, prostaglandins and leucotrienes.
Nowadays glucocorticoids are widely used in the treatment of vasculitis. They are used in the treatment of all types of vasculitis. 1) Glucocorticoid therapy Glucocorticoid therapy is the most common method of treatment of some types of vasculitis and giant cill arteritis. Less commonly glucocorticoids are used in the treatment of Takayasu’s arteritis and some necrotic arteritis associated with local vessel involvement and absence of any signs of progression of the disease. Prednisolone is typically administered in severe abdominal forms of acute vascular purpura. It is supposed that glucocorticoid therapy in acute vascular purpura helps avoid renal involvement. However, some scientists do not agree with it. Glucocorticoids have both a systemic and local action. They can be used in the form of ointments and creams in the treatment of oral and genital organ ulcers. The dose of prednisolone in the treatment of systemic vasculitis is typically 1 – 2mg/kg (it should be administered in divided doses). Larger doses of prednisolone are used in the treatment of Churge-Strauss syndrome, Bechterew’s disease, Tacayasu’s vasculitis, acute vascular purpura and Wegener’s granulomatosis. If the treatment is effective, prednisolone should be given once a day, mainly in the morning. Suppressive therapy usually lasts for 3 – 4 weeks. Then the dose is gradually reduced until maintenance dose of 0,15 – 0,2 mg/kg/day is reached. The maintenance dose is typically administered for 1 – 5 years. Glucocorticoids may be given in a different regimen. 2) Alternating therapy Alternating glucocorticoid therapy is a method of treatment of systemic vasculitis which includes the use of glucocorticoids of a short action without pronounced mineral and corticoid activity, such as prednisone, prednisolone, methylprednisolone, once a day every 48 hours, mainly in the morning. Alternating therapy is typically administered to reduce adverse effects of glucocorticoids and preserve their therapeutic efficacy. This method of treatment is usually prescribed to patients taking glucocorticoids for a long period of time (for more than several weeks). Alternating therapy should not be administered if the patient takes glucocorticoids for a short period of time. It should not be administered at the initial stage of treatment or in an exacerbation of the disease. In case of systemic vasculitis this treatment is usually ineffective. It is considered that in systemic vasculitis alternating glucocorticoid therapy is administered as maintenance therapy. 3) Pulse therapy According to research, 75% of patients with active lupus nephritis, central nervous system involvement, pneumonitis, polyserositis, vasculitis and thrombopenia make a quick recovery with pulse therapy. Nowadays the earlier the patient begins to receive pulse therapy, the quicker the disease activity is suppressed in systemic vasculitis. It is believed that pulse therapy makes it easier for the patient to take glucocorticoids later in life. Early findings demonstrate that repeated courses of pulse therapy (1 – 3 days a month) are considered as alternatives to treatment with cytostatics. In Wegener’s granulomatosis, microscopic polyvasculitis, nodular periarteritis, systemic lupus erythematosus and rheumatoid vasculitis pulse therapy is typically administered every month for 9 – 24 month successively. It means that repeated courses are usually administered. According to Rheumatology Institute findings, repeated courses of pulse therapy are of great benefit. For example, in Takayasu’s arteritis, repeated courses of pulse therapy are usually administered once a month for 7 – 12 months. Methylprednisolone in the form of solution of sodium hemosuccinate is most commonly used for pulse therapy. Dexamethasone (for example, dexaven in the dose of 2mg/kg a day) has been used instead of methylprednisolone lately. It is 7 times as active as prednisolone. Dexamethasone has a well pronounced anti-inflammatory action. It does not retain Na+ ions in the body and does not affect excretion of K+ ions. The half-life of dexamethasone is 36 – 54 hours, while for methylprednisolone it ranges from 12 to 36 hours. There is evidence for high effectiveness of pulse therapy with dexamethasone in patients with thrombocytopenic purpura. Pulse therapy with dexaven (dexamethasone sodium phosphate) in the dose of 2mg/kg per day is beneficial in patients with systemic lupus erythematosus and rheumatoid arthritis. It has been proved that pulse therapy with dexaven has a well pronounced anti-inflammatory action. It also regulates hemostasis due to suppression of immunopathologic processes which initiate blood coagulation. Reasons for administration of pulse therapy in combination with glucocorticoids in the treatment of systemic angiitis
Disease Clinical manifestations which suggest the use of pulse therapy
Periarteritis nodosa* Peripheral gangrene, polyneuropathy, gastrointestinal  involvement, exacerbation of the disease
Microscopic polyangiitis* Rapidly progressing glomerulonephritis, exacerbation of the disease
Wegener’s granulomatosis* Renal and pulmonary involvement, exacerbation of the disease
Churg-Strauss syndrome * Exacerbation of the disease
Giant cell arteritis Ocular involvement
Takayasus arteritis* Remission  induction, exacerbation of the disease, preoperative preparation at an active stage of the disease
Acute vascular purpura* Gastrointestinal involvement, exacerbation of the disease
Essential purpura** Renal involvement, exacerbation of the disease
Obliterating thromboangiitis* Remission induction, gangrene of the extremity
Behçet’s disease Ocular involvement
Rheumatic gout* Gangrene of the extremity, polyneuropathy, digital arteritis, skin vasculitis
Sjögren’s disease* Cryoglobulinemical angiitis
* – pulse therapy is administered in combination with cyclophosphan; **- pulse therapy is administered in combination with plasmapheresis However, the results of clinical research testify to low effectiveness of glucocorticoid therapy, especially in the treatment of systemic necrotic vasculitis associated with severe, rapidly progressing impairment of small vessels. It is necessary to emphasize that large doses of glucocorticoids should be combined with active cytostatic therapy, mainly with cyclophosphamide, in patients with systemic necrotic vasculitis as well as in severe forms of hemorrhagic vasculitis, Churge-Strausse syndrome, severe rapidly progressing impairment of vessels and kidneys. Such combined therapy can help improve prognosis of the disease. 2. Cytotoxic drugs. Cytotoxic drugs of three basic groups are used in the treatment of systemic vasculitis. They are the following: alkylating agents (for example, cyclophosphamide), purine analogs (for example, azathioprine), antagonists of folic acid (for example, methotrexate). The latter do not have well pronounced cytotoxic activity in small doses. 1) Cyclophosphamide has been used in the treatment of vasculitis for more than 25 years. Cyclophosphamide affects different links of pathogenesis of vasculitis. Basic mechanisms of action of cyclophosphan in angiitis
1. T- and B-cell lymphopenia is typically noted.
2. The synthesis of antibodies by B-lymphocytes is suppressed.
3. The functional activity of neutrophils, natural killers, activated CD8+ T-lymphocytes is suppressed.
4. Expression of adhesive molecules on the surface of endothelial cells is decreased.
a) Cyclophosphamide is used in the treatment of necrotic vasculitis due to its effects on the mediators of vessel involvement. Along with immunosuppressive activity, cyclophosphamide has an immunostimulatory action which might be associated with different sensitivity of T- and B- lymphocytes to this drug. Its effects on the immune system depend on certain features of therapy. It is determined that taking small doses of cyclophosphamide for a long period of time may lead to depression of cellular immunity, while intermittent administration of large doses of cyclophosphamide may cause suppression of its humoral link. Cyclophosphamide is beneficial in the treatment of necrotic vasculitis, such as Wegener’s granulomatosis, nodular periarteritis and Churge-Strausse syndrome. b) Intermittent pulse therapy with cyclophosphamide is considered as the most effective method of treatment of systemic rheumatoid vasculitis. Pulse therapy with cyclophosphamide in combination with glucocorticoids is typically administered in the treatment of Takayasu’s arteritis, obliterating thrombovasculitis and Behchet’s disease. Development of rapidly progressing glomerulonephritis is considered as indication for administration of cyclophosphamide therapy in hemorrhagic vasculitis. c) There are two basic ways of administration of cyclophosphamide. They are the following:
  • Oral administration of cyclophosphamide in the dose of 1 – 2 mg/kg/day for 10 – 14 days with the following titration depending on the level of leukocytes in peripheral blood.
In rapidly progressing vasculitis cyclophosphamide is administered in the dose of 4 mg/kg/day for 3 days. Then the dose should be reduced to 2 mg/kg/day and it should be administered for 7 days. The total duration of treatment with cyclophosphamide is 12 months as soon as complete remission is achieved. Then the dose is gradually reduced for 2 – 3 months by 25 – 50 mg. Titration of the dose of cyclophosphamide cubic of great importance. The concentration of leukocytes must not be more than 3000-3500 mm3 and the concentration of neutrophils should be 1000-1500 mm3. At the beginning of treatment the concentration of leukocytes should be checked every other day and when the number of leukocytes has been stabilized, their concentration should be checked once every 2 weeks. The dose of cyclophosphamide should be reduced by 25 – 50 % in patients with renal failure (serum creatinine is more than 2 mg). The second way of administration of cyclophosphamide is the following:
  • Bolus intermittent intravenous administration of large doses of cyclophosphamide (500 – 1000 mg/m2 sguare metre a day or 10 – 15 mg/kg a day) once a month for first 4 – 6 months and then once every 3 months.
Treatment with cyclophosphamide is usually combined with moderately large or large doses of glucocorticoids, including pulse therapy. It is believed that both ways of administration of cyclophosphamide are equally well. But when intermittent intravenous administration of cyclophosphamide is used, the risk of development of toxic reactions is lower. However, there is evidence for positive results of pulse therapy and oral administration of cyclophosphamide in relation to short-term results as, for example, in Wegener’s granulomatosis. Long-term remission of disease is possible only if cyclophosphamide is administered every day for a long period of time. Thus, pulse therapy and prolonged administration of small doses of cyclophosphamide have different therapeutic effects. According to T. Cupps, administration of small doses of cyclophosphamide has an advantage over intermittent administration of large doses of the drug. For example, the risk of development of suppression of the bone marrow in the induction phase is higher in patients who received pulse therapy than in those receiving small doses of cyclophosphamide. As the amount of leukocytes in peripheral blood can be determined only 10 – 20 days after the beginning of treatment, the dose of cyclophosphamide to be taken is changed during this period. Alternatively, in daily administration of cyclophosphamide the dosage can be selected considering renal function and the amount of leukocytes in peripheral blood. Thus, the risk of development of toxic reactions at an early stage of treatment with large doses of cyclophosphamide is higher in patients with dysfunction of many organs as well as in rapidly progressing renal failure, intestinal ischemia and in patients receiving large doses of glucocorticoids. However, according to R.A. Lugmani, et al., suppression of the bone marrow and infectious complications most commonly occur in constant administration of cyclophosphamide rather than in pulse therapy. Hemorrhagic cystitis is the most common complication occurring during treatment with cyclophosphamide. It occurs in 30% of patients with systemic vasculitis. Its occurence is much lower in parenteral administration of cyclophosphamide than in oral administration. It is recommended to take mesna, a detoxicant, for prevention of hemorrhagic cystitis. Mesna is typically administered intravenously in the dose which makes up 20% of that of cyclophosphamide. Mesna should be administered before cyclophosphamide and 4 – 8 hours after taking cyclophosphamide. If the patient develops severe cystitis, cyclophosphamide should be withdrawn. Patients with mild cystitis can be treated with small doses of cyclophosphamide under thorough clinical and instrumental (cystoscopy) control. Granulopenia is another common complication of cyclophosphamide therapy. It is the most common complication which requires immediate withdrawal of the drug. At the beginning of treatment complete blood analysis should be performed every two weeks and as soon as the process has stabilized and the dosage has been adjusted, it should be performed every 2 – 3 months. The drug is usually withdrawn if the number of leucocytes is less than 3,5*109 /l. Cases of persistent hypogammaglobulinemia have also been reported. This complication is very dangerous especially in combination with granulopenia as it increases the risk of development of infectious complications. Patients receiving cyclophosphamide therapy are vulnerable to infections even when the concentration of neutrophils and antibodies is normal. The drug should be withdrawn if the patient develops any infectious complications. Patients taking cyclophosphamide for a long period of time run the greatest risk of development of malignancies. About a hundred cases of non-Hodgkin’s lymphoma and thirteen cases of lymphogranulomatosis have already been reported. It was found out that the incidence of cancer of the vagina and uterine cervix is greater in the first four years of treating systemic lupus erythematosus with cyclophosphamide. Nausea is a common toxic complication which makes it impossible to administer pulse therapy with cyclophosphamide. Intravenous administration of metoclopramide in the dose of 1 – 3 mg/kg (the maximum dose is 10 mg/kg) in 100 ml of 0,9% solution of sodium chloride 15 minutes before the beginning of infusing cyclophosphamide in combination with sedatives (for example, diazepam 5 – 10 mg) is used for prevention of nausea. Alopecia most frequently occurs when the patient takes large doses of cyclophosphamide. As soon as the drug is withdrawn, hair stops falling out. Oligospermia or azoospermia in the male and oligomenorrhea or amenorrhea in the female are common side effects of cyclophosphamide therapy. Patients run the greatest risk of development of oligospermia or oligomenorrhea when they take cyclophosphamide for a long period of time or in large doses. It is considered that pulse therapy with cyclophosphamide during menstruation makes it possible to reduce the risk of sterilization. 2) Azathioprine In the human body azathioprine is metabolized in erythrocytes and in the liver with the formation of biologically active molecules. It is excreted through kidneys. In contrast to alkylating agents azathioprine has a cytostatic action. Azathioprine can cause peripheral T- and B- lymphopenia. If the patient takes large doses of azathioprine, it can cause reduction of the level of CD4+ T- lymphocytes and prolonged administration of azathioprine increases synthesis of antibodies. As T-suppressors are particularly sensitive to azathioprine, administration of small doses may lead to increased production of antibodies. Nowadays in the treatment of systemic vasculitis azathioprine is used as a second option drug. It is usually administered as soon as remission of the disease with the help of cyclophosphamide has been achieved. The optimum dose is 1 – 3 mg/kg/day. In the first two weeks it is necessary to have the blood checked and the amount of platelets determined. At a later period of time the laboratory analysis of blood should be made every 6 – 8 weeks. The dose should be reduced by 50 – 70% in patients with renal failure or those taking allopurinol. The maintenance dose of azathioprine is usually 50mg/day. Combined therapy with azathioprine and prednisolone helps prevent the progression of vessel involvement in patients with rheumatoid arthritis, vasculitis and Behçet’s disease. Nausea and vomiting are most common side effects of azathioprine therapy.  They usually subside when the drug is taken with meals or in divided doses. Hepatic involvement occurs in 1% of patients and might be associated with allergy to azathioprine. It is recommended to check the level of bilirubin and hepatic enzymes once every three months. Leukopenia which usually occurs at the beginning of treatment with azathioprine can be associated with increased sensitivity to the drug. However, in most cases leukopenia testifies to suppression of the bone marrow. Leukopenia occurs in 30% of cases. Azathioprine is typically withdrawn until indices of blood become normal. Treatment is usually renewed with smaller doses. Herpetic infection is the most common infectious complication. It does not always correlate with the extent of granulopenia. Patients taking azathioprine may develop malignancies. It is believed that people are genetically predisposed to the development of toxic reactions to azathioprine. Azathioprine is contra-indicated in pregnancy. 3) Methotrexate Methotrexate belongs to the group of antimetabolites. Its structure is similar to that of folic acid. The maximum concentration of methotrexate in the blood is reached 2 – 4 hours after administering the drug. Taking the drug with meals does not affect the extent of its absorption and bioavailability. Excretion of methotrexate occurs mainly through kidneys due to glomerular filtration and canalicular secretion. The half-life of methotrexate ranges from 2 to 6 hours. Renal failure can slow down excretion of methotrexate and increase its toxicity. Polyglutamine metabolites of methotrexate are typically found in cells 7 days after administration of methotrexate, though it is easily excreted through the blood. Common mechanisms of action of methotrexate are presented in table. Basic mechanisms of action of methotrexate in angiitis
Proliferation of mononuclear cells and synthesis of antibodies by B-lymphocytes is suppressed.
IL-1 activity is suppressed.
Proliferation of endothelial cells is suppressed.
The functional activity of neutrophils is suppressed.
Methotrexate is administered 3 times a week. Oral or parenteral administration is beneficial. More frequent administration of methotrexate can cause acute or chronic toxic reactions. It is recommended to take the medicine in the morning or in the evening with a 12-hour interval. The initial dose of methotrexate is usually 7, 5 mg/week and in the elderly – 5 mg weekly. One decides on efficacy 4 – 8 weeks after the beginning of treatment. If there are no side effects and the patient is tolerable of the drug, the dose of methotrexate is gradually increased by 2,5 mg weekly. The maximum dose can be 25 mg. In systemic vasculitis the dose of methotrexate is typically 12,5 – 17,5 mg a week. When the dose of methotrexate is increased, the evaluation of toxicity is carried out 6 days after taking the drug. The biopsy of liver is usually undertaken when the total amount of methotrexate taken by the patient equals 1500 mg. Methotrexate is usually administered parenterally if oral administration is ineffective or if the patient develops any toxic reactions. Sometimes oral administration of methotrexate is ineffective due to its poor absorption in the gastrointestinal tract. Thus, the optimum concentration of methotrexate in the blood is not reached. Nowadays effectiveness of small doses of methotrexate (0,15 – 0,3 mg/kg/week) in combination with large doses of prednisolone (1mg/kg/day) is being studied in patients with nodular periarteritis associated with skin involvement and in patients with Wegener’s granulomatosis without any life-threatening complications. The most common side effects of methotrexate therapy include nausea and vomiting which develop 1 – 8 days after the beginning of treatment and they usually last for 1 – 3 days. The dose of methotrexate is usually reduced or parenteral administration is used. The use of symptomatic drugs, for example metoclopramide, is beneficial. In gastric and duodenal ulcers methotrexate is contra-indicated. In 6% of cases methotrexate is withdrawn due to stomatitis. Severe hematological abnormalities develop quite rarely. The risk of development of hematological complications increases in renal failure, deficit of folic acid and in combination of methotrexate with salicylates and other drugs having an antifolate action, especially trimethoprime and sulfamethoxasole. Alopecia and skin vasculitis develop less commonly. Pneumonitis occurs in 1 – 8% of cases due to allergy to methotrexate. It is typically used in patients with rheumatoid arthritis. Transitory increase of transaminase level which goes up upon taking large doses of methotrexate is also common. Two- or three-fold increase of transaminase concentration does not mean that methotrexate should be withdrawn. However, if transaminase concentration increases, methotrexate is withdrawn or the dose is reduced. Treatment with small doses of methotrexate can be associated with increased sensitivity to infectious complications. Methotrexate is withdrawn if the patient develops any infectious complications. 3 Intravenous immunoglobulin. 1) Intravenous immunoglobulin has been used in the treatment of vasculitis lately. Immunoglobulin has been used in medicine for the treatment of autoimmune diseases for 15 years. It is believed that therapeutic effectiveness of intravenous immunoglobulin in the treatment of autoimmune diseases and vasculitis is mediated by the following mechanisms:
  • Reversible blockade of IgG Fc-receptors of reticuloendothelial cells which helps prevent elimination of circulating cells sensitized by IgG autoantibodies from the bloodstream.
  • Blockade of  leukocyte and lymphocyte Fc-receptors.
  • Fc- dependent inhibition of the synthesis of autoantibodies by B-lymphocytes.
  • Modulation of suppressor and helper activity of T-lymphocytes; suppression of the compliment- dependent impairment of tissues.
  • Suppression of the synthesis of autoantibodies through the influence on the idiotype-antiidiotypic net.
  • Modification of recognition of antigen by target cells associated with the presence of soluble CD4, CD8 and HLA molecules in the drug.
  • Suppression of TNF-a production and increase of the synthesis of IL-1R.
  • V-gene dependent modulation of autoimmune response due to the presence of antibodies against idiotypic determinants of autoantibodies to neutrophilic cytoplasmic antigens, glycoprotein of IIb/IIIa platelets, DNA and phospholipids in the drug.
  • Suppression of the development of autoimmune and toxic reactions caused by superantigens of some microorganisms (the drug contains antibodies to some superantigens).
  • Suppression of the functional activity of cytokines due to the presence of natural anticytokine antibodies in the drug.
  • Changes of the structure and solubility of circulating immune complexes.
  • Platelet disaggregation due to their interaction with IIb/IIIa receptors on their membrane.
The scheme of administration of intravenous immunoglobulin has not been standardized yet. The dose usually varies from 0,4 to 2 g/kg/day. Immunoglobulin is administered intravenously for 3 – 5 days. If necessary, immunoglobulin is infused once every 4 weeks. 2) Treatment with intravenous immunoglobulin is a safe method of treatment, however, some patients develop side effects due to rapid infusion of immunoglobulin. Most common side effects include headaches, fever, chills, difficulty in breathing, pain in the abdomen and back, moderate hypotension. Antihistamine drugs or small doses of glucocorticoids are typically administered for prevention of side effects. True anaphylactic reactions caused by intravenous immunoglobulin occur quite rarely. Cases of aseptic meningitis and hemolytic anemia associated with the presence of agglutinins in immunoglobulin have already been reported. Moreover, transmission of infectious agents poses a threat to patients. However, this process occurs very rarely. 3) In systemic vasculitis intravenous immunoglobulin is typically the choice in the treatment of Kavasaki’s disease. Numerous studies have shown that the use of intravenous immunoglobulin may help avoid aneurysm of coronary arteries. It may also help eliminate other signs of systemic inflammation. It is considered that single administration  of immunoglobulin in the dose of 2 g/kg/day is similar to the standard course of treatment in the dose of 0,4 g/kg/day for 4 days. Intravenous immunoglobulin is also used in the treatment of Wegener’s granulomatosis and microscopic polyangiitis. According to K. Pirner and et. al., intravenous immunoglobulin can be used in those cases when cytostatics are not indicated, for example, in infectious complications, in pregnancy, before and after surgery. Intravenous immunoglobulin is effective in the treatment of systemic lupus erythematosus, in patients with severe central nervous system involvement, pronounced thrombocytopenia, proliferative skin and mucous membrane involvement as well as in patients who are torpid to large doses of steroids. 4) However, the latest findings about effectiveness of intravenous immunoglobulin in the treatment of systemic vasculitis are controversial. In a single prospective double blind placebo-controlled study single administration of intravenous immunoglobulin to patients with Wegener’s granulomatosis and microscopic polyangititis with preserved clinical activity led to pronounced improvement of clinical and laboratory indices, though the patients had been treated with glucocorticoids and cytotoxins for two months. However, positive dynamics was preserved for only 3 months. After that the differences between the basic and control groups levelled out. Thus, effectiveness of intravenous immunoglobulin, especially of its repeated courses, in patients with systemic vasculitis requires further studying. 4. Plasmapheresis. 1) Its mechanisms of action are associated with improvement of functional activity of reticulo-endothelial system, elimination of antibodies and inflammatory mediators from the bloodstream. Recommendations for administration of plasmapheresis
  1. Not less than 40 ml/kg/day of the plasma should be removed 3 times a week for 3 weeks or 60 ml/kg/day of the plasma should be removed within 6 days.
  2. In all cases, except thrombocytopenic purpura, 4 – 5% albumin solution should be used to compensate for the loss of fluid.
  3. Plasmapheresis should be combined with intensive glucocorticoid and cytostatic therapy. On the day of plasmapheresis glucocorticoids and cytostatics  should be administered after completing the procedure.
2) It is considered that plasmapheresis is justified in patients with systemic lupus erythematosus, cryoglobulinemia, increased blood viscosity, thrombotic thrombocytopenic purpura, severe vasculitis as well as in patients with proliferative nephritis who are unresponsive to glucocorticoid and cytostatic therapy, in autoimmune hemolytic anemia and hemorrhagic lupus pneumonitis. In systemic vasculitis plasmapheresis in combination with glucocorticoids is used in the treatment of nodular periarteritis associated with B hepatitis virus, essential cryoglobulinemic vasculitis and Wegener’s granulomatosis. According to most researchers, acute progressive course of the disease which is manifested by rapidly progressing nephritis and severe vasculitis are indications for administration of plasmapheresis. Repeated courses of plasmapheresis in the dose of 750-1000 ml/day in the treatment of Takayasu’s arteritis are quite effective. 3) The incidence of complications during plasmapheresis ranges from 4, 5 to 25%. Cardiogenic shock, anaphylactic and citrate reactions are most common complications. Infectious complications occur quite rarely. In patients with active inflammatory processes  elimination of antibodies usually stimulates their synthesis. Thus, I’ve told you about the most common principles of treatment of systemic vasculitis. But I’d like to emphasize one more thing. 5. Combined therapy of systemic vasculitis. The results of clinical research testify to low effectiveness of glucocorticoid therapy, especially in the treatment of necrotizing vasculitis which is characterized by severe rapidly progressing involvement of small vessels. In this case combined therapy with glucocorticoids, cyclophosphamide and pulse therapy is usually undertaken. Therapeutic intervention with glucocorticoids or cytotoxic agents should be started as early as possible. Scheme of administration of large doses of cyclophosphan and methylprednisilone in the form of pulse therapy in the treatment of systemic angiitis (by R.A.Luqmani et al., 1996)
Cyclophosphan 15mg/kg/day  (the maximum dose is 1000 mg intravenously) Prednisolone 10mg/kg/day ( the maximum dose is 1000 mg  intravenously)
Courses of pulse therapy in the 0, 2, 4, 7, 10, 13, 17, 21, 25, 30, 35, 40, 46 and 52th week.
Blood creatinine  (micromole/l) <150 150 – 250 251 – 500 >500 Bone marrow involvement           Age >70       15mg/kg 10mg/kg 7, 5mg/kg 5mg/kg The drug should be withdrawn; the dose should be reduced by 25% as soon as the indices have become normal.   10mg/kg     10mg/kg 10mg/kg 10mg/kg 10mg/kg             10mg/kg 10mg/kg  
Glucocorticoid therapy in combination with azathioprine and methotraxate cause more profound clinical effect in comparison with glucocorticoids, azathioprine or methotraxate alone. Most researchers think that cyclophosphamide should be administered at the beginning of treatment, while azathioprine is considered as a second option drug which should be given to patients as soon as remission has been achieved. In some patients with Wegener’s granulomatosis glucocorticoid therapy in conjugation with methotraxate is considered as an alternative to conventional therapy. However, glucocorticoids alone or methotraxate are adequate for treatment of systemic vasculitis in patients without pulmonary or renal involvement or cyclophosphamide -resistant patients. Giant cell arteritis is typically treated with glucocorticoids. In giant cell arteritis cyclophosphamide is usually used as an adjunct in the form of pulse therapy in eye involvement. It has not been proven that combined glucocorticoid and methotraxate therapy is more effective in the treatment of giant cell arteritis than prednisolone. Corticosteroids are the mainstream of therapy for active Takayasu’s arteritis. However, some patients appear to be resistent to steroids. In such cases in addition to prednisolone, methotraxate or pulse therapy with glucocorticoids and cyclophosphamide is usually administered. Pulse therapy with glucocorticoids and cyclophosphamide or oral administration of these drugs is indicated in the treatment of rapidly progressing obliterating thromboangiitis until complete obliteration of the main arteries of the upper and lower extremities occurs. In some cases prednisolone and cyclophosphamide are combined with plasmapheresis.plasma exchange. Such combined therapy is typically administered in a fulminant (rapidly progressing) course of vasculitis associated with disorders of the function of vital organs as well as in Takayasu’s arteritis. In periarteritis nodosa associated with hepatitis B virus antiviral drugs and prednisolone are typically administered in average doses both to adults and children. They are often used in conjugation with repeated courses of plasmapheresis. 6. Pulse synchronization. The scheme called “pulse synchronization” has been developed to increase efficacy of cytotoxic therapy. This method foresees withdrawal of maintenance glucocorticoid and cytotoxic therapy for 4 weeks. It may cause stimulation of proliferation of lymphoid cells and development of “rebound/ricochet” syndrome. The latter is usually treated with three courses of intensive plasmapheresis and large doses of cyclophosphamide. It is supposed that such treatment helps achieve more effective elimination of pathologic cell clones which synthetize autoantibodies. Soloviev S.K. and Nasonova V.A. formulated the main principles of administration of synchronous intensive therapy with subsequent administration of plasmapheresis or hemosorption or large doses of methylprednisolone and cyclophosphamide in the treatment of systemic lupus erythematosus. The same regimen is used by pediatricians to treat acute and rapidly progressing forms of periarteritis nodosa. However, pulse synchronization therapy for the treatment of other types of vasculitis has not been developed yet. Intravenous immunoglobulin in conjugation with glucocorticoids is useful for the treatment of Wegener’s granulomatosis and some other types of vasculitis. Most researchers advise to use other drugs affecting rheological properties of blood (for example, heparin, fraxiparin), disaggregants (for example, pentoxyphilline, ticlid, aspirin), prostaglandin E drugs, such as vasoprostan, prostacycline drugs (for example, iloprost) as well as peripheral vasodilators in the treatment of vasculitis. Prevention of infections and gastrointestinal involvement is of great importance in the treatment of vasculitis. As patients with vasculitis run the risk of development of early atherosclerosis or cardiovascular involvement, anti-inflammatory, antithrombotic drugs and drugs with a hypodermic action (for example, plaquinil, delagil, aspirin, pentoxyphillin) should be administered to prevent any complications. Now we’re going to speak about some other drugs and methods of treatment of systemic vasculitis. 7. Pentoxyphilline. Pentoxyphilline (i.e. trental) is an inhibitor of xanthine phosphodiesterase which improves delivery of oxygen to tissues and organs in peripheral vascular involvement. Pentoxyphilline is widely used in the treatment of systemic vasculitis, especially in vasospastic and ischemic syndromes, skin and renal involvement. According to clinical and experimental findings, pentoxyphilline has an anti-inflammatory immunomodulatory action. It decreases renal toxicity and potentiates the effect of cyclosporine A. It increases anti-inflammatory activity of methotraxate. It is often administered in combination with glucocorticoids and cyclophosphamide. Some researchers consider it as a first option drug used in the treatment of hemorrhagic vasculitis. The treatment is usually initiated with intravenous infusions of pentoxyphilline in the dose of 200 – 300 mg/day in 200 ml of saline solution. The course of treatment includes 10 – 15 infusions. As soon as infusion therapy has been stopped, pentoxyphilline is administered orally in the dose of 600 – 800 mg/day for 30 – 40 days. Then the dose is reduced up to 200 – 300 mg/day for 6 – 12 months. Sometimes intravenous pentoxyphilline is administered in conjugation with reopolyglucan which decreases blood viscosity, aggregation of platelets and erythrocytes. It also has an antithrombotic action. According to Semenkova E.N. and Krivosheev O.G., pentoxyphilline should be administered in the dose of 1000 – 1200 mg/day to treat hemorrhagic vasculitis. Some patients may require coadministration of pentoxyphilline with dapsone in the dose of 100 – 200 mg/day. 8. Cyclosporine A. 1) In addition to immunosuppressive activity, cyclosporine A in pharmacologic concentration have anti-inflammatory properties. It inhibits histamine and triptase release and leukotriene synthesis by basophils and mast cells. 2) At the beginning of treatment cyclosporine A is administered in the dose of 2 – 3 mg/kg/day divided for 1 or 2 administrations for 4 – 8 weeks. If cyclosporine A is ineffective, the dose is gradually increased by 0, 5 – 1, 0 mg/kg/day until the maximum dose of 5 mg/kg/day is reached. As soon as the process has stabilized, the dose should be reduced gradually by 0, 5 mg/kg within 1 month until the minimum effective dose is reached. The minimum effective dose can be reached within 3 months. If the drug is ineffective after 6 months of administration, it should be withdrawn. 3) The level of blood serum creatinine should be checked during the treatment with cyclosporine A. If blood serum creatinine level is increased (more than 30% of the initial level), the dose of cyclosporine A should be reduced immediately. Patients with disturbed renal function, severe arterial hypertension, infectious diseases and malignancies should not receive cyclosporine A. At the same time treatment with cyclosporine A may cause some specific complications, the most severe of which is renal involvement. Cyclosporine A may cause the so-called functional renal toxicity which can lead to increased concentration of blood creatinine and urea. It is associated with vasoconstriction of afferent arterioles of glomerules which may cause decreased renal blood flow correlating with the dose of the drug. However, it is not associated with any morphologic disturbances. In 5 – 15% of patients cyclosporine A in the dose of 2, 5 mg/kg/day may cause dose-dependant increase of arterial blood pressure by 2 – 3 mm Hg, while cyclosporine A in the dose of 5 mg/kg/day may cause 5 mm Hg increase of arterial blood pressure. The treatment of choice for therapy of systemic vasculitis is calcium antagonists, especially in patients with arterial hypertension triggered by administration of cyclosporine A. In comparison with dilthiasem and verapamil, nifedipine and isradipine do not affect pharmacokinetics of cyclosporine A. The most common side effects of cyclosporine A therapy include hypertrichosis, oral mucosa hyperplasia, parasthesia, tremor, gastrointestinal disorders, moderate hyperbilirubinemia, anemia. Patients typically begin to develop side effects several days after the beginning of treatment. The symptoms usually subside after some time. In Behçet syndrome treatment of patients suffering from active uveitis with cyclosporine A is more effective than with pulse therapy. The dose is typically 2, 5 mg/kg/day. Cyclosporine A in the dose of 5 mg/kg/day in combination with glucocorticoids is typically administered to patients who are unresponsive to cyclophosphamide. It turns out that in some cases cyclosporine A is used as an alternative to cyclophosphamide which is effective in the treatment of systemic vasculitis. However, it often causes some infectious complications in Wegener’s granulomatosis. Besides, cyclosporine A is beneficial in the treatment of necrotizing rheumatoid vasculitis. It is typically used in the dose of 4 mg/kg/day and in conjugation with prednisolone and vasaprostan for 16 weeks. Some researchers point out to positive effects of cyclosporine A in the treatment of recurrent polychondritis, Weber-Krisgen syndrome and pyoderma gangrenosum. 9. Aminoquinoline drugs. According to a toxicologic research, chloroquine is 2 – 3 times as toxic as plaquinil. These drugs are rarely used in the treatment of systemic vasculitis. They do not belong to first line therapy. However, due to varied anti-inflammatory effects of delagil and hydroxychloroquine (plaquinil) these drugs are often used as a combined therapy of systemic vasculitis. According to the latest findings, plaquinil has antiviral properties. Aminoquinoline drugs suppress thrombocyte aggregation and adhesion and decrease blood viscosity and thrombocyte size. Antimalarial drugs have hypolipidic properties. These findings testify to the fact that antimalarial drugs can be used as a combined therapy of systemic vasculitis. Antimalarial drugs should be administered to the patients who run the greatest risk of development of cardiovascular complications as well as to those taking glucocorticoids for a long period of time. The daily dose of plaquinil is 400 mg (6, 5 mg/kg). The daily dose of chloroquine is 250 mg (4, 0 mg/kg). The drugs are well tolerated. Skin rash is the commonest complication of aminoquinoline drug therapy. The most serious complication is eye involvement (retinopathy), including central scotoma, narrowing of peripheral visual fields, general impairment of vision. However, plaquinil causes retinopathy less commonly than chloroquine. 10. Enzymatic drugs. Enzymes of plant and animal origin have been widely used in the treatment of cardiovascular diseases recently. They include vobenzim, flogenzim, mulsal. It has been proven that they decrease blood viscosity, accelerate fibrinolysis, increase erythrocyte deforming capacity, suppress erythrocyte and thrombocyte aggregation, inhibit IL-1 and FHO-α production. They also have immunomodulatory properties in T-lymphocyte subpopulation which are manifested by normalization of disbalance of these cells in the body. However, enzymatic drugs should be used in conjugation with glucocorticoids and cyclophosphamide in the treatment of systemic vasculitis. 11. Antiviral drugs. As I have already mentioned, hepatitis B and C viruses play an important role in the pathogenesis of some types of vasculitis. If there are any signs of replication of these viruses, interferon (realderon, IF-α) in combination with glucocorticoids and plasmapheresis is typically indicated. Some cases of successful treatment of patients suffering from ulceration of the oral mucosa, Behçet’s disease and eye involvement with INF-α have already been reported. 12. Aspirin. Aspirin (acetylsalicylic acid) is one the main drugs used in the treatment of conditions characterised by increased thrombocyte aggregation. Single administration of aspirin produces a disaggregating effect on thrombocytes. The effect usually lasts for 4 – 7 days. It is due to blockade of cyclooxygenase metabolism of arachidonic acid by aspirin. It is better pronounced in thrombocytes that in the endothelium of vessels. Administration of aspirin in vasculitis is mediated by the following mechanisms:
  • disaggregating effect of aspirin on thrombocytes due to inhibition of thrombocytic cyclooxygenase-1 by small doses of aspirin (less than 100 mg/day);
  • anti-inflammatory action of aspirin due to inhibition of IL-1-dependent expression of cyclooxygenase-2 in the culture of endothelial cells;
  • immunomodulatory action of aspirin due to stimulation of IL-3 synthesis.
Nowadays aspirin in the dose of 3 – 5 mg/kg/day in combination with intravenous immunoglobulin is administered in the treatment of Kawasaki disease in the active phase of the disease. It is usually used to prevent thrombosis of coronary arteries. However, in Kawasaki disease aspirin alone does not help prevent progression of artery involvement. Small doses of aspirin are widely used for prevention of thrombosis. 13. Dipiridamol. Dipiridamol is most commonly used in combination with aspirin to increase the effect of the latter. The daily dose is usually 200 – 400 mg/kg. Prolonged administration of dipiridamol in the dose of 5 mg/kg/day is indicated in stenosis of coronary arteries in Kawasaki disease. The most common side effects of dipiridamol therapy are headaches, dizziness, nausea. 14. Tiklopedin (tiklid). Tiklopedin is a disaggregating drug. Its effects are due to inhibition of thrombocyte aggregation. Its effects can be seen 24 – 48 hours after oral administration of tiklopedin. The most common side effects of tiklopedin therapy are the following: diarrhea, allergic skin reactions and granulopenia which is considered as the most untoward side effect. It occurs in 0, 9% of patients. The average dose of tiklopedin is 500 mg/day. It is used in the treatment of hemorrhagic vasculitis and Kawasaki disease. 15. Heparin. Heparin is used in the management of microcirculatory disturbances occurring in some types of vasculitis. Heparin is indicated in hemorrhagic vasculitis. The daily dose is 15 000 – 20 000 activity units. It is usually administered subcutaneously for 3 weeks in skin purpura and for 4 – 6 weeks in nephritis. When the level of antithrombin III is low, heparin is administered in combination with fresh frozen or native plasma. Fraksiparin (Sanofi) and other low-molecular heparins have been widely used in the treatment of vasculitis lately. 16. Prostacycline. In periarteritis nodosa small-sized digital necrosis subsided after administration of the stable analog of prostaglandin α-2, iloprost. No defects of the soft tissues were noted. 17) Vasaprostan (alprostadil, prostaglandin E). Vasaprostan is a drug which has various biological properties. It regulates and modifies the processes of synthesis of other hormones and mediators. There are some mechanisms of action of vasaprostan. They are the following:
  • vasaprostan may enhance blood flow due to widening of blood vessels;
  • vasaprostan activates fibrinolysis due to stimulation of tissue-type plasminogen activator synthesis;
  • vasaprostan may obstruct thrombocyte activation caused by adenosine diphosphate (ADP), thrombin or collagen due to reduction of the amount of free potassium ions;
  • vasaprostan inhibits thrombocyte aggregation and adhesion to the subendothelium; it decreases β-thromboglobulin, serotonin and adenosine diphosphate release; vasaprostan inhibits thromboxane synthesis;
  • vasaprostan inhibits neutrophil activation, release of superoxide ions and leukotrienes B4; it inhibits neutrophil aggregation; and decreases neutrophil adhesion to the endothelium;
  • vasaprostan increases capability of erythrocytes to change their form; it decreases erythrocyte aggregation;
  • vasaprostan restores normal metabolism in ischemic tissues by means of improving oxygen and glucose utilization (transition from anaerobic to aerobic cellular respiration);
  • vasaprostan inhibits mitotic activity and proliferation of smooth muscle cells.
Intravenous or intra-arterial administration of vasaprostan is typically used. Intravenous vasaprostan is administered in the dose of 60 – 80 mgk/day. Intra-arterial vasaprostan is administered in the dose of 20 mgk/day. The course of treatment usually lasts for 3 weeks. Nowadays vasaprostan is widely used in the treatment of severe ischemia in obliterating atherosclerosis of vessels of the lower extremity as well as in diabetic angiopathy. The use of vasaprostan in the treatment of obliterating thromboangiitis has also been reported. In the treatment of vasculitis vasaprostan is typically administered in combination with glucocorticoids or cyclophosphamide. 18. Peripheral vasodilators. 1) Peripheral vasodilators and calcium channel blockers such as corinfar (nifedipine) and their analogs are used to reduce vasoconstriction in vasculitis. Corinfar is administered in the dose of 10 mg 3 – 4 times a day. In arterial hypertension the dose should be increased up to 60 – 80 mg/day. Corinfar is used in the following cases: vasospastic and ischemic syndromes, arterial and vasorenal hypertension, bronchospastic syndrome, coronary disease, initial stage of cardiac insufficiency. Corinfar decreases vasospastic syndrome and accelerates trophic ulcer healing. Corinfar is often combined with disaggregants to enhance its effects. 2) In intermittent claudication antagonists of serotonin receptor Type II are typically used. They include naphthidrofuril, peritol. 19. Sulfamethoxazole/trimetoprime. The conjugation of two drugs having bacteriostatic properties provides for bactericidal activity of gram-positive and gram-negative microorganisms. It also has an immunosuppressive action which is manifested by inhibiting the functional activity of neutrophils. Sulfamethoxazole/trimetoprime is usually administered in the dose of 160 – 800 mg twice a day to treat Wegener’s granulomatosis. The drug is usually used in limited forms of Wegener’s granulomatosis as well as in the period of induction of remission for prevention of infectious complications. 20. Dapsone. According to Semenkova E.N. and Krivosheev O.G., dapsone should be used in the dose of 100 – 200 mg/day. Prolonged administration of dapsone in combination with pentoxyphelline is useful for the treatment of hemorrhagic vasculitis. 21. Colchicine. Colchicine suppresses neutrophil mobility, chemotaxis, adhesion to the endothelium and diapedesis in the area of inflammation. Colchicine impedes release of histamine from mast cells. It obstructs the synthesis of chemotoxic factors, including that of leukotriene B4. In Behçet’s disease administration of colchicine in the dose of 0, 5 – 1, 5 mg/day decreases the frequency and severity of disease attacks as well as the progression of the disease. 22. Immunotherapy. 1) New approaches to immunotherapy of systemic vasculitis are being developed now. They are associated with the use of monoclonal antibodies to a broad spectrum of membraneous antigens of mononuclear cells and endothelium, cytokines, natural ligands of cytokine receptors and soluble cytokine antagonists or chemical substances which have immunomodulatory properties. It is supposed that administration of antibodies can lead to elimination of target cells and can change their functional activity. Types of treatment of systemic angiitis
Type of treatment Method of treatment
Passive  Selective Nonselective Analogous peptides  Monoclonal antibodies to idiotypes found in autoreative T- and B-lymphocytes. Monoclonal antibodies to peptide-specific areas of T-cell a, b-receptors.   Monoclonal antibodies to T-cell receptors. Monoclonal antibodies to antigen-specific areas of HKG class II molecules. Monoclonal antibodies to CD4 lymphocyte molecules. Monoclonal antibodies to cytokines. Monoclonal antibodies to CD4 lymphocyte molecules and cytokines (combined therapy). Immunoadhesins.  
Active Monoclonal antibodies carrying internal information about HKG class II antigens.  Monoclonal antibodies carrying internal information about CD4 lymphocyte molecules.
  a) In rheumatoid arthritis administration of monoclonal anti-CD4+ antibodies may produce positive effects in relation to extraarticular manifestations (e.g. crus ulcer). The use of antibodies helps achieve prolonged remission in patients with severe rheumatoid vasculitis, Wegener’s granulomatosis. b) In systemic vasculitis (Wegener’s granulomatosis, Takayasu’s arteritis, periarteritis nodosa, giant cell arteritis) FHO-α and adhesive molecule antibodies, such as Infliximab (Remicade) are beneficial. 2) Immunocorrectors of plant origin, such as thymus preparations and their synthetic analogs, have been widely used in medicine lately. In our country taktivin which is a thymus preparation is used in the treatment of vasculitis. It appears to be heterogenous. Taktivin restores the amount of T-lymphocytes in patients with decreased amount of T-lymphocytes. Taktivin increases killer activity. Depending on the dose taktivin affects the functions of natural killer cells. In small doses it stimulates IF-α production. However, it turns out to be ineffective if it is used as a monotherapy. It is more effective in combination with glucocorticoids and cyclophosphamide. 3) In general new approaches to immunotherapy are associated with administration of biotechnological drugs which affect the functional activity of immunologically competent cells selectively. They also affect cytokine synthesis, expression of adhesive molecules, etc. 23. Diet. Low-fat diet plays a major role in the treatment of hemorrhagic vasculitis. In essential cryoglobulinemic purpura low-protein diet is beneficial. 24. Topical treatment. 1) Topical treatment is used in skin ulcerations. Topical treatment consists of several phases. Lotions or ointments with proteolytic enzymes are typically used. 0,5% solution of novocain in combination with chemopsin (100 mg per 100 ml) is typically used as a lotion. “Iruksol” ointment is usually applied to lesions once or twice a day. The ulcerative surface should be washed with hydrogen peroxide or potassium permanganate solution to achieve a disinfecting effect. 2) As soon as the ulcerative surface has been cleaned and suppurative and necrotic slough has been removed, epithelizing and disinfecting agents are applied. If the patient suffers from bad pain, they are usually combined with anesthetics (for example, 5% anesthesin or 5% dermatol- anesthesin ointment, levomicol, levocin, Vishnevsky ointment, 10% methyluracil ointment, “Pantenol” foam, collagen sponges, etc.). 3) Argosulfan (Jelfa), a 2% cream with silver salt of sulfathiasol, is typically used as a topical therapy. It has well pronounced topical antimicrobial and anesthetic properties. It is useful for the treatment of trophic ulcers of the leg of various origins. Argosulfan is well tolerated by patients. It should be used in the treatment of skin ulcerations associated with vascular involvement, including systemic vasculitis. 25. Other aspects of systemic vasculitis. Specialists from various fields of medicine should be involved in the treatment of systemic vasculitis. Patients need to be monitored by therapeutists, nephrologists, otolaryngologists, neurologists, surgeons, ophthalmologists, etc. due to development of complications. Thus, a cooperative approach plays an important role in the treatment of systemic vasculitis.