Inflammatory myopathies: treatment

Treatment of inflammatory myopathies

The use of drugs in inflammatory myopathies has an empirical character. Their efficacy has not been confirmed in large-scale, double-blind, placebo-controlled trials. Moreover, in many clinical studies, subgroups of patients with dermatomyositis and polymyositis were not isolated. In this regard, the course and the true effectiveness of various treatments for each of these differing diseases remain unclear. Thus, modern treatment regimens are often based only on individual casuistic observations. Despite the lack of comprehensive information, most specialists agree that immunosuppressive therapy is effective in many patients with inflammatory myopathies. This will create ethical difficulties in the conduct of large-scale controlled trials of these funds in the future. Nevertheless, such studies are extremely important for evaluating the effectiveness of new, more specific approaches to the treatment of inflammatory myopathies directed against those immunological "targets" that are not currently being exposed (for example, to the complement-mediated humoral "attack" on the vessels of perimisation Dermatomyositis or attack of oligoclonal cytotoxic T-lymphocytes on muscle fibers in polymyositis).

Treatment and dermatomyositis, and polymyositis usually begin with corticosteroids. The initial dose of prednisolone administered intravenously varies from 30 to 100 mg / day, but a more aggressive approach is preferred, since the higher the total dose, the more significant the clinical effect will be in the first few months of treatment. In addition, the earlier treatment is initiated, the better it can be. With late treatment, its effectiveness is reduced. The daily dose of prednisolone (80-100 mg, or 1 mg / kg) is usually taken once a day every day for 4-6 weeks until the muscle strength increases and / or the level of CPK begins to decrease. Although it was reported that the drop in the level of CK generally precedes the increase in muscle strength, we observed a number of patients in whom a decrease in CKK activity occurred some time after the reduction of muscle weakness. Thus, when determining the dose of a corticosteroid, you can focus on both indicators, but the clinical response is more reliable than the change in a laboratory indicator.

With a favorable reaction and no undesirable side effects, the dose of prednisolone can be gradually reduced by 20 mg every 3-4 weeks until the maintenance dose (usually 4-6 months) is reached: 15-20 mg daily or 30 mg every other day. Subsequent dose reduction is very slow - by 2.5 mg (with daily intake) or 5 mg (if taken every other day) every 4-6 weeks, provided that the therapeutic effect is maintained or enhanced. To maintain the effect, it is often necessary to take a maintenance dose of prednisolone <10-20 mg every other day for many months, even in patients that respond well to steroids. A retrospective analysis of the efficacy of corticosteroids and other ingested immunosuppressants in 113 patients with inflammatory myopathies showed that dermatomyositis responds better to treatment with prednisolone: in 30% of patients the symptoms regressed completely, in 60% of patients a partial effect was noted, and only 10% of patients were resistant to treatment . Among patients with polymyositis, a complete regression of symptoms was noted in 10% of patients, partial improvement in 73%, absence of effect in 17%. In myositis with inclusions, these indices were respectively 0, 58, and 42%.

In severe cases, often used in / in the introduction of a high dose of methylprednisolone (1 g / day). Although no controlled studies comparing the efficacy of the oral and intravenous routes of administration have been conducted, the high efficacy in / in the administration of high doses of steroids in inflammatory diseases presumably associated with immunological mechanisms (eg, in vasculitis and connective tissue diseases) justifies the use of this method in the treatment of dermatomyositis and polymyositis. Experience shows that the daily administration of methylprednisolone (1 g IV in the morning for 2 hours) for 3-5 days allows to solve the problem of early active relief of the inflammatory process. This method of treatment can be carried out under the conditions of a "day hospital", subject to careful monitoring of the level of electrolytes, glucose, vital functions, adverse emotional responses. In some cases, the administration of high doses of corticosteroids has to be canceled because of the onset of severe hyperactivity or, conversely, severe depression. After completion of IV administration, patients are transferred to the intake of prednisolone. Initially, a relatively high dose is prescribed - 80 mg / day, which patients take 2 weeks. Then the dose is gradually reduced, initially to 60 mg / day (3-4 weeks), then 50 mg / day (3-4 weeks) and 40 mg / day (3-4 weeks). An alternative to this scheme may be a repeated single ("booster") iv injection of methylprednisolone every 3-4 weeks, but this approach is more expensive and less convenient in practice.

In the absence of objective signs of improvement (increase in muscle strength), after 3 months after the onset of oral or intravenous corticosteroid therapy, resistance to corticosteroids can be noted - in this case, the drug should be accelerated.

When prescribing corticosteroids, the patient should be carefully examined to exclude concomitant diseases that increase the risk of side effects. In the presence of diabetes, gastritis, stomach ulcers, hypertension, osteoporosis or infection due to the danger of complications, corticosteroids are contraindicated. But even in the absence of these conditions, side effects such as weight gain, impaired glucose tolerance, cushingoid traits, high blood pressure, gastritis and stomach ulcers, osteoporosis, avascular necrosis of the thigh, cataracts, glaucoma, irritability can develop along with corticosteroids, in children, growth retardation. The introduction of the drug every other day reduces the likelihood of these side effects. Although there are no studies showing that the efficacy of treatment every other day is lower than with daily intake of the drug, most clinicians prefer to administer a corticosteroid every day for several months until a therapeutic effect is achieved and then transfer the patient to a regimen every other day. To prevent side effects, antacids and H2-receptor antagonists are prescribed, a low-calorie diet and limited salt intake are recommended. Often there is face hyperemia and general irritability, but many patients are ready to accept these side effects as soon as they learn that these effects will decrease as soon as the dose of corticosteroids is reduced. Insomnia can be weakened by prescribing prednisone early in the morning. If intolerable side effects occur, you should reduce the dose of prednisolone or cancel the drug.

Steroid myopathy is one of the most serious side effects, hard to correct. With prolonged use of high doses of prednisolone, selective atrophy of muscle fibers of type 2 can develop, which leads to an increase in muscle weakness. Weakness is especially often amplified in the proximal muscles of the lower limbs, for example, the hip flexors. The same muscles are often affected and with exacerbation of dermatomyositis or polymyositis. Thus, steroid myopathy can be difficult to distinguish from the progression of the most inflammatory myopathy. Preservation of fibrillation and positive acute waves (according to EMG data) testifies in favor of inflammatory myopathy. From a practical point of view, the increase in muscle weakness is more often caused by the progression of the disease and, therefore, requires an increase in the dose of prednisolone. Nevertheless, in each such case, the condition of the patient should be carefully assessed - whether it has signs of a systemic disease or infection that could provoke an exacerbation, whether the increase in the dose of prednisolone preceded the worsening of the condition, or in which muscle groups grew weak. For example, if the increase in the weakness of the proximal muscles of the lower extremities is accompanied by an increase in the weakness of the flexors of the neck and an increase in dysphagia, then steroid myopathy is less likely. On the other hand, a combination of steroid myopathy with exacerbation of inflammatory myopathy is possible. In this case, it is necessary to reduce the dose of corticosteroids, compensating it by the appointment of another ("steroid-substituting") immunosuppressor.

Azathioprine is often used in combination with corticosteroids. Patients with dermatomyositis and polymyositis are appointed to reduce the dose of prednisolone with the development of side effects or as a primary agent in the resistance to corticosteroids. The appointment of azathioprine before the use of corticosteroids is not justified. The dose of azathioprine is 2 mg / kg / day, but some clinicians use higher doses - up to 3 mg / kg / day. The main side effects of azathioprine are usually dose-dependent and, therefore, can be eliminated by lowering the dose of the drug. When taking azathioprine, bone marrow depression can occur with the development of leukopenia, thrombocytopenia and anemia, as well as toxic liver damage. A significant disadvantage of azathioprine is that its effect is manifested within 3-6 months, which makes its appointment impractical in those cases when a rapid effect is needed. Therefore, azathioprine is worth adding to the treatment regimen only with insufficient corticosteroid effectiveness.

According to some reports, methotrexate can be effective in patients with inflammatory myopathies, resistant to corticosteroids. Methotrexate acts faster than azathioprine, although its absorption with oral administration is variable. Methotrexate can have a hepatotoxic effect, cause stomatitis, bone marrow depression, pneumonitis. If administered orally during the first 3 weeks, methotrexate is given at a dose of 5-10 mg per week (2.5 mg taken at an interval of 12 hours), then gradually the dose is increased by 2.5 mg per week - up to 20-25 mg per week. The drug can be prescribed and intravenously - in a dose of 0.4-0.8 mg / kg per week. In general, neurologists often treat inflammatory myopathies with other immunosuppressors and rarely resort to methotrexate.

Intravenous immunoglobulin in inflammatory myopathies is most often used when corticosteroid therapy is ineffective. In children and the elderly, as well as in other categories of patients with a high risk of complications in corticosteroid therapy, IV immunoglobulin is often considered as a first-choice drug. In combined studies, intravenous immunoglobulin caused clinically significant improvement in 20 of 23 patients with dermatomyositis and 11 of 14 patients with polymyositis. In patients with dermatomyositis, intravenous immunoglobulin reduced the severity of muscle weakness, skin changes, deviations in immunological parameters, and increased the density of capillaries, reduced the detectability of the membrane-invoking complex in the vessels, and the degree of expression of MHC-1 on muscle fibers. The results of controlled trials comparing different treatment regimens were not reported, but empirically the immunoglobulin is most often prescribed in a total dose of 2 g / kg, which is administered for 2-5 days. The effect of IV immunoglobulin usually lasts no more than 4-8 weeks. Therefore, to maintain the effect for several months, the drug continues to be administered once a month ("boosters"). If there is no effect for 3-4 months, then a further monthly administration of the drug is inappropriate. The intake of small doses of corticosteroids inside and the administration of IV immunoglobulin can act synergistically, but controlled studies are needed to confirm this effect.

The main disadvantages of IV immunoglobulin are the high cost and short duration of the effect, making it necessary for its monthly maintenance introduction. Side effects of IV immunoglobulin are usually minimal if the injection rate does not exceed 200 ml / h, and the dose is 0.08 ml / kg. Adverse reactions include headache, chills, malaise, myalgia, chest discomfort, and an increase in blood pressure, which is often corrected by a decrease in the rate of infusion. Anaphylactic reactions are rare, but are possible when the patient has low IgA (possibly due to the presence of antibodies to it), and the immunoglobulin preparation contains at least a small amount of IgA. It is also possible to have a toxic effect on the kidneys, especially in individuals with renal dysfunction. Cases of aseptic meningitis are described, more often in patients with migraine. There is also an increased risk of thromboembolic complications, since the IV immunoglobulin increases the viscosity of the serum.

The mechanism of action of intravenous immunoglobulin remains unclear. Experimental data show that high doses of immunoglobulin can weaken complement-dependent immune damage, which may explain its therapeutic effect. In addition, intravenous immunoglobulin can inhibit complement deposition, neutralize cytokines, inhibit Fc receptor-mediated phagocytosis, reduce autoantibody production (due to negative feedback), or perform other modulatory effects associated with the presence of anti-idiotypic antibodies. The mechanism of the action of intravenous immunoglobulin in inflammatory myopathies in humans remains to be seen.

Cyclophosphamide and cyclosporine have also been used in dermatomyositis and polymyositis, but their side effects, the possibility of persistent complications with moderate efficacy limits their use only to certain cases with aggressive course, resistance to corticosteroids and increasing systemic manifestations. The lack of controlled trials of these compounds (alone or in combination with other drugs) also limits their use. Cyclophosphamide is administered internally at a dose of 1-2.5 mg / kg / day, the number of leukocytes against the background of treatment should not fall below 2500 / μL. Because of serious side effects - haemorrhagic cystitis, alopecia, infertility, bone marrow suppression, and an increased risk of malignant tumors - the drug is used only as a last resource. In this situation, it can be used according to the scheme used in the treatment of necrotic vasculitis - 3 g IV in 5-6 days under the control of the number of leukocytes and granulocytes, followed by maintenance therapy in the form of monthly injections in a dose of 750-1000 mg / m ².

Cyclosporine, which inhibits the activation of T cells with interleukin-2 or other reactions that activate T cells, acts by binding to a specific immunophilin and can cause nephrotoxic and hepatotoxic effects, as well as arterial hypertension. In several studies conducted on small groups of patients with dermatomyositis and polymyositis, a positive effect of cyclosporine was noted, however the high cost of the drug and its potential side effects limit its use. Treatment is started at a dose of 6 mg / kg / day, then it is reduced to 4 mg / kg / day to reduce the risk of nephrotoxic action. Controlling the concentration of the drug in the serum can make its use more safe. The recommended level of the drug in the serum is from 100 to 150 μg / ml.

Theoretically, plasmapheresis can have a positive effect in inflammatory myopathies, especially with dermatomyositis, as it can reduce the level of circulating immune complexes and immunoglobulins. However, in a double-blind, placebo-controlled study, 39 patients with polymyositis and dermatomyositis, resistant to corticosteroids, failed to demonstrate the efficacy of plasmapheresis.

The most important feature that distinguishes myositis from inclusions from dermatomyositis and polymyositis is the low effectiveness of immunosuppressive therapy. In cases of polymyositis resistant to corticosteroids, repeated biopsy often reveals morphological signs of myositis with inclusions. Nevertheless, a small percentage of patients with myositis with inclusions react positively to corticosteroids. Therefore, in all cases, a trial 3-month treatment with prednisolone is recommended. In the absence of effect, the appointment of an IV immunoglobulin is indicated. In a double-blind, placebo-controlled study in 19 patients with myositis with inclusions, "a functionally significant improvement was noted in 6 (28%) cases. However, at best, the effect was mild, however, a study in a small number of patients could not adequately detect the beneficial effect of IV immunoglobulin in myositis with inclusions. Further studies are needed on the pathogenesis of this disease and the search for its effective treatment.

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