Inflammatory Myopathies - Treatment

Treatment of inflammatory myopathies

The use of drugs in inflammatory myopathies is empirical. Their effectiveness has not been confirmed in large-scale double-blind placebo-controlled trials. Moreover, many clinical trials have not identified subgroups of patients with dermatomyositis and polymyositis. Therefore, the course and true effectiveness of certain treatments for each of these different diseases remain unclear. Thus, current treatment regimens are often based on isolated case reports. Despite the lack of comprehensive information, most experts agree that immunosuppressive therapy is effective in many patients with inflammatory myopathies. This will create ethical difficulties in conducting large-scale controlled trials of these drugs in the future. However, such studies are of great importance to assess the efficacy of new, more specific approaches to the treatment of inflammatory myopathies that are directed against immunological “targets” that are not currently being addressed (e.g., the complement-mediated humoral “attack” on perimysial vessels in dermatomyositis or the oligoclonal cytotoxic T-lymphocyte attack on muscle fibers in polymyositis).

Treatment of both dermatomyositis and polymyositis usually begins with corticosteroids. Initial doses of oral prednisolone range from 30 to 100 mg/day, but a more aggressive approach is preferred because the higher the total dose, the greater the clinical benefit in the first few months of treatment. In addition, the earlier treatment is started, the better the outcome is likely to be. Late initiation of treatment reduces its effectiveness. Prednisolone is usually given once daily in the morning (80 to 100 mg, or 1 mg/kg) for 4 to 6 weeks until muscle strength improves and/or CPK levels begin to decline. Although a fall in CPK levels has been reported to usually precede an increase in muscle strength, we have seen a number of patients in whom a decline in CPK activity occurred some time after muscle weakness had improved. Thus, when determining the dose of a corticosteroid, one can rely on both indicators, but the clinical response is considered more reliable, rather than a change in one or another laboratory indicator.

If the response is favorable and there are no undesirable side effects, the prednisolone dose can be gradually reduced by 20 mg every 3-4 weeks until a maintenance dose of 15-20 mg daily or 30 mg every other day is reached (usually after 4-6 months). Subsequent dose reductions are made very slowly - by 2.5 mg (for daily use) or 5 mg (for every other day) every 4-6 weeks, provided that the therapeutic effect is maintained or increased. Maintenance of the effect often requires taking a maintenance dose of prednisolone (< 10-20 mg every other day) for many months, even in patients who have responded well to steroids. A retrospective analysis of the efficacy of corticosteroids and other oral immunosuppressants in 113 patients with inflammatory myopathies showed that dermatomyositis responded better to prednisolone treatment: 30% of patients had complete regression of symptoms, 60% had a partial effect, and only 10% of patients were resistant to treatment. Among patients with polymyositis, complete regression of symptoms was noted in 10% of patients, partial improvement in 73%, and no effect in 17%. In myositis with inclusions, these figures were 0, 58, and 42%, respectively.

In severe cases, high-dose intravenous methylprednisolone (1 g/day) is often used. Although controlled studies comparing the efficacy of oral and intravenous routes of administration have not been conducted, the high efficacy of high-dose intravenous steroids in inflammatory diseases presumably associated with immunological mechanisms (e.g., vasculitis and connective tissue diseases) justifies the use of this method in the treatment of dermatomyositis and polymyositis. Experience shows that daily administration of methylprednisolone (1 g intravenously in the morning for 2 hours) for 3-5 days allows for early active relief of the inflammatory process. This treatment method can be carried out in a day hospital setting, provided that electrolyte levels, glucose, vital functions, and adverse emotional reactions are carefully monitored. In some cases, high-dose corticosteroids have to be discontinued due to the development of severe hyperactivity or, conversely, severe depression. After completion of the intravenous administration, patients are transferred to oral prednisolone. At first, a relatively high dose is prescribed - 80 mg/day, which patients take for 2 weeks. Then the dose is gradually reduced, first to 60 mg/day (for 3-4 weeks), then 50 mg/day (3-4 weeks) and 40 mg/day (3-4 weeks). An alternative to this scheme is a repeated single ("booster") intravenous administration 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) 3 months after the start of oral or intravenous corticosteroid therapy, resistance to corticosteroids can be diagnosed - in this case, drug withdrawal should be accelerated.

When prescribing corticosteroids, the patient should be carefully examined to exclude concomitant diseases that increase the risk of side effects. Corticosteroids are contraindicated in the presence of diabetes mellitus, gastritis, gastric ulcer, arterial hypertension, osteoporosis or infection due to the risk of complications. But even in the absence of these conditions, side effects such as weight gain, impaired glucose tolerance, Cushingoid features, high blood pressure, gastritis and gastric ulcer, osteoporosis, avascular necrosis of the hip, cataracts, glaucoma, irritability, and growth retardation in children may develop during treatment with corticosteroids. Administration of the drug every other day reduces the likelihood of these side effects. Although there are no studies proving that the effectiveness of treatment with every other day administration is lower than with daily administration of the drug, most clinicians prefer to prescribe a corticosteroid daily for several months until a therapeutic effect is manifested, and then transfer the patient to an every other day regimen. To prevent side effects, antacids and H2 receptor antagonists are prescribed, a low-calorie diet and limited salt intake are recommended. Facial flushing and general irritability are common, but many patients are willing to put up with these side effects once they learn that these effects will subside once the corticosteroid dose is reduced. Insomnia can be reduced by prescribing prednisolone early in the morning. If intolerable side effects occur, the prednisolone dose should be reduced or the drug discontinued.

Steroid myopathy is one of the most serious side effects and is difficult to correct. With long-term use of high doses of prednisolone, selective atrophy of type 2 muscle fibers may develop, leading to increasing muscle weakness. Weakness is particularly often increased in the proximal muscles of the lower extremities, such as the hip flexors. The same muscles are often affected during exacerbations of dermatomyositis or polymyositis. Thus, steroid myopathy can be difficult to distinguish from the progression of the inflammatory myopathy itself. Persistence of fibrillations and positive sharp waves (as determined by EMG) indicates inflammatory myopathy. From a practical point of view, increasing muscle weakness is more often caused by disease progression and, therefore, requires an increase in the prednisolone dose. However, in each such case, the patient's condition should be carefully assessed - whether there are signs of a systemic disease or infection that could provoke an exacerbation, whether the deterioration was preceded by an increase in the dose of prednisolone, in which muscle groups the weakness has increased. For example, if the increase in 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 and an exacerbation of inflammatory myopathy is possible. In this case, it is necessary to reduce the dose of corticosteroids, compensating for this by prescribing another ("steroid-replacing") immunosuppressant.

Azathioprine is often used in combination with corticosteroids. In patients with dermatomyositis and polymyositis, it is prescribed to reduce the dose of prednisolone in case of side effects or as the main agent in case of resistance to corticosteroids. Prescribing azathioprine before using 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 reducing the dose of the drug. When taking azathioprine, bone marrow suppression with the development of leukopenia, thrombocytopenia and anemia, as well as toxic liver damage are possible. A significant disadvantage of azathioprine is that its effect manifests itself within 3-6 months, which makes its use inappropriate in cases where a rapid effect is needed. Therefore, it makes sense to add azathioprine to the treatment regimen only if corticosteroids are insufficiently effective.

Methotrexate has been reported to be effective in patients with inflammatory myopathies that are resistant to corticosteroids. Methotrexate acts more rapidly than azathioprine, although its absorption when taken orally is variable. Methotrexate can have a hepatotoxic effect, cause stomatitis, bone marrow suppression, and pneumonitis. When taken orally, methotrexate is prescribed at a dose of 5-10 mg per week for the first 3 weeks (2.5 mg taken at 12-hour intervals), then gradually increase the dose by 2.5 mg per week to 20-25 mg per week. The drug can also be prescribed intravenously at a dose of 0.4-0.8 mg/kg per week. In general, neurologists more often treat inflammatory myopathies with other immunosuppressants and rarely resort to methotrexate.

Intravenous immunoglobulin is most often used in inflammatory myopathies when corticosteroid therapy is ineffective. In children and the elderly, as well as in other categories of patients with a high risk of complications during corticosteroid therapy, intravenous immunoglobulin is often considered the drug of first choice. In combination 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, and immunological abnormalities, and also increased capillary density, decreased the detection of the membrane attack complex in vessels, and the degree of MHC-1 expression on muscle fibers. Controlled studies comparing different treatment regimens have not been reported, but immunoglobulin is most often given empirically at a total dose of 2 g/kg given over 2-5 days. The effect of intravenous immunoglobulin usually lasts no more than 4-8 weeks. Therefore, to maintain the effect for several months, the drug is continued to be administered once a month ("boosters"). If there is no effect within 3-4 months, then further monthly administration of the drug is not advisable. Low-dose oral corticosteroids and intravenous immunoglobulin may act synergistically, but controlled studies are needed to confirm this effect.

The main disadvantages of IV immunoglobulin are its high cost and short duration of action, necessitating monthly maintenance administration. Side effects of IV immunoglobulin are usually minimal if the infusion 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 increased blood pressure, which is often corrected by decreasing the infusion rate. Anaphylactic reactions are rare but may occur if the patient has low IgA levels (possibly due to the presence of antibodies to it) and the immunoglobulin preparation contains at least a small amount of IgA. Renal toxicity is also possible, especially in individuals with renal dysfunction. Cases of aseptic meningitis have been described, more often in patients with migraine. There is also an increased risk of thromboembolic complications, since IV immunoglobulin increases serum viscosity.

The mechanism of action of IV immunoglobulin remains unclear. Experimental data indicate that high doses of IV immunoglobulin can attenuate complement-dependent immune damage, which may explain its therapeutic effect. In addition, IV immunoglobulin may inhibit complement deposition, neutralize cytokines, interfere with Fc receptor-mediated phagocytosis, reduce autoantibody production (via negative feedback), or exert other modulatory effects associated with the presence of anti-idiotypic antibodies. The mechanism of action of IV immunoglobulin in human inflammatory myopathies remains to be elucidated.

Cyclophosphamide and cyclosporine have also been used in dermatomyositis and polymyositis, but their side effects, the possibility of persistent complications with moderate effectiveness limit their use to certain cases with an 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 prescribed orally at a dose of 1-2.5 mg / kg / day, the number of leukocytes during treatment should not fall below 2500 / μl. Due to serious side effects - hemorrhagic cystitis, alopecia, infertility, bone marrow suppression, as well as an increased risk of developing malignant tumors - the drug is used only as a last resort. In this situation, it can be used according to the scheme used in the treatment of necrotic vasculitis - 3 g intravenously for 5-6 days under the control of the number of leukocytes and granulocytes, subsequently maintenance therapy is necessary in the form of monthly administrations at a dose of 750-1000 mg/ ^m2.

Cyclosporine, which inhibits T-cell activation by interleukin-2 or other T-cell activating reactions, acts by binding to specific immunophilin and may cause nephrotoxicity, hepatotoxicity, and hypertension. Several studies in small groups of patients with dermatomyositis and polymyositis have shown a beneficial effect of cyclosporine, but its high cost and potential side effects limit its use. Treatment is initiated at a dose of 6 mg/kg/day, subsequently tapered to 4 mg/kg/day to reduce the risk of nephrotoxicity. Monitoring serum drug concentrations may make its use safer. The recommended serum level is 100 to 150 μg/mL.

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

The most important feature that distinguishes inclusion body myositis from dermatomyositis and polymyositis is the low response to immunosuppressive therapy. In cases of polymyositis resistant to corticosteroids, repeat biopsy often reveals morphologic features of inclusion body myositis. However, a small percentage of patients with inclusion body myositis respond positively to corticosteroids. Therefore, a 3-month trial of oral prednisolone is recommended in all cases. If there is no effect, intravenous immunoglobulin is indicated. In a double-blind, placebo-controlled study of 19 patients with inclusion body myositis, "functionally significant improvement was noted in 6 (28%) cases. However, the effect was moderate at best; nevertheless, a study on a small number of patients may not have revealed a sufficiently positive effect of intravenous immunoglobulin in inclusion body myositis. Further studies of the pathogenesis of this disease and the search for its effective treatment are needed.

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