Treatment of multiple sclerosis exacerbations

Glucocorticoids and corticotropin in the treatment of multiple sclerosis

In 1949, Philipp Hench reported improvement in 14 patients with rheumatoid arthritis with compound E (cortisone) and corticotropin. Dr. Hench and two biochemists, E.C. Kendall and T. Reichstein, were awarded the Nobel Prize in Medicine or Physiology for their discovery of the clinically significant anti-inflammatory effect of steroids. This led to widespread use of these drugs in the treatment of autoimmune diseases and inflammatory conditions. The first report of their use in multiple sclerosis was in 1950, when adrenocorticotropic hormone (ACTH) was administered to a small group of patients using an open method. Although these studies failed to demonstrate the effectiveness of ACTH, the patients' condition improved with the treatment. However, other uncontrolled studies of ACTH have shown that it has no significant effect on the chronic course of the disease, although it does provide some benefit by reducing the severity of exacerbations. Similarly, trials of ACTH in optic neuritis found significant improvement in the rate and extent of visual recovery within the first month of treatment but no difference between groups after 1 year. Although several studies using oral prednisolone reported similar improvements in function after an exacerbation, chronic oral steroid use for up to 2 years had no effect on the progression of neurologic deficit.

In the early 1980s, both open-label and blinded studies were published showing that intravenous prednisolone improved the short-term outcome of patients with relapsing-remitting multiple sclerosis. Randomized trials comparing ACTH with intravenous methylprednisolone showed that the latter was as effective as ACTH but had fewer side effects. The initial dose of intravenous methylprednisolone ranged from 20 mg/kg/day for 3 days to 1 g for 7 days. As a result of these reports, interest in glucocorticoid therapy was renewed because short-course intravenous methylprednisolone was more convenient for the patient and had fewer side effects than ACTH.

The recommended dose of methylprednisolone for intravenous administration ranges from 500 to 1500 mg per day. It is administered daily as a single dose or in divided doses for 3 to 10 days. The duration of therapy may be shortened if there is a rapid response or increased if there is no improvement.

The risk of complications with short courses of intravenous methylprednisolone is minimal. Cardiac arrhythmia, anaphylactic reactions, and epileptic seizures occur rarely. The risk of these side effects can be minimized by infusing the drug over 2-3 hours. It is advisable to conduct the first course in a hospital setting under the supervision of experienced health care workers. Other complications associated with the introduction of this drug are minor infections (urinary tract infections, oral or vaginal candidiasis), hyperglycemia, gastrointestinal disorders (dyspepsia, gastritis, exacerbation of peptic ulcer disease, acute pancreatitis), mental disorders (depression, euphoria, emotional lability), facial flushing, taste disturbances, insomnia, mild weight gain, paresthesia, and acne. Steroid withdrawal syndrome is also well known, which occurs when high doses of hormones are suddenly discontinued and is characterized by myalgia, arthralgia, fatigue, and fever. It can be minimized by gradually discontinuing glucocorticoids using oral prednisone starting at a dose of 1 mg/kg/day. Nonsteroidal anti-inflammatory drugs such as ibuprofen can also be used instead of prednisone.

Administration of high doses of glucocorticoids reduces the number of gadolinium-enhancing lesions on MRI, probably due to restoration of the integrity of the blood-brain barrier. A number of pharmacological properties of glucocorticoids may contribute to these effects. Thus, glucocorticoids counteract vasodilation by inhibiting the production of its mediators, including nitric oxide. The immunosuppressive effect of glucocorticoids may reduce the penetration of inflammatory cells into the perivenular spaces of the brain. In addition, glucocorticoids inhibit the production of proinflammatory cytokines, reduce the expression of activation markers on immunological and endothelial cells, and reduce antibody production. They also inhibit the activity of T-lymphocytes and macrophages and reduce the expression of IL-1, -2, -3, -4, -6, -10, TNFa and INFy. Glucocorticoids also inhibit the expression of IL-2 receptors and, accordingly, signal transmission, as well as the expression of class II MHC molecules on macrophages. In addition, the use of these agents weakens the function of CD4 lymphocytes to a greater extent than CD8 lymphocytes. At the same time, glucocorticoids do not have any permanent effect on immune parameters in multiple sclerosis. In most patients, the oligoclonal antibody index does not change during treatment, and a temporary decrease in IgG synthesis in the cerebrospinal fluid does not correlate with clinical improvement.

It is difficult to separate the immunosuppressive effect from the direct anti-inflammatory effect of glucocorticoids in multiple sclerosis. However, the results of the Glucocorticoid Efficacy in Optic Neuritis Study are noteworthy, showing that high-dose methylprednisolone (as opposed to placebo or oral prednisone) reduced the risk of a second episode of demyelination over 2 years.

In the study by Beck et al (1992), 457 patients were randomized into three groups: one received intravenous methylprednisolone at a dose of 1 g/day for 3 days followed by a switch to oral prednisone at a dose of 1 mg/kg/day for 11 days. The second group was given oral prednisone at a dose of 1 mg/kg/day for 14 days, and the third was given placebo for the same period. On the 15th day, the degree of recovery of visual functions was assessed; the state of the visual fields and contrast sensitivity (but not visual acuity) were better in the group of patients who received intravenous methylprednisolone than in the other two groups. By the 6th month after treatment, a slight but clinically significant improvement in the studied parameters was maintained. After 2 years of follow-up, the relapse rate of optic neuritis was significantly higher in patients receiving prednisone (27%) than in those receiving methylprednisolone (13%) or placebo (15%). Of patients who did not meet the criteria for definite or probable multiple sclerosis at study entry, 13% (50 of 389) had a second relapse within 2 years that would allow the disease to be diagnosed. The risk was higher in cases where MRI at entry revealed at least two lesions with typical sizes and locations for multiple sclerosis. In this group, the risk of relapse was significantly lower with intravenous methylprednisolone (16%) than with prednisone (32%) or placebo (36%). However, the effect of intravenous methylprednisolone in slowing the progression of clinically significant multiple sclerosis was not maintained at 3 and 4 years after treatment.

Based on these results, high-dose intravenous methylprednisolone may be recommended for the treatment of exacerbations of optic neuritis in the presence of abnormal MRI scans, if not to speed recovery, then to delay the development of clinically evident multiple sclerosis.

However, subsequent studies comparing oral glucocorticoids (prednisone and methylprednisolone) with standard doses of intravenous methylprednisolone in the treatment of exacerbations found no benefit from high-dose intravenous methylprednisolone. However, the results of this study should be viewed with caution because nonequivalent doses were used, there was no control group, and the improvement with intravenous therapy that has been demonstrated in other studies was not demonstrated. Moreover, MRI was not used to assess the effect. Therefore, more convincing clinical trials that include blood-brain barrier assessment (including MRI) are needed to assess the usefulness of intravenous glucocorticoids.

Chronic immunosuppression in the treatment of multiple sclerosis

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Immunosuppression with cyclophosphamide

Cytotoxic drugs are used to induce long-term remission in patients with rapidly progressive multiple sclerosis. The best studied drug for its efficacy in multiple sclerosis is cyclophosphamide, an alkylating agent developed over 40 years ago for the treatment of cancer. Cyclophosphamide has a dose-dependent cytotoxic effect on leukocytes and other rapidly dividing cells. Initially, the number of lymphocytes decreases more than the number of granulocytes, while higher doses affect both cell types. At a dose of less than 600 mg/m ², the number of B cells decreases to a greater extent than the number of T cells, and the drug affects CD8 lymphocytes to a greater extent than CD cells. Higher doses affect both types of T cells equally. Temporary stabilization for up to 1 year in patients with rapidly progressive disease is achieved with high-dose intravenous cyclophosphamide (400-500 mg daily for 10-14 days), which reduces the white blood cell count by 900-2000 cells/mm ³. These studies failed to maintain blinding because of the unexpected development of alopecia in patients receiving cyclophosphamide. Resumption of progression after 1 year was noted in two-thirds of intensively treated patients, requiring repeated induction of remission with high-dose cyclophosphamide or monthly single ("booster") administration of 1 mg. This treatment regimen was more effective in younger individuals with a shorter duration of disease. Another randomized, placebo-controlled study failed to confirm the efficacy of cyclophosphamide induction of remission.

Other studies have confirmed the efficacy of maintenance cyclophosphamide regimens administered primarily or after an induction regimen in patients with secondary progressive or remitting disease. Monthly "booster" cyclophosphamide administration after an induction regimen can significantly (up to 2.5 years) delay the onset of treatment resistance in patients under 40 years of age with secondary progressive multiple sclerosis. However, the use of the drug is significantly limited by its side effects, including nausea, vomiting, alopecia, and hemorrhagic cystitis. Currently, cyclophosphamide is used in a small proportion of young patients capable of independent movement, whose disease is resistant to other treatment methods and continues to progress.

Immunosuppression with cladribine

Cladribine (2-chlorodeoxyadenosine) is a purine analogue that is resistant to deamination by adenosine deaminase. Cladribine has a selective toxic effect on dividing and resting lymphocytes by affecting the bypass pathway preferentially used by these cells. A single course of treatment can induce lymphopenia that persists for up to 1 year. Although one double-blind crossover study showed that treatment resulted in stabilization of patients with rapidly progressive disease, these results have not been reproduced in patients with primary or secondary progressive multiple sclerosis. Cladribine can suppress bone marrow function, affecting the formation of all blood elements. A significant decrease in the number of lymphocytes with CD3, CD4, CD8, and CD25 markers persists for one year after treatment. Cladribine remains an experimental treatment at present.

Immunosuppression with migoxantrone

Mitoxantrone is an anthracenedione antitumor drug that inhibits DNA and RNA synthesis. The drug's efficacy has been studied in both relapsing-remitting and secondary progressive multiple sclerosis, with doses of 12 mg/m2 ^and 5 mg/ ^m2 administered intravenously every 3 months for 2 years tested. The results show that, compared with placebo, a higher dose of mitoxantrone leads to a significant decrease in the frequency of exacerbations and the number of new active lesions on MRI, and also reduces the rate of accumulation of neurological defect. In general, mitoxantrone is well tolerated. However, its ability to cause cardiotoxicity is of particular concern, which is why it is recommended to limit the total dose of mitoxantrone received during life. In this regard, continuous quarterly administration of the drug at a dose of 12 mg/m2 ^can continue for no more than 2-3 years. Currently, the drug is approved for use in patients with both relapsing-remitting multiple sclerosis (with a tendency to progression and ineffectiveness of other drugs) and secondary progressive multiple sclerosis.

Other immunosuppressive agents

The need for long-term treatment of multiple sclerosis has forced the study and use of other immunosuppressive agents that would be safer for long-term administration. Since studies have shown that some of these agents have a partial effect and somewhat slow the progression of the disease, they are still used in a certain proportion of patients.

Azathioprine

Azathioprine is a purine antagonist that is converted to its active metabolite 6-mercaptopurine in the intestinal wall, liver, and red blood cells. The drug is primarily used to prevent allograft rejection, to suppress the reaction of grafted tissue against the host, and in the treatment of rheumatoid arthritis resistant to other treatments. 6-mercaptopurine inhibits the activity of enzymes that ensure purine production, which leads to depletion of cellular purine reserves and suppression of DNA and RNA synthesis. As a result, the drug has a delayed toxic effect on leukocytes, which is relatively selective for replicating cells that respond to antigens. In neurological diseases, azathioprine is especially widely used in myasthenia gravis and multiple sclerosis at doses of 2.0 to 3.0 mg/kg/day. However, only a limited therapeutic effect of the drug has been shown in patients with multiple sclerosis. A 3-year, double-blind, randomized study conducted by the British and Dutch Multiple Sclerosis Azathioprine Trial Group (1988) involving 354 patients showed that the mean EEDS score decreased by 0.62 points during treatment, while it decreased by 0.8 points during placebo. A slight decrease in the mean exacerbation frequency from 2.5 to 2.2 was not statistically significant. Another study showed a moderate decrease in the exacerbation frequency, which was more pronounced in the second year of treatment. An extensive meta-analysis of blinded studies of azathioprine confirmed small differences in favor of patients treated with azathioprine, which became apparent only in the second and third years of therapy.

There is a minimal long-term risk associated with azathioprine treatment, associated with a slight increase in the likelihood of developing cancer, but this is only detected when the duration of treatment exceeds 5 years. Side effects on the gastrointestinal tract may lead to mucositis, the manifestations of which (if mild) can be reduced by reducing the dose or taking the drug with food.

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Cyclosporine

Cyclosporine A is isolated from the soil fungus Tolypocladium inflatum. It blocks the proliferation of autoreactive T-lymphocytes by inhibiting signal transduction pathways, is effective in preventing graft rejection in organ transplants, and improves allogeneic bone marrow transplant outcomes. Cyclosporine binds to intracellular immunophilin receptors and acts on calneurin and serine-threonine phosphatase. Administration of cyclosporine to patients with rapidly progressing multiple sclerosis in doses sufficient to maintain its blood concentration at 310-430 ng/ml for 2 years resulted in a statistically significant but moderate reduction in the severity of functional impairment and delayed the time when the patient became wheelchair-bound. However, during the course of the study, a significant number of patients dropped out of both the cyclosporine group (44%) and the placebo group (33%). The initial dose was 6 mg/kg/day, subsequently adjusted so that the serum creatinine level did not increase more than 1.5 times from the initial level. Nephrotoxicity and arterial hypertension were the two most common complications that required drug discontinuation. Another 2-year randomized double-blind study showed a favorable effect of the drug on the rate of progression of multiple sclerosis, the frequency of its exacerbations, and the severity of functional impairment. In general, the use of cyclosporine in multiple sclerosis is limited due to low efficacy, nephrotoxicity, and the possibility of other side effects associated with long-term use of the drug.

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Methotrexate

Oral administration of small doses of methotrexate has proven to be an effective, relatively non-toxic method of treating various inflammatory diseases, primarily rheumatoid arthritis and psoriasis. Methotrexate, a folic acid antagonist, inhibits various biochemical reactions, affecting the synthesis of proteins, DNA, and RNA. The mechanism of methotrexate action in multiple sclerosis remains unknown, but it has been established that the drug inhibits IL-6 activity, reduces the level of IL-2 and TNFa receptors, and has an antiproliferative effect on mononuclear cells. In relapsing-remitting multiple sclerosis, methotrexate use significantly reduces the frequency of exacerbations. However, an 18-month study failed to demonstrate the drug's effectiveness in the secondary progressive course. In a large, randomized, double-blind study of 60 patients with secondary progressive disease, low-dose methotrexate (7.5 mg weekly) did not prevent deterioration in ambulation but did preserve upper-limb function. Thus, methotrexate is a relatively safe treatment for patients with progressive multiple sclerosis who retain independent ambulation.

Other non-specific immunotherapy methods

Total lymph node irradiation

Total lymph node irradiation is used to treat both malignancies and autoimmune diseases, including Hodgkin's disease and rheumatoid arthritis, resistant to other treatments. In addition, this method prolongs graft survival in organ transplants and causes long-term immunosuppression with an absolute decrease in lymphocyte counts. In two double-blind, placebo-controlled studies (the control group received sham radiation), total lymph node irradiation at a dose of 1980 c1p for 2 weeks slowed disease progression. The effect correlated with the degree of lymphopenia and was prolonged by the administration of low doses of glucocorticoids.

Plasmapheresis

There are reports of the ability of plasmapheresis to stabilize the condition of patients with fulminant forms of CNS demyelination, including acute disseminated encephalomyelitis. In patients with multiple sclerosis, plasmapheresis in combination with ACTH and cyclophosphamide accelerated recovery in patients with relapsing-remitting multiple sclerosis, but after a year, no significant clinical effect was observed. In a small randomized, single-blind crossover study in patients with secondary progressive disease, a comparison of plasmapheresis and azathioprine did not reveal significant differences in the number of active lesions according to MRI data.

Intravenous immunoglobulin

A double-blind, randomized study showed that intravenous immunoglobulin, when administered monthly at a dose of 0.2 g/kg for 2 years, can reduce the frequency of exacerbations and the severity of neurological impairment in patients with relapsing-remitting multiple sclerosis. However, these results require confirmation. Like plasmapheresis, immunoglobulin is used to stabilize patients with ADEM and fulminant forms of multiple sclerosis. The drug is currently being tested in the treatment of resistant forms of optic neuritis and secondary progressive multiple sclerosis. In general, the place of intravenous immunoglobulin in the treatment of multiple sclerosis, as well as the optimal scheme for its use, remain unclear.

Glatiramer acetate

Glatiramer acetate, previously called copolymer, was approved for use in patients with relapsing-remitting multiple sclerosis in 1996. The drug is injected subcutaneously daily at a dose of 20 mg. Blood levels of the drug are undetectable. The drug is a mixture of synthetic polypeptides consisting of acetate salts of four L-amino acids - glutamine, alanine, tyrosine and lysine. After injection, glatiramer acetate quickly breaks down into smaller fragments. The drug is used to reduce the frequency of exacerbations in patients with relapsing-remitting multiple sclerosis. In the main phase III clinical trial, glatiramer acetate reduced the frequency of exacerbations by a third. A more pronounced reduction in the frequency of exacerbations was noted in patients with minimal or mild functional impairment. Mild skin reactions, including erythema or oedema, may occur at the injection site. Although the drug rarely causes systemic side effects, its use may be limited in patients experiencing "vasogenic" reactions immediately after administration. In terms of safety during pregnancy, the drug is classified as category C, indicating the absence of complications when administered to pregnant animals, while interferons are classified as category B. Therefore, in the event of pregnancy, preference should be given to glatiramer acetate among immunomodulatory agents.

Glatiramer acetate is one of a series of drugs developed at the Weizmann Institute in the early 1970s to study experimental allergic encephalomyelitis. It contains amino acids that are abundant in myelin basic protein. However, rather than causing EAE, the drug prevented its development in a number of laboratory animals that were injected with white matter extract or myelin basic protein with complete Freund's adjuvant. Although the mechanism of action is unknown, it is thought to bind directly to MHC class II molecules to form a complex or to prevent their binding to myelin basic protein. Induction of MBP-specific suppressor cells is also possible.

The results of the main study replicated those of an earlier placebo-controlled trial, which found a significant reduction in relapse rate and an increase in the proportion of patients without relapse. However, the two-center study failed to find a significant slowdown in the progression of functional impairment in secondary progressive multiple sclerosis, although one center did show a slight but statistically significant effect.

The main phase III study was performed on 251 patients in 11 centers and revealed that the introduction of glatiramer acetate significantly reduced the frequency of exacerbations, increased the proportion of patients without exacerbations, and prolonged the time to the first exacerbation in patients. The ability of the drug to slow the progression of neurological defect was indirectly evidenced by the fact that a greater proportion of patients treated with placebo had a deterioration in the EDSS by 1 point or more and that a greater proportion of patients treated with the active drug had an improvement in the EDSS score by 1 point or more. However, the percentage of patients whose condition did not worsen was approximately the same in both groups. Side effects during treatment with glatiramer acetate were generally minimal compared with those during treatment with interferons. However, 15% of patients experienced a transient reaction characterized by flushing, a feeling of chest tightness, palpitations, anxiety, and shortness of breath. Similar sensations occurred in only 3.2% of patients treated with placebo. This reaction, the cause of which is unknown, lasts from 30 seconds to 30 minutes and is not accompanied by changes in the ECG.