Treatment of exacerbations of multiple sclerosis

Glucocorticoids and corticotropin in the treatment of multiple sclerosis

In 1949, Philip Genc (E. Hench) reported improvement in 14 patients with rheumatoid arthritis with the use of compound E (cortisone) and corticotropin. For the discovery of the clinically significant anti-inflammatory effect of steroids, Dr. Gench and the two biochemists E.K. Kendall (ES Kenda11) and T. Reichstein (T. Reichstein) were awarded the Nobel Prize in Medicine and Physiology. A consequence was the widespread use of these drugs in the treatment of autoimmune diseases and inflammatory conditions. The first report on the use of these agents for multiple sclerosis dates back to 1950, when adrenocorticotropic hormone (ACTH) was used in a small group of patients using an open technique. Although these studies failed to prove the efficacy of ACTH, the condition of patients on the background of treatment improved. However, other uncontrolled studies of ACTH have shown that it has no significant effect on the chronic course of the disease, although it does bring some benefit, reducing the severity of exacerbations. Similarly, ACTH tests with optic neuritis revealed a significant improvement in the speed and completeness of recovery of visual function during the first month of treatment, but no differences between the groups after 1 year. Although several studies using prednisolone were reported to have similar improvement in function after exacerbation, prolonged use of steroids for up to 2 years did not affect the progression of the neurologic defect.

In the early 1980s, both open and blind studies were published that showed that intravenously administered prednisolone improves the condition of patients with remitting multiple sclerosis in the short term. In randomized trials comparing ACTH with intravenous methylprednisolone, it was shown that the latter is not inferior to ACTH, but causes 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 again increased, as the short course of intravenous methylprednisolone was more convenient for the patient and caused fewer side effects than ACTH treatment.

The recommended dose of methylprednisolone for intravenous administration varies from 500 to 1500 mg per day. It is administered daily once or in divided doses for 3-10 days. The duration of therapy can be shortened by rapid reaction or increased if there is no improvement.

The risk of complications with short courses of intravenous methylprednisolone is minimal. Occasionally there are heart rhythm disturbances, anaphylactic reactions and epileptic seizures. The risk of these side effects can be minimized if the drug is infused within 2-3 hours. The first course should preferably be conducted in a hospital under the supervision of experienced medical personnel. Other complications associated with the administration of this drug are small infections (urinary tract infections, oral or vaginal candidiasis), hyperglycemia, gastrointestinal disorders (dyspepsia, gastritis, exacerbation of peptic ulcer, acute pancreatitis), mental disorders (depression, euphoria, emotional lability), flushing of the face, a taste disorder, insomnia, a slight increase in body weight, paresthesia, the appearance of acne. Also well-known is the steroid withdrawal syndrome that occurs when a sudden discontinuation of the administration of high doses of hormones and manifested by myalgia, arthralgia, fatigue, fever. It can be minimized by the gradual elimination of glucocorticoids by prednisone inwards, starting at a dose of 1 mg / kg / day. Instead of prednisone, non-steroidal anti-inflammatory drugs, for example, ibuprofen, can be used.

The introduction of high doses of glucocorticoids reduces the number of foci on MRI, accumulating gadolinium, probably due to restoration of the integrity of the blood-brain barrier. A number of pharmacological properties of glucocorticoids can contribute to these effects. Thus, glucocorticoids counteract vasodilation, inhibiting the production of its mediators, including nitric oxide. The immunosuppressive effect of glucocorticoids can reduce the penetration of inflammatory cells into the periveneular spaces of the brain. In addition, glucocorticoids inhibit the production of pro-inflammatory cytokines, reduce the expression of activation markers on immunological and endothelial cells, reduce the production of antibodies. They also inhibit the activity of T-lymphocytes and macrophages and reduce the expression of IL-1, -2, -3, -4, -6, -10, TNFa and INFO. Glucocorticoids also inhibit the expression of IL-2 receptors and, accordingly, signal transduction, as well as the expression of class II MHC molecules on macrophages. In addition, against the background of the use of these funds, the function of CD4 lymphocytes is weaker than that of CD8 lymphocytes. At the same time, glucocorticoids do not have any permanent effect on immune parameters in multiple sclerosis. In most patients, the oligoclonal antibodies do not change on the background of treatment, and the temporary decrease in IgG synthesis in CSF 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 a study of the efficacy of glucocorticoids in optic neuritis, which showed that high doses of methylprednisolone (in contrast to placebo or prednisone taken orally), reduce the risk of a second episode of demyelination within 2 years.

In a study by Weck et al (1992), 457 patients were randomized to 3 groups: one was administered methylprednisolone IV at a dose of 1 g / day for 3 days, followed by a transition to prednisone by mouth at a dose of 1 mg / kg / day for 11 days. The second group was prescribed prednisone oral at a dose of 1 mg / kg / day for 14 days, and the third for the same period was assigned a placebo. On the 15th day, the degree of restoration of visual functions was assessed, while the condition of the visual fields and contrast sensitivity (but not visual acuity) were better in the group of patients who received IV methylprednisolone IV than in the other two groups. By the 6th month after treatment, an easy, but clinically meaningful, improvement was observed in the indicators studied. After 2 years of follow-up, it was found that the frequency of relapse with optic neuritis was significantly higher in patients taking prednisone (27%) than in patients who received methylprednisolone (13%) or placebo (15%). Of the patients who did not meet the criteria for reliable or probable multiple sclerosis when enrolled in the study, 13% (50 of 389) had a second exacerbation within 2 years, which made it possible to diagnose this disease. The risk was higher in those cases when the MRI at the time of inclusion detected at least two foci with typical for multiple sclerosis size and localization. In this group, the risk of re-attack was significantly lower with intravenous methylprednisolone (16%) compared with prednisone (32%) or placebo (36%). However, the effect of intravenously injected methylprednisolone, which consisted in slowing the development of clinically reliable multiple sclerosis, did not persist for the third and fourth year after treatment.

Based on these results, intravenous administration of high doses of methylprednisolone can be recommended for the treatment of exacerbations of optic neuritis in the presence of pathological changes in MRI, if not to increase the rate of recovery, in order to delay the development of clinically reliable multiple sclerosis.

But in subsequent studies, the comparison of intraocular glucocorticoids (prednisone and methylprednisolone) with standard doses of methylprednisolone administered intravenously in the treatment of exacerbation did not reveal the benefits of intravenous high doses of methylprednisolone. However, the results of this study should be treated critically, since nonequivalent doses were used, no control group was present, no improvement was seen with intravenous therapy, which was demonstrated in other studies. Moreover, no MRI was used to evaluate the effect. Therefore, more convincing clinical trials are needed that would include assessment of the blood-brain barrier status (including MRI), in order to assess the appropriateness of intravenous glucocorticoids.

Chronic immunosuppression in the treatment of multiple sclerosis

[1], [2]

Immunosuppression with cyclophosphamide

Cytotoxic drugs are used to induce long-term remission in patients with rapidly progressive multiple sclerosis. The efficacy of multiple-sclerosis cyclophosphamide, an alkylating drug developed more than 40 years ago for the treatment of cancer, has been best studied. Cyclophosphamide exerts a dose-dependent cytotoxic effect on leukocytes and other rapidly dividing cells. Initially, the number of lymphocytes decreases more than the number of granulocytes, whereas higher doses affect both types of cells. In a dose of less than 600 mg / m ^{2, the} number of B-cells decreases more than the number of T cells, and the CD8-lymphocyte affects the drug more than CD cells. Higher doses equally affect both types of T cells. Temporary stabilization up to 1 year in patients with rapidly progressive disease is provided by intravenous administration of high doses of cyclophosphamide (400-500 mg per day for 10-14 days), while the number of leukocytes decreases by 900-2000 cells per 1 mm ³. These studies failed to maintain a blind character due to the unexpected development of alopecia in patients who received cyclophosphamide. Renewal of progression after 1 year was noted in 2/3 of intensively treated patients, which required a repeated induction of remission with high doses of cyclophosphamide or a monthly single dose ("booster") dose of 1 mg. This scheme of treatment was more effective in young people with shorter duration of the disease. In another randomized, placebo-controlled study, it was not possible to confirm the efficacy of remission induction with cyclophosphamide.

Other studies have confirmed the efficacy of cyclophosphamide support regimens, administered primarily or after an induction regimen in patients with a secondary progressive or remitting course. The monthly "booster" injection of cyclophosphamide after the induction scheme can significantly (up to 2.5 years) delay the moment of the emergence of resistance to treatment in patients younger than 40 with secondary progressive multiple sclerosis. However, the use of the drug is significantly limited by its side effects, including nausea, vomiting, alopecia, hemorrhagic cystitis. Currently, cyclophosphamide is used in a small number of young patients, capable of independent movement, in which the disease is resistant to other methods of treatment and continues to progress.

Immunosuppression with cladribine

Cladribine (2-chlorodeoxyadenosine) is a purine analog, resistant to deamination by adenosine deaminase. Cladribine has a selective toxic effect on fission and resting lymphocytes, affecting the shunt pathway, which is predominantly used by these cells. A single course of treatment can induce lymphopenia lasting up to 1 year. Although in one of the double-blind cross-over studies it was shown that after stabilization of the condition in patients with rapidly progressive disease, these results were not reproduced in patients with primary or secondarily progressive multiple sclerosis. Cladribine is able to inhibit the function of the bone marrow, affecting the formation of all elements of the blood. A significant decrease in the number of lymphocytes with markers CD3, CD4, CD8 and CD25 persists for a year after the course of treatment. At present, the use of cladribine remains an experimental method of treatment.

Immunosuppression with miGoxantrone

Mitoxantrone is an anthracenedione antitumor drug that inhibits the synthesis of DNA and RNA. The efficacy of the drug has been studied both in remittent and secondarily progressive multiple sclerosis, with doses of 12 mg / m ² and 5 mg / m ² administered intravenously every 3 months for 2 years. The results show that, in comparison with placebo, a higher dose of mitoxantrone leads to a significant reduction in the frequency of exacerbations and the number of new active foci on MRI, and also reduces the rate of neurological defect accumulation. In general, mitoxantrone is well tolerated. However, of particular concern is its ability to have a cardiotoxic effect, which is why it is recommended to limit the total dose of mitoxantrone received in the course of life. In this regard, the constant quarterly administration of the drug at a dose of 12 mg / m ² can last no more than 2-3 years. Currently, the drug is approved for use in patients with both remittent multiple sclerosis (with a tendency to progression and ineffectiveness of other agents), and with secondarily progressive multiple sclerosis.

Other immunosuppressive agents

The need for long-term treatment of multiple sclerosis makes it necessary to investigate and use other immunosuppressive drugs that would be safer with prolonged administration. Since the studies showed that some of these drugs had a partial effect and somewhat slowed the progression of the disease, they are still used in a certain part of the patients.

Azathioprine

Azathioprine is a purine antagonist that converts into its active metabolite 6-mercaptopurine in the wall of the intestine, liver, and erythrocytes. The drug is mainly used to prevent rejection of the allograft, to suppress the reaction of the transplanted tissue against the host, and also in the treatment of rheumatoid arthritis, resistant to other methods of treatment. 6-mercaptopurine inhibits the activity of enzymes that provide purine products, which leads to depletion of purine cell stocks and suppression of DNA and RNA synthesis. As a result, the drug has a retarded toxic effect on leukocytes, which is relatively selective for replicating cells reacting to antigens. In neurological diseases, azathioprine is particularly widely used in myasthenia and multiple sclerosis at doses of 2.0 to 3.0 mg / kg / day. Nevertheless, in patients with multiple sclerosis only a limited therapeutic effect of the drug is shown. In a 3-year, double-blind, randomized trial conducted by the Britis and Dutch Multiple Sclerosis Azathioprine Trial Group (1988), which included 354 patients, it was shown that, compared with treatment, the mean EEDS score decreased by 0.62 points, compared with placebo - by 0,8 points. A slight decrease in the mean frequency of exacerbations from 2.5 to 2.2 was not statistically significant. Another study showed a moderate reduction in the frequency of exacerbations, which was more pronounced in the second year of treatment. An extensive meta-analysis of blind azathioprine studies confirmed small differences in favor of patients treated with azathioprine, which occur only in the second and third years of therapy.

In the treatment of azathioprine, there is a minimal long-term risk associated with a certain increase in the likelihood of developing cancer, but it is only detected when the duration of treatment exceeds 5 years. Side effect on the gastrointestinal tract can lead to mucositis, manifestations of which (if they are small) can be weakened by reducing the dose or taking the drug while eating.

[3], [4], [5], [6], [7], [8]

Cyclosporin

Ciclosporin A is isolated from the soil fungus Tolypocladium inflatum. It blocks the proliferation of autoreactive T-lymphocytes, having a retarding effect on signaling pathways, is effective in preventing graft rejection during organ transplants and improves the outcome of allogeneic bone marrow transplantation. Cyclosporine binds to intracellular immunophilin receptors and acts on calnevrin, serine threonine phosphatase. The administration of cyclosporine to patients with rapidly progressing multiple sclerosis in doses sufficient to maintain its concentration in the blood at a level of 310-430 ng / ml for 2 years resulted in a statistically significant but moderate decrease in the severity of the functional defect and allowed delaying the moment when the patient was chained to a wheelchair. However, during the course of the study, a significant number of patients dropped out of it, both from the group taking cyclosporine (44%) and from the placebo group (33%). The initial dose was 6 mg / kg / day, subsequently it was corrected so that the serum creatinine level did not increase more than 1.5 times from the baseline level. Nephrotoxicity and arterial hypertension are the two most common complications that required the discontinuation of the drug. In another 2-year, randomized, double-blind study, a favorable effect of the drug on the rate of progression of multiple sclerosis, the frequency of its exacerbations and the severity of the functional defect was shown. In general, the use of cyclosporine in multiple sclerosis is limited due to low efficiency, nephrotoxicity and the possibility of other side effects associated with prolonged use of the drug.

[9], [10], [11], [12]

Methotrexate

Ingestion of small doses of methotrexate has proved to be an effective, relatively non-toxic treatment for various inflammatory diseases, primarily rheumatoid arthritis and psoriasis. Methotrexate, which is an antagonist of folic acid, inhibits various biochemical reactions, affecting the synthesis of proteins, DNA, RNA. The mechanism of action of methotrexate in multiple sclerosis remains unknown, but it is found that the drug inhibits the activity of IL-6, decreases the level of IL-2 and TNFa receptors, and has an antiproliferative effect on mononuclear cells. With relapsing multiple sclerosis, methotrexate significantly reduces the frequency of exacerbations. However, in the 18-month study, it was not possible to demonstrate the effectiveness of the drug in the secondarily progressing course. In a large, randomized, double-blind study involving 60 patients with a secondary progressive disease, small doses of methotrexate (7.5 mg per week) did not prevent impairment of mobility, but contributed to the preservation of upper limb function. Thus, methotrexate is a relatively safe method of treatment for patients with progressive multiple sclerosis, who retain the ability to move independently.

Other non-specific methods of immunotherapy

Total lymph node irradiation

Total irradiation of lymph nodes is used to treat both malignant neoplasms and autoimmune diseases, including lymphogranulomatosis and rheumatoid arthritis, resistant to other methods of treatment. In addition, this method prolongs the survival time of the transplant during organ transplantation and causes prolonged immunosuppression with an absolute decrease in the number of lymphocytes. In two double-blind, placebo-controlled studies (in the control group, the irradiation was simulated), it was shown that total irradiation of the lymphatic catch in a dose of 1980 c1p for 2 weeks slows the progression of the disease. The effect correlated with the degree of lymphopenia and was prolonged by the appointment of small doses of glucocorticoids.

Plasmapheresis

There are reports of the ability of plasmapheresis to stabilize the condition of patients with fulminant forms of central nervous system demyelination, including acute disseminated encephalomyelitis. In patients with multiple sclerosis plasmapheresis in combination with ACTH and cyclophosphamide accelerated recovery in patients with a remitting form of multiple sclerosis, however, after a year, no significant clinical effect was noted. In a small, randomized, simple, blind, cross-over study, in patients with a progressively progressive course, comparison of plereferesis and azathioprine did not reveal significant differences in the number of active foci according to MRI.

Intravenous immunoglobulin

In a double-blind, randomized study, it was shown that with a monthly dose of 0.2 g / kg for 2 years, intravenous immunoglobulin can reduce the frequency of exacerbations and the severity of the neurologic defect in patients with remitting multiple sclerosis. However, these results need to be confirmed. Like plasmapheresis, immunoglobulin is used to stabilize patients with OREM and fulminant forms of multiple sclerosis. Currently, the drug is tested in the treatment of resistant forms of optic neuritis and secondarily progressive multiple sclerosis. In general, the place of intravenous immunoglobulin in the treatment of multiple sclerosis, as well as the optimal scheme of its use, remain unclear.

Glatiramer acetate

Glatiramer acetate, formerly called a copolymer, was approved for use in patients with relapsing multiple sclerosis in 1996. The drug is administered subcutaneously daily at a dose of 20 mg. The level of substance in the blood can not be determined. The preparation is a mixture of synthetic polypeptides consisting of acetic acid salts of four L-amino acids - glutamine, alanine, tyrosine and lysine. After the injection of glatiramer acetate, the acetate rapidly decomposes into smaller fragments. The drug is used to reduce the frequency of exacerbations in patients with remitting multiple sclerosis. In the main clinical trial of Phase III, glatiramer acetate reduced the frequency of exacerbations by one third. A more pronounced decrease in the frequency of exacerbations was noted in patients with a minimal or mild functional defect. At the injection site, mild skin reactions may occur, including erythema or edema. Although the drug rarely causes systemic side effects, its use may be limited in patients experiencing "vasogenic" reactions immediately after administration. According to the degree of safety during pregnancy, the drug is classified in category C, which indicates the absence of complications when it is administered to pregnant animals, whereas interferons are classified in category B. Therefore, in the perspective of pregnancy, it is glatiramer acetate that should be given the preference from immunomodulating 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, which are in large numbers present in the main myelin protein. However, instead of causing EAE, the substance prevented its development in a number of laboratory animals, which were injected with a white matter extract or the main myelin protein with Freund's complete adjuvant. Although the mechanism of action is not known, it is believed that the drugs directly bind to MHC class II molecules with complex formation or prevent its binding to the main myelin protein. In addition, the induction of MBM-specific suppressor cells is possible.

The results of the main study reproduced the data of an earlier placebo-controlled study that revealed a significant reduction in the frequency of exacerbations and an increase in the proportion of patients without exacerbations. However, in a two-center study, it was not possible to detect a significant delay in the growth of a functional defect in secondarily progressive multiple sclerosis, although one of the centers had a slight but statistically significant effect.

The main phase III study was performed on 251 patients in 11 centers and found that against the background of the introduction of glatiramer acetate, there was a significant reduction in the frequency of exacerbations, an increase in the proportion of patients without exacerbations, lengthening the time before the onset of the first exacerbation in patients. The ability of the drug to slow the progression of the neurological defect was indirectly indicated by the fact that a larger proportion of patients treated with placebo experienced an EDSS deterioration of 1 point or more and that in a larger proportion of patients treated with the active drug, the EDSS score improved by 1 point and more. However, the percentage of patients in whom the condition did not deteriorate was approximately the same in both groups. The side effects in the treatment of glatiramer acetate in general were minimal, compared with those in the treatment of interferons. Nevertheless, 15% of patients had a transient reaction characterized by hot flashes, a feeling of chest compression, palpitation, anxiety, and dyspnea. Similar sensations occurred only in 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.