Interferons and Multiple Sclerosis

Preliminary tests of interferons in the treatment of multiple sclerosis were started in the early 1980s. Interferons were first described by Isaacs and Lindemann in 1957 as a soluble substance that protects cells from a viral infection. Later, it was found that interferons have an antiproliferative and immunomodulatory effect and can serve as an effective antitumor agent. Type I interferons are distinguished, which include INFA (15 subtypes) and INF B * (1 subtype), and Type II interferons, to which the INF belong. In addition, there are two more types of interferons - INF-titta and INF-omega. Type I interferons have similar structural and functional characteristics and a common receptor. Type II interferons differ in structure and interact with another receptor. Nevertheless, the biological mechanisms of their action are similar. Interferons bind to receptors on the cell surface and activate a family of transcription agents called STAT proteins (Signa1 Transducers and Activators of Transcription) that form a complex with a DNA bound protein that translates into the nucleus and modulates transcription interferon-stimulating genes - ISG. Type I and II interferons differently activate proteins involved in tyrosine-dependent phosphorylation of STAT proteins, which may predetermine the specificity of their action.

Type I interferons. INF and INFB * are glycoproteins, comprising 166 amino acids, 34% of the amino acid sequence being the same. Their genes are localized on the 9th chromosome. The INF is predominantly produced by leukocytes, and INFB * is fibroblasts. However, some cells produce both types of interferon. Interferon production is induced by double crimped viral DNA, INF and INF. The antiviral effect is provided by selective induction of certain enzymes, carried out through the 2'5'-oligoadenylate, which is a marker of interferon activity. Type I interferons also have an antiproliferative effect and promote cell differentiation.

The first important step in the long-term management of multiple sclerosis was made in 1993, when INFBeta1b was the first non-cytotoxic drug that was able to exert a significant influence on the course of the disease and was resolved for use in multiple sclerosis. The efficacy of the drug was proven in a multicenter phase III study, which showed that the frequency of exacerbations significantly decreases, the duration of the period before the onset of the first exacerbation decreases, and the severity of exacerbations and the degree of brain damage from MPT data. In addition, there was a trend towards a decrease in the degree of functional defect in patients treated with interferon, compared with the control group. MRI served as an important auxiliary marker of efficacy and demonstrated that the total volume of foci detected on T2-weighted images was stabilized against the background of treatment with INFB, whereas in the control group, the number and volume of foci increased.

The second drug INFB (INFB 1a) was approved for use in patients with multiple sclerosis in 1996 on the basis of the results of Phase III study, which showed that the drug causes a moderate decrease in functional defect within 2 years. There was also a decrease in the activity of the disease, estimated by the number of gadolinium-contrasted foci on MRI.

Interferon beta-1b. INFBeta1b is a non-glycosylated protein produced by Escherichia co1i containing the recombinant INFBb gene. In the molecule INFFet1i on the 17th position of the series is replaced by cysteine, which ensures its stability. In patients with multiple sclerosis, the drug is administered subcutaneously in a dose of 8 million international units (MME), or 0.25 mg, every other day. The concentration of the drug in the serum after the introduction of 0.25 mg reaches a peak after 8-24 hours, and then decreases to the baseline by 48 hours. The biological activity of INFBeta1b is assessed by measuring serum levels of beta2-microglobulin, neopterin, and activity in peripheral blood mononuclear cells of the 2 ', 5'-oligoadenylate synthetase. In healthy individuals, a single injection of 8MME drug causes an increase in the level of these biological markers, peaking at 48-72 hours. The level remains stably elevated after 1-week treatment with the administration of the drug every other day. After a single injection, the level of beta2-microglobulin reaches a peak concentration of 2 mg / ml, and after 1 week of treatment it remains stably elevated.

The clinical efficacy of INF-beta 1b in the treatment of multiple sclerosis was demonstrated in a double-blind, placebo-controlled clinical trial involving 372 patients with a remitting multiple sclerosis course. The average age of patients in the group was 36 years, and the average duration of the disease was 4 years. On average, the patients had 3.5 exacerbations in the 2 years preceding inclusion in the study. Three groups were formed - in one patient, the drug was administered at a dose of 8 MME, in another - in 1.6 MMU, in the third placebo was used. After 2 years of treatment, the average number of exacerbations per year was significantly higher in the group where patients were injected with a higher dose of interferon - compared with the control group. In patients who received a lower dose of the drug, intermediate results were noted (the average number of exacerbations for the year was 1.27 in the control group, against the background of the introduction of 1.6 MME-1.17, against the background of 8 MME - 0.84). In patients who injected 8 MME, there was a two-fold decrease in the frequency of moderate and severe exacerbations. A larger proportion of patients who injected a higher dose had no exacerbations in 2 years, 36 (8 MME) and 18 (placebo, respectively). MRI data also confirmed the effectiveness of the drug. MRI was performed annually for all patients, and in a subgroup of 52 patients - every 6 weeks for 1 year. In both cases, a group that injected a higher dose of interferon showed a statistically significant decrease in the activity of the disease, expressed in a decrease in the number of new foci and the total volume of foci. Despite these data, the severity of the functional defect, measured with EDSS, did not change significantly during the 3 years either in the groups that injected interferon or in the control group. Nevertheless, there was a tendency towards a decrease in the functional defect in the group where high-dose interferon was used. Thus, the study was inadequate to reveal a moderate effect on the condition of the functional defect.

Because of the side effects, 16 people came out of the study, 10 of them from the group where interferon was used in high dose and 5 from the group, where low-dose interferon was used. The cause of the exit from the study were changes in liver functional parameters, pain at the injection site, fatigue, heart rhythm disturbances, allergic reactions, nausea, headache, flu-like syndrome, malaise, confusion. Among the patients treated with INFBeta1b, one suicide and four suicidal attempts were also noted. In general, side effects were more frequent in the group where the drug was used in a high dose: reactions at the injection site were noted in 69% of cases, fever in 58% of cases, myalgia in 41% of cases. These side effects tended to weaken after 3 months of treatment and reached the frequency observed in the control group after 1 year.

Based on the results of this study, INFBeta1b was approved for use in patients with a remittent form of multiple sclerosis, which retained the ability to move independently. A five-year follow-up of the initial cohort of patients showed that although the reduction in the frequency of exacerbations persists, it loses statistical significance in the third year. It was noted that patients who withdrew from the study of all groups had a higher frequency of exacerbations and a more pronounced progression of the disease according to MRI data than those who completed the study. In several studies, the efficacy of the drug was also evaluated in secondarily progressive multiple sclerosis. In one of them, a decrease in the rate of progression was noted, both according to clinical data and MRI data; in another, INFBeta1b reduced the frequency of exacerbations and improved MRT), but did not have a statistically significant effect on the rate of functional defect accumulation.

Side Effects of INFBET1b

• Neutropenia 18%
• Disorders of the menstrual cycle 17%
• Leukopenia 16%
• A malaise of 15%
• Palpitation 8%
• Shortness of breath 8%
• Necrosis at the injection site 2%
• Reactions at the injection site 85%
• Complex of influenza-like symptoms of 76%
• Fever 59%
• Asthenia 49%
• Chilliness 46%
• Myalgia 44%
• Sweating 23%

A number of studies have attempted to elucidate the mechanism of action of INFBb in multiple sclerosis. It is noted that it inhibits the secretion of gelatinase by activated T-lymphocytes in vitro, inhibiting migration through an artificial basal membrane. In other studies, it was found that under the influence of INFP, a decrease in the concentration of adhesive molecules, increased secretion of IL-10, inhibition of T-cell activation, a decrease in TNF level, and stimulation of IL-6 production.

Interferoe-beta1a. INFB 1a is a glycosylated recombinant interferon with a complete amino acid sequence produced by Chinese hamster ovary cells. The drug is administered intramuscularly at a dose of 6 MMU1 once a week. A single injection of this dose to healthy individuals raises the level of beta2-microglobulin in serum, which peaks at 48 hours and remains elevated, albeit at a lower level, for 4 days. This dose was chosen for the study, as it induced biological markers. Side effects could be corrected with acetaminophen (paracetamol), which made it possible to preserve the blind nature of the experiment.

In a clinical trial evaluating the efficacy of INFB1a and its ability to slow the progression of the neurologic defect, the time taken for the EDSS score reduction of 1 point and the frequency of exacerbations were used as the main outcome measures. The study showed that by the end of the second year of treatment, 34.9% of patients in the placebo group and 21.4% of the patients in the group treated with the drugs tested reached the established endpoint (p = 0.02). The frequency of exacerbations was significantly reduced by 30% in patients who completed the 2-year study, and only 18% in all patients. Measurement of the number and volume of foci contrasted with gadolinium, but not the total lesion volume on T2-weighted images, revealed a significant decrease in these parameters in patients treated with INF1b. Side effects were similar to those observed with INFBet1b, and included headache, flu-like symptoms, muscle pain, fever, asthenia, and chills.

Based on these results, INF 1b was approved for use in patients with a remitting form of multiple sclerosis. In subsequent studies, there was a certain positive effect of the drug and with the secondarily progressive form of multiple sclerosis, however it was less specific than in the remitting form. Recently, it has been shown that INFF1a slows the development of clinically significant multiple sclerosis in patients who underwent a single episode of demyelinating disease, manifested by optic neuritis, myelitis, or stem-cerebellar symptoms.

Other interferons. Although the INF was tested in patients with remittent as well as in patients with a secondarily progressive form of multiple sclerosis, it is not allowed for use in MS in the United States. The results of a small study indicate a significant decrease in the frequency of exacerbations and a decrease in the progression of the disease, estimated from the MRI data.

INFT differs from Type I interferons in that its secretion is not so intensively induced by viruses or double crimped DNA. It is less toxic, and its synthesis is more prolonged. It was first identified as a hormonal marker of pregnancy in ruminant animals, such as a sheep or a cow. INFT has immunomodulating activity, like type I interferons, and blocks the development of EAE induced by superantigenic activation.

The treatment of patients with interferons. Indications for the use of INFBb with multiple sclerosis are formulated based on the design of clinical trials. Thus, INFBb 1b is recommended for use in patients with relapsing multiple sclerosis, which retained the ability to move independently, to reduce the frequency of clinical exacerbations. INFB 1a is recommended for the treatment of patients with remittent form of multiple sclerosis to slow the development of a functional defect and reduce the frequency of clinical exacerbations. None of the drugs is officially approved for use in secondarily progressive or primarily progressive multiple sclerosis. Moreover, although these drugs differ in frequency and severity of side effects, dose and method of administration, there is no consensus on which cases this or another drug should be preferred.

In 1994, a panel of experts was specially organized to decide whether it is advisable to administer IFNbb 1b in patients with a more severe disease or with other forms of the disease than those included in the study. The group concluded that INFBb 1b may be useful in remitting multiple sclerosis, when the patient's age exceeds 50 years or has lost the ability to move independently if they experience frequent exacerbations. The group also concluded that in patients with progressively recurrent course, treatment with interferon can also be effective. It is noted that the same criteria as in the study can be used as criteria for cessation of treatment of INFBb 1b.

Side effects. The side effects of interferons are dose-dependent and tend to weaken with continued treatment. These include reactions at the injection site, influenza-like symptoms, affective disorders, a decrease in the number of blood cells, an increase in the level of hepatic enzymes. Gradual dose increase, training of patients or caregivers, proper injection techniques, more frequent monitoring of patients at the beginning of treatment, contribute to successful treatment with interferons. Reactions at the injection site often cause particular concern to patients. They range from mild erythema to skin necrosis. At a biopsy in a place of introduction leucoclastic infiltrates and thromboses of vessels are revealed. The heating of the solution and the slower injection rate reduce the associated discomfort. Flu-like symptoms can be reduced with acetaminophen (paracetamol), non-steroidal anti-inflammatory drugs or pentoxifylline, and with the administration of the drug at a time when the patient is less active (for example, before going to bed). Easy depression can be corrected with the help of pharmacological agents. However, the doctor should be on his guard against a persistent or severe form of depression or emotional lability. Short-term medicinal vacations will help determine the contribution of interferon to the development of affective disorders. If intolerance to one of the drugs, the patient's INFF can be transferred to another drug.

The expert group suggested that interferon 1b may be useful in patients who move with or have lost their ability to move, and also in patients with a progradient-relapsing course and over 50 years of age.

To reduce the likelihood of side effects, it is recommended to administer the drug in a half dose at the first 2-4 weeks of treatment, prescribe an antipyretic / analgesic (acetaminophen, aspirin or other non-steroidal anti-inflammatory drug) 4 hours before injection, at the time of injection and 4 hours after injection, in the evening. Patients should be taught the correct technique of injection.

It is possible to temporarily cancel the drug with a slight increase in the activity of transaminases before it returns to the baseline, after which the treatment is resumed from one quarter of the full dose, further increasing the dose depending on the tolerability. With a persistent and high increase in the level of transaminases (10 and more times higher than normal), it is necessary to cancel the drug.

Patients who are permanently on treatment for 1 year with increased exacerbations or other worsening of the condition have been shown to study neutralizing antibodies (the test kit is available from the Velekh laboratory). Two positive results with an interval of a 3 months indicate the production of neutralizing antibodies.

An easier degree of depression can be corrected with antidepressants and psychotherapy. Selective serotonin reuptake inhibitors may have an advantage, since they are less likely to cause fatigue.

With a mild reaction at the injection site, treatment can be continued. Periodically, a qualified health professional should check the correctness of the injections. Necrosis of the skin at the injection site or other expressed reactions at the injection site (eg, fasciitis) require a temporary or complete discontinuation of the drug.

Neutralizing antibodies of cINF / f. Neutralizing antibodies occur upon administration of both INFBeta1b and INFP1a. In clinical trials, neutralizing antibodies were detected in 38% of patients treated with INFBeta1b. The frequency of exacerbations in patients with antibodies is equal to or greater than the frequency of exacerbations in the group treated with placebo. The percentage of patients with neutralizing antibodies is approximately the same in patients treated with INFBb 1b at doses of 1.6 MIU and 8 MME. Side effects in patients with antibodies occurred with the frequency that patients with antibodies were not detected. In patients who are on treatment with INFB, it is recommended to carry out a study for neutralizing antibodies in cases where it lasts 1 year, with frequent exacerbation or progression of the disease. If the result of the initial study was positive or questionable, a follow-up study is recommended after 3 months.

In the treatment of INFB1a, neutralizing antibodies were detected in 14% of patients by the end of 1 year and in 22% of patients by the end of the second year of the study - and only 4% of patients in the placebo-treated group. According to preliminary data, when neutralizing antibodies are detected, the effectiveness of INFB1a in both clinical and MRI data is also reduced.

It was noted that the risk of exacerbations increases at the beginning of treatment of INFBb, possibly due to the induction of secretion of INF. This assumption is based on data showing an increase in the number of INF-secreting mononuclear cells in the peripheral blood that is detected in the first 2 months after initiation of treatment of INFBb 1b. In the first 3 months, the treatment of INF 1a also shows an increase in the frequency of exacerbations and the appearance of new foci on MRI. In the clinical trial of INFIb, a reduction in the frequency of exacerbations was observed only 2 months after the start of treatment.

[1], [2], [3], [4], [5], [6], [7]