Interferons and multiple sclerosis

Preliminary trials of interferons in the treatment of multiple sclerosis began in the early 1980s. Interferons were first described by Isaacs and Lindemann in 1957 as a soluble substance that protects cells from viral infection. Interferons were later found to have antiproliferative and immunomodulatory effects and can serve as an effective antitumor agent. There are type I interferons, which include INFa (15 subtypes) and INFb* (1 subtype), and type II interferons, which include INFu. In addition, there are two more types of interferons - INF-theta 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 a different receptor. However, their biological mechanisms of action are similar. Interferons bind to receptors on the cell surface and activate a family of transcriptional agents called STAT proteins (Signa1 Transducers and Activators of Transcription), which form a complex with a DNA-bound protein, through which they are translocated into the nucleus and modulate the transcription of interferon-stimulated genes (ISG). Types I and II interferons activate proteins involved in tyrosine-dependent phosphorylation of STAT proteins differently, which may determine the specificity of their action.

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

The first major step in the long-term treatment of multiple sclerosis was made in 1993, when INFbeta1b became the first non-cytotoxic drug that was able to exert a significant effect on the course of the disease and was approved for use in multiple sclerosis. The drug's efficacy was proven in a multicenter phase III study, which showed that the treatment significantly reduced the frequency of exacerbations, the duration of the period before the first exacerbation, as well as the severity of exacerbations and the extent of brain damage according to MRI. In addition, a tendency toward a decrease in the degree of functional impairment was noted in patients treated with interferon compared with the control group. MRI served as an important auxiliary marker of efficacy and demonstrated that INFbeta treatment was accompanied by stabilization of the total volume of lesions detected on T2-weighted images, whereas in the control group the number and volume of lesions increased.

A second INF-β drug (INF-β 1a) was approved for use in patients with multiple sclerosis in 1996 based on the results of a phase III study showing that the drug produced a modest reduction in functional impairment over 2 years. A reduction in disease activity, as measured by the number of gadolinium-enhancing lesions on MRI, was also noted.

Interferon beta-1b. INFbeta1b is a nonglycosylated protein produced by Escherichia coli containing the recombinant INFb gene. In the INFbeta1i molecule, position 17 of the series is replaced by cysteine, which ensures its stability. In patients with multiple sclerosis, the drug is administered subcutaneously at a dose of 8 million international units (IU), or 0.25 mg, every other day. The concentration of the drug in the serum after administration of 0.25 mg reaches a peak in 8-24 hours, and then decreases to the initial level by 48 hours. The biological activity of INFbeta1b is assessed by measuring the serum level of beta2-microglobulin, neopterin, as well as the activity of 2', 5'-oligoadenylate synthetase in peripheral blood mononuclear cells. In healthy individuals, a single 8MME injection of the drug causes an increase in the level of these biological markers, reaching a peak after 48-72 hours. The level remains stably elevated after 1 week of treatment with the drug being administered 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 IFN-beta 1b in the treatment of multiple sclerosis was demonstrated in a double-blind, placebo-controlled clinical trial involving 372 patients with relapsing-remitting multiple sclerosis. The average age of patients in the group was 36 years, and the average duration of the disease was 4 years. On average, patients had 3.5 exacerbations over the 2 years preceding inclusion in the study. Three groups were formed - in one, patients were administered the drug at a dose of 8 MME, in another - at 1.6 MME, and in the third, a placebo was used. After 2 years of treatment, the average number of exacerbations per year was significantly higher in the group where patients were administered 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 per year was 1.27 in the control group, 1.17 with 1.6 MME, and 0.84 with 8 MME). In patients who received 8 MME, a twofold decrease in the frequency of moderate and severe exacerbations was noted. A larger proportion of patients who received a higher dose had no exacerbations over 2 years - 36 (8 MME) and 18 (placebo), respectively. MRI data also confirmed the efficacy of the drug. MRI was performed annually for all patients, and every 6 weeks for 1 year in a subgroup of 52 patients. In both cases, a statistically significant decrease in disease activity was noted in the group that received a higher dose of interferon, expressed in a decrease in the number of new foci and the total volume of foci. Despite these findings, the severity of functional impairment, as measured by the EDSS, did not change significantly in either the interferon or control groups over 3 years. However, there was a trend toward decreased functional impairment in the high-dose interferon group. Thus, the study was underpowered to detect a modest effect on functional impairment.

A total of 16 subjects withdrew from the study due to adverse events, including 10 subjects in the high-dose interferon group and 5 in the low-dose interferon group. The reasons for withdrawal from the study were changes in liver function tests, pain at the injection site, fatigue, abnormal heart rhythms, allergic reactions, nausea, headache, flu-like syndrome, malaise, and confusion. Among the patients treated with INFbeta1b, there was also one suicide and four suicide attempts. Overall, adverse events were more common in the high-dose group: injection site reactions were noted in 69% of cases, fever in 58% of cases, and myalgia in 41%. These adverse events tended to subside 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 relapsing-remitting multiple sclerosis who retained the ability to independently move. Five-year follow-up of the initial cohort of patients showed that although the reduction in the frequency of exacerbations was maintained, it lost statistical significance in the third year. It was noted that patients in all groups who dropped out of the study had a higher frequency of exacerbations and more pronounced disease progression according to MRI data than patients who completed the study. Several studies have assessed the efficacy of the drug in secondary progressive multiple sclerosis. One of them noted a decrease in the rate of progression, both according to clinical data and according to MRI data, while in another, INFbeta1b reduced the frequency of exacerbations and improved MRI parameters but did not have a statistically significant effect on the rate of accumulation of functional impairment.

Side effects of INFbeta1b

• Neutropenia 18%
• Menstrual cycle disorders 17%
• Leukopenia 16%
• Malaise 15%
• Heart palpitations 8%
• Shortness of breath 8%
• Injection site necrosis 2%
• Injection site reactions 85%
• Complex of flu-like symptoms 76%
• Fever 59%
• Asthenia 49%
• Chills 46%
• Myalgia 44%
• Sweating 23%

A number of studies have attempted to elucidate the mechanism of action of INFb in multiple sclerosis. It has been noted that it inhibits the secretion of gelatinase by activated T-lymphocytes in vitro, inhibiting migration through an artificial basement membrane. Other studies have found that under the influence of INFb there is a decrease in the concentration of adhesion molecules, an increase in the secretion of IL-10, inhibition of T-cell activation, a decrease in the level of TNF and stimulation of IL-6 production.

Interferon-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 MME1 once a week. A single injection of this dose to healthy individuals increases the level of beta2-microglobulin in serum, which peaks at 48 h and remains elevated, albeit at a lower level, for 4 days. This dose was chosen for the study because it induced biological markers. Side effects could be corrected with acetaminophen (paracetamol), which made it possible to maintain the blinded nature of the experiment.

A clinical trial evaluating the efficacy of INFb1a and its ability to slow the progression of neurologic deficits used the time to a 1-point decrease in EDSS and the relapse rate as primary outcome measures. The study found that by the end of the 2nd year of treatment, 34.9% of patients in the placebo group and 21.4% of patients in the study drug group had reached the established end point (p = 0.02). The relapse rate was significantly reduced by 30% in patients who completed the 2-year study, but only by 18% in all patients. Measurement of the number and volume of gadolinium-enhancing lesions, but not the total lesion volume on T2-weighted images, revealed a significant reduction in these parameters in patients treated with INFb1a. Side effects were similar to those seen with INFbeta1b and included headache, flu-like symptoms, muscle pain, fever, asthenia, and chills.

Based on these results, INFb 1a was approved for use in patients with relapsing-remitting multiple sclerosis. Subsequent studies also noted some beneficial effect of the drug in secondary progressive multiple sclerosis, but it was less definitive than in relapsing-remitting multiple sclerosis. Recently, INFb1a was shown to slow the progression of clinically significant multiple sclerosis in patients who had a single episode of demyelinating disease, manifested by optic neuritis, myelitis, or brainstem-cerebellar symptoms.

Other interferons. Although INFa has been tested in both relapsing-remitting and secondary progressive MS, it is not approved for use in MS in the United States. A small study showed significant reductions in relapse rates and disease progression as measured by MRI.

INFt differs from type I interferons in that its secretion is not so intensely induced by viruses or double-stranded DNA. It is less toxic and its synthesis is more prolonged. It was first identified as a hormonal marker of pregnancy in ruminants such as sheep and cows. INFt has immunomodulatory activity, like type I interferons, and blocks the development of EAE induced by superantigen activation.

Treatment of patients with interferons. Indications for the use of INFb in multiple sclerosis are formulated based on the design of clinical trials. Thus, INFb 1b is recommended for use in patients with relapsing multiple sclerosis who have retained the ability to move independently, to reduce the frequency of clinical exacerbations. INFb 1a is recommended for the treatment of patients with a relapsing 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 secondary progressive or primary progressive multiple sclerosis. Moreover, although these drugs differ in the frequency and severity of side effects, dose and route of administration, there is no consensus on when one or the other drug should be preferred.

In 1994, a special expert group was convened to decide whether it was appropriate to prescribe INFb 1b to patients with more severe disease or with different forms of disease than those included in the study. The group concluded that INFb 1b may be useful in relapsing-remitting multiple sclerosis, when the patient is over 50 years of age or has lost the ability to move independently, if they experience frequent exacerbations. The group also concluded that interferon treatment may also be effective in patients with a progressive-relapsing course. It is noted that the same criteria as in the study can be used as criteria for stopping INFb 1b treatment.

Side effects. Side effects of interferons are dose-dependent and tend to decrease with continued treatment. They include injection site reactions, flu-like symptoms, affective disorders, decreased blood cell counts, and increased liver enzymes. Gradual dose increases, patient or caregiver training in proper injection technique, and more frequent monitoring of patients at the beginning of treatment contribute to the success of interferon treatment. Injection site reactions are often particularly bothersome to patients. They range from mild erythema to skin necrosis. Injection site biopsy has revealed leukocytic infiltrates and vascular thrombosis. Warming the solution and a slower injection rate reduce the discomfort associated with it. Flu-like symptoms can be reduced by using acetaminophen (paracetamol), nonsteroidal anti-inflammatory drugs, or pentoxifylline, and by administering the drug at a time when the patient is less active (eg, before bedtime). Mild depression can be corrected with pharmacological agents. However, the physician should be alert to persistent or severe depression or emotional lability. Short-term drug holidays will help determine the contribution of interferon to the development of affective disorders. If one of the INFb drugs is intolerable, the patient can be transferred to another drug.

The expert group suggested that interferon 1 b may be useful in patients who are assisted or have lost the ability to move, as well as in patients with a progressive-relapsing course and over 50 years of age.

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

Temporary discontinuation of the drug is possible in case of a slight increase in transaminase activity until it returns to the initial level, after which treatment is resumed with one quarter of the full dose, subsequently increasing the dose depending on tolerability. In case of persistent and high increase in transaminase levels (10 or more times exceeding the norm), discontinuation of the drug is necessary.

In patients who have been continuously treated for 1 year, if exacerbations become more frequent or their condition deteriorates in any other way, a neutralizing antibody test is indicated (the test kit is produced by the Veleh laboratory). Two positive results at an interval of 3 months indicate the production of neutralizing antibodies.

Milder depression may be treated with antidepressants and psychotherapy. Selective serotonin reuptake inhibitors may be beneficial because they cause less fatigue.

If a mild injection site reaction occurs, treatment may be continued. Periodically, a qualified healthcare professional should check that injections are being given correctly. Skin necrosis at injection sites or other severe reactions at injection sites (e.g., fasciitis) require temporary or complete discontinuation of the drug.

Neutralizing antibodies to cIFN/f. Neutralizing antibodies occur with both cIFNbeta1b and cIFNb1a. In clinical trials, neutralizing antibodies were detected in 38% of patients treated with cIFNbeta1b. The frequency of exacerbations in patients with antibodies is equal to or higher than the frequency of exacerbations in the placebo group. The percentage of patients with neutralizing antibodies is approximately the same in patients treated with cIFNb 1b at doses of 1.6 MME and 8 MME. Adverse events in patients with antibodies occurred with the same frequency as in patients in whom antibodies were not detected. In patients undergoing cIFNb treatment, it is recommended to conduct a study for neutralizing antibodies in cases where the treatment continues for 1 year and frequent exacerbations occur or disease progression is noted. If the result of the initial study is positive or questionable, a repeat study is recommended after 3 months.

In the treatment with INFb1a, neutralizing antibodies were detected in 14% of patients by the end of year 1 and in 22% of patients by the end of year 2 of the study - and only in 4% of patients in the placebo group. According to preliminary data, in cases where neutralizing antibodies are detected, the effectiveness of INFb1a, both clinically and according to MRI data, also decreases.

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

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