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The basic pillar of the long-term treatment of MS has consisted of disease-modifying drugs (DMD) – interferon beta (INF-beta) and glatiramer acetate (GA) – in our country since the 1990s. 

These are biological medicines applied by injection – by subcutaneous or intramuscular injection. Their efficacy is approximately the same; however, the tolerance to them may vary considerably.

Interferon Beta 

In 1993, the results of the first clinical study with subcutaneously applied interferon beta-1b were published. For the first time, the natural course of the disease was modified. Since 1996, interferon beta is also available to our patients. Several years later, interferon beta-1a was added to it. Interferon beta (IFNB) reduces activity of inflammation and limits the procreation of inflammatory cells. It improves the function of the hematoencephalic barrier; as a result, less inflammatory cells penetrate into the CNS. It is a substance produced by the human organism’s own cells; for therapeutic purposes, it is produced by means of genetic engineering.

There are three medicinal products of this type available in our country: IFNB-1a i.m. 30 ug applied once a week; IFNB-1a s.c. 22 and 44 ug to be applied 3 times a week; and IFNB-1b s.c. 250 ug to be applied every other day.  The results of clinical studies are very similar for all these medicinal products; the number of acute attacks is reduced by approximately 30 % relative to placebo (meaning 50-60 % in practice because placebo accounts for up to 30 % of the effect). High-dosage medicinal products have somewhat higher efficacy. The effect on each patient is highly individual and cannot be predicted in advance. It is evaluated particularly by monitoring the patient clinically (the number of attacks, deterioration of the neurological finding) and using MR (growth of new niduses; the course of CNS atrophy in the future, too).

Adverse Reactions to IFNB and Their Monitoring and Prevention

At present, treatment is commenced with a quarter or a third of the dose (depending on the type of medicinal product) in order to reduce the sensation of flu-like symptoms (high temperature, fever, joint and muscle pains, fatigue), which the injection induces in most patients at the beginning of the treatment. This is why 1-2 tablets of paracetamol or ibuprofen are administered along with the injection. In some of the patients, the flu-like syndrome will disappear; others have problems without these medicines even years later. Therefore, it is necessary to provide the patient with information and to proceed on a strictly case-by-case basis.

Injections may cause variously severe local reactions, ranging from a short-term reddening of the puncture spot, through hard spots lasting for several days, to rare necrosis. Reddening can be treated with creams containing ibuprofen, heparin, corticoids. The patient should always try different options and stick with the one that suits them the most. If necrosis occurs, it is necessary that the patient comes to an MS centre as soon as possible. The injection technology has improved significantly after the introduction of autoinjector; however, the puncture locations are only limited to thighs when an autoinjector is used.

IFNB may cause a rise in liver enzymes as well as a decline in blood cells of all types; this is why it is necessary to regularly monitor liver tests and the total blood count. It is also necessary to be careful with patients suffering from thyroid gland disorders; this is why the treatment is preferentially commenced with glatiramer acetate with these patients.

A long discussed and not quite clarified topic is the incidence of depression during IFNB treatment. During the disease, approximately 50 % of patients are affected by depression; if a patient has a rather severe depression before commencement of the treatment, they should start the treatment with glatiramer acetate. If depression does not appear until during the IFNB treatment, the treatment may be partly responsible for its incidence. In any case, it is necessary to detect depression and treat it. Since a patient often finds it easier to confide to a nurse than to a physician, it is absolutely crucial that the nurse passes on this piece of information to the physician.

IFNB and Pregnancy

All interferons beta are included in the “Pregnancy Category C” according to the FDA (the Food and Drug Administration, an authority which approves all medicines in the USA), meaning that they should not be used in during pregnancy. Based on experience, there is no reason to stop taking the medicine if a female patient is planning pregnancy.

It is sufficient to stop taking the medicine when pregnancy is detected. It has proven to be disadvantageous for a female patient to stop taking the medicine before a planned impregnation because another attack may occur during this period, in which case it is then necessary to treat the attack with corticosteroids and to postpone the pregnancy.

The number of attacks after a childbirth correlates to the number of attacks before pregnancy. Therefore, it is desirable that the activity of the disease is suppressed as much as possible. It is not recommended administering the medicine during breast-feeding.

Sometimes the adverse reactions to IFNB are intolerable for the patient even after two medicinal products are tried; they limit the patient’s quality of life and the treatment needs to be changed even without the production of neutralising antibodies.

Glatiramer Acetate

Glatiramer acetate (GA) is another first line injection medicine. The history of its development dates back to the 1960s; it was registered as a medicine for remitting MS in 1996. Unlike IFNB, it is not a substance that is proper to the body but it is an artificial antigen composed of 4 amino acids (alanine, glutamate, lysine and tyrosine), which, however, does not induce inflammation in the CNS. On the contrary, it makes the immune cells change into anti-inflammatory cells which travel into the CNS and attenuate the inflammation there and also produce substances, which protect nerve fibres. Its clinical effect is the same as that of IFNB; the number of attacks is reduced by 30 % relative to placebo.

Adverse Reactions

When GA is applied, there are no flu-like symptoms. Sporadically, a sudden post-injection reaction may occur with palpitation (heart racing), reddening, nausea, anxiety, which is caused by the outpouring of histamine, if GA gets directly into a vein during the injection. The patient must be notified of this reaction when the injections are introduced because otherwise the patient may we afraid that they are experiencing a serious cardiac event. This is not the case; the reaction will disappear within 15 minutes without any complications. However, the experienced anxiety may, of course, have longer-lasting somatic symptoms.

Local reactions are similar to those of IFNB; necrosis is rarer. A phenomenon typical of GA application is atrophy of hypodermis, which is difficult to treat. We do not recommend using GA in patients with psoriasis or another autoimmune skin disease where generalised manifestations of psoriasis may occur. Even patients with more severe eczemas need to be monitored carefully.

GA and Pregnancy

According to the FAD, GA has been put into the “Pregnancy Category B”; therefore, there is no reason to stop taking the medicine before pregnancy. It is sufficient to stop taking it when pregnancy is detected. Administration of GA is not recommended during lactation.

Teriflunomide

Orally administered medicine (a tablet containing 14 mg of teriflunomide, administered once a day) with the same clinical effect as the previously described first line injection medicines. The medicine is very well tolerated; in some patients, it may cause increased hair loss; it is necessary to monitor laboratory parameters like with interferon beta.

The biggest problem of the medicine is that it cannot be used for female patients who plan to get pregnant. It is teratogenic, meaning it affects incidence of congenital developmental defects and its elimination from a human organism takes two years. If pregnancy is planned, it is necessary to undergo a fast elimination procedure with the help of active carbon or cholestyramine and pregnancy is only possible after verification laboratory tests.

Due to the fact that two thirds of patients with MS are women of childbearing age, this limitation is the most important obstacle to wider use of this medicine in patients with freshly diagnosed MS or in the first years of the disease. However, it will apparently be a pleasant relief from injections for all those patients who do not tolerate injections easily even though their effect is sufficient.

Dimethyl Fumarate

Dimethyl fumarate (a capsule administered twice a day in a dose of 240 mg) is one of the first-choice medicines abroad. In the Czech Republic, it will probably be limited only to patients who do not experience the sufficient effect with the medicines of the classic fist line for some time yet. The studies carried out with dimethyl fumarate have proven its ability to reduce the number of acute attacks by approximately 50 %. This means that it is a medicine more effective than the previously mentioned first-choice medicines. The medicine has anti-inflammatory effects and also starts processes limiting the action of free radicals in an inflammatory nidus and thus protecting the tissue.

During treatment, it is necessary to monitor total blood count and liver tests; treatment cannot be started in patients with low number of lymphocytes (lymphopenia). The patient must be made well aware of the problems with tolerance because these problems occur particularly when the treatment is commenced and their intensity decreases or they disappear over time. An uninformed patient might discontinue the treatment prematurely for this reason in spite of the fact that the treatment might be beneficial to them.

Adverse Reactions 

A large part of patients experiences hot flashes, reddening and a burning sensation in their faces and elsewhere on their bodies within several hours of swallowing the capsules. The sensation lasts 15-30 minutes and does not indicate any pathology. It can be controlled by administering a small dose of acetylsalicylic acid and, according to our experience, medicines against allergy, too. Patients get accustomed to this over time; the frequency of the sensation declines during the treatment.

Other problems such as nausea, vomiting a stomach aches are more difficult to resolve and may result in discontinuation of the treatment. However, they disappear within several weeks in most cases. It is possible to use common medicines to mitigate these problems.