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All DMD medicinal products primarily have an anti-inflammatory effect. Therefore, their ability to modify the natural course of the disease only concerns the initial stages of the disease.

When the disease transitions to the stage of secondary progression, these medicines lose their efficacy.

Approximately merely 30 % of patients respond well to the first line injection medicines in the long-term; a certain effect but not fully stabilisation of their state is achieved in approximately 40 % of patients; and no effect or merely a temporary effect is achieved in approximately 30 % of patients. Therefore, with patients in whom sufficient effect was not achieved, it is necessary to escalate the treatment in time because ineffective treatment results in the same damage to the CNS as if the patient were not treated at all.

Escalation treatment mostly provides higher efficacy but it is necessary to monitor the adverse reactions more intensively because this treatment generally features more of them.

Fingolimod

Fingolimod is an orally administered medicine (a tablet containing 0.5 mg administered once a day), which keeps lymphocytes in lymph nodes to reduce their number in bloodstream and to limit the possibility of their entry into the CNS. The mechanism of its action is unique. In addition to its anti-inflammatory effect, fingolimod protects brain cells from damage and dying off and slows down atrophy of nerve tissue. In clinical studies, the effect of fingolimod achieved 54 % reduction of the number of relapses relative to placebo.

Adverse Reactions to Fingolimod

Its effect on the cardiac conduction system is manifested as the slowing down of heart activity, which occurs in the first hours after application of the first dose. Heart rhythm disorders, referred to as atrioventricular blocks, may also occur. Conditions requiring anti-arrhythmic medication are, of course, a contraindication; these patients are not suitable candidates for fingolimod treatment. Fingolimod may also mildly raise blood pressure.

In clinical studies, macular oedema (damage to veins in the eye) sporadically occurred; this is why it is necessary to examine the eye ground before commencement of the treatment and 3-4 months after commencement of the treatment and to exclude this complication. Total blood count is monitored through laboratory tests. There may be an increased incidence of infectious diseases, particularly infections of lower respiratory tract and herpetic infections. Before commencement of the treatment, antibodies against chicken-pox (herpes zoster virus) are tested. If the patient does not have any, it is necessary to vaccinate them carefully and to postpone commencement of the treatment. It is necessary that the patient reports all infections during every check-up.

The treatment is very well tolerated but it is necessary to make the patient aware of the importance of their compliance with the monitoring regime. With this, it is possible to avoid complications of the treatment.

Natalizumab

Natalizumab is the first monoclonal antibody (meaning that it is produced by cloning cells originating in a single plasmatic cell) introduced into treatment in neurology. The effect in clinical studies achieved reduction of the number of relapses by 68 % relative to placebo; in clinical practice, the effect is between 80 and 90 %. If the inflammation is suppressed in such intensive manner, it is, of course, possible to expect postponement of disability. Regrettably, in our country, the treatment is often started late, only when significant disability is already present.

However, approximately 20 % of patients may even get better within a year of administration of natalizumab. For the first time in neurology, clinical studies with natalizumab made it possible to create a concept of what is referred to as “long-term remission” (disease-free concept) where a part of the patients achieves stabilisation of the neurological finding, is without relapses and has no new lesions shown in magnetic resonance imaging. This is the goal of all newly tested medicines today.
It is administered as infusion in a dose of 300 mg once a month.

Adverse Reactions

Natalizumab is very well tolerated; allergic reactions occur sporadically (more often after interruption and resumption of the treatment); antibodies against natalizumab, blocking its effect, are produced in approximately 6 % of patients.

PML

Natalizumab remains a second-choice medicine due to possible incidence of a rare viral infection – progressive multifocal leukoencephalopathy (PML). Its etiological agent is a mutated JC virus and its penetration into the CNS. PML was an infection of which a part of patients with AIDS, patients with malign diseases and after transplantations used to die in the past. With RS, mortality is merely 24 %; survival is mostly accompanied with severe neurological impairment (except for patients diagnosed with this disease at its beginning while still without clinical symptoms).

Thus, the risk of incidence of PML can be well estimated to a certain degree. It must be carefully discussed with the patient. Before the treatment, during the treatment and particularly after two years of the treatment, it is necessary to carefully consider the risk/reward ratio of continued treatment. All patients treated with natalizumab are monitored in great detail in order to detect the signs of clinical infection (disorders of cognitive functions, vision, mobility, sensitivity, epileptic seizures, cerebellar disorders) in a timely manner.

After two years of the treatment, it is necessary that the patient signs once again their informed consent that they insist on the treatment by their own decision. Otherwise, it is necessary to change the treatment, which is not so simple due to the amazing efficacy of natalizumab (there is a risk of re-emergence of the disease, known as the “rebound phenomenon”).

Alemtuzumab

Another substance for treating MS is alemtuzumab, an antibody against CD52, an antigen on immune cells. The use for MS is derived from many-year experience with alemtuzumab in treatment of blood malignancies (malignant tumours) where, however, higher doses are used in combination with cytostatic drugs. At present, this medicine is indicated for escalation treatment.

The advantage of alemtuzumab is the schedule for its administration: 5 infusions over 5 days with 12 mg for each infusion in the first year; 3 infusions over 3 days with 12 mg for each infusion in the next year; and further treatment is provided only if the disease is active. It has been shown that remission after two cycles of treatment can last for several years and the patient needs not be treated with anything for several years.

Adverse Reactions

A frequent consequence of alemtuzumab treatment is a rapid decline in the number of certain immune cells. However, natural immunity is completely preserved. By switching the immune system over, alemtuzumab may start another autoimmune disease, predominantly that of thyroid gland (approximately 30 = of patients within 3 years of commencement of the treatment), may result in decrease of blood platelets with a risk of haemorrhaging (idiopathic thrombocytopenic purpur, ITP), sporadically it may result in autoimmune disease of kidneys. The thyroid gland disorder is temporary in most patients.

During the period of infusions, the patient is at risk of having a higher number of infections. During clinical studies, acyclovir was included in the treatment regimen as prevention against herpetic infections (400 mg per day always at the time of infusions and 28 days after them). If a patient gets an infection, it is necessary that they contact the MS centre where alemtuzumab was administered.

It is possible to get pregnant 4 months after application of alemtuzumab; it does not cause congenital developmental disorders and defects.