The expectations and needs of patients concerning the treatment of multiple sclerosis focus on the improvement of chances for the pursuit of their life goals. The contemporary patient has an increasing amount of information on the indications for the use of different medicines. Therefore, the conclusions derived from the BENEFIT study summarised results, especially those concerning the last follow-up – after 11 years, have generated knowledge of vital importance to the patients. It was demonstrated that the patients who started their therapy earlier had a longer time to conversion to multiple sclerosis – by 2.7 years compared to the group with postponed treatment. The annualised relapse rate was significantly lower and the time to the next relapse was significantly longer in patients who received treatment early. Only 13.3% of individuals left employment immediately after they were diagnosed with multiple sclerosis and only 12.2% went on disability pension. The results of the BENEFIT 11 study, especially those relating to professional activity, support the idea of starting the treatment as early as possible and are important particularly to those patients for whom work is a value in itself. The knowledge derived from the BENEFIT 11 study that early interferon beta treatment provides a chance for maintaining professional activity, delays the conversion from the relapsing-remitting multiple sclerosis to the secondary progressive form of the disease and minimises the progression of disability, significantly affects the patient’s willingness to comply with the recommendations and treatment regimens, i.e. promotes patient adherence. This knowledge should also be the basis of communication with those individuals who will be diagnosed with multiple sclerosis and who will be asking questions about their future.
The aim of relapsing-remitting multiple sclerosis therapy is to achieve the maximum clinical effect of reducing the number of or eliminating relapses of the disease and achieving the lack of progression of physical disability with a minimum or nonexistent disease activity observed in magnetic resonance imaging. Treatment should be started as soon as possible in order to limit the inflammatory and autoimmune process which leads to neurodegenerative lesions. There are a number of first-line medicines which are used at the beginning of the disease such as interferon beta and glatiramer acetate. Oral drugs have recently been introduced into this group such as dimethyl fumarate and teriflunomide, among others. They are characterised by a good safety profile and moderate efficacy. If first-line therapies turn out to be ineffective, second-line medicines are used such as, for example, natalizumab or fingolimod. The views on when second-line therapy should be started and what substances to use have been constantly evolving and the recommendations sometimes differ depending on the country. For instance, fingolimod was approved by the European Medicines Agency as a second-line therapy for relapsing-remitting multiple sclerosis, while Food and Drug Administration approved it as a first-line therapy for this disease. When selecting a medicine one should take into account disease activity, the efficacy of the treatment used so far, comorbidities as well as potential side effects.
Multiple sclerosis is a chronic autoimmune disease of the central nervous system which has an unknown origin and variable course. In about 85% of cases it starts as the relapsing-remitting form that, in different periods of time depending on the patient, turns into the secondary progressive form with constant progression of disability, sometimes with preserved relapse and magnetic resonance imaging activity at the beginning. The treatment options for the secondary progressive form of multiple sclerosis are still limited. Based on the results of Mitoxantrone in Multiple Sclerosis Study, mitoxantrone has been registered for the treatment of secondary progressive multiple sclerosis. In addition, the drugs that have received registration in Europe are interferon beta-1b and interferon beta-1a given subcutaneously. These drugs have a proven effect in slowing the progression of disability (interferon beta-1b, mitoxantrone) as well as reducing the annualised relapse rate (interferon beta-1b, interferon beta-1a, mitoxantrone) and the number of new outbreaks in magnetic resonance imaging (interferon beta-1a, interferon beta-1b). The study of North American Study Group on Interferon β-1b in Secondary Progressive MS showed no effect of the therapy with interferon beta-1b on the inhibition of disability progression and as a result, the drug has not obtained registration for the treatment of secondary progressive multiple sclerosis in the United States. The patients who benefit most from the therapy which modifies the course of the progressive form of multiple sclerosis are younger, with a shorter history of the disease, preserved relapse activity and rapidly increasing disability.
In 2014 after phase 3 ADVANCE clinical study was finished, a new, pegylated form of interferon beta-1a with less frequent dosing was accepted for treatment in relapsing-remitting multiple sclerosis. One thousand five hundred and twelve patients with relapsing-remitting multiple sclerosis were enrolled to the ADVANCE study from 183 sites in 26 countries (500 to the placebo group, 512 to the 125 μg subcutaneous peginterferon beta-1a every 2 weeks group and 500 to the 125 μg subcutaneous peginterferon beta-1a every 4 weeks group). The investigated groups were similar in terms of age, sex, duration of the disease and disability rated using the Expanded Disability Status Scale. The primary and secondary endpoints were efficacy and safety of 2-year peginterferon beta-1a treatment in patients with relapsing-remitting multiple sclerosis compared to the placebo group, which after 1 year also received peginterferon beta-1a 125 μg every 2 or every 4 weeks. The results from the 2-year ADVANCE study demonstrate efficacy of treatment with peginterferon beta-1a 125 μg administered subcutaneously every 2 weeks compared with placebo: significantly reduced annualized relapse rate (by 37%), the number of new/newly enlarged T2 lesions (by 67%), the risk of relapse (by 39%) and the risk of 12-week sustained disability progression (by 33%). The most common adverse events (94% of patients) associated with peginterferon beta-1a treatment were: injection site reactions, flu-like symptoms, pyrexia and headache. Sixteen percent of patients taking the study drug every 2 weeks and 22% of patients taking the study drug every 4 weeks reported serious adverse events; relapse, pneumonia and urinary tract infections were the most common. Interpretation: the treatment with peginterferon beta-1a with less frequent administration is effective, well tolerated and safe for patients with relapsing-remitting multiple sclerosis.
Multiple sclerosis is a disorder of the nervous system affecting over 500,000 Europeans. It affects three times as many women as men, with the diagnosis typically occurring in patients aged in their 20s and 30s, and is more prevalent in Northern Europe. In recent years progress has been observed in the therapy of patients with this disease. At present there are ten medicines on the market which reduce the annualised relapse rate and progression of disability. Dimethyl fumarate is a new oral drug which significantly reduces the risk of multiple sclerosis relapse, slows the progression of disability and decreases the number of new magnetic resonance imaging demyelinating lesions. In comparison with the first-line medicines used so far such as interferon beta-1b, interferon beta-1a and glatiramer acetate, dimethyl fumarate is characterised with a higher clinical and radiological efficacy. In clinical trials it showed over 56% reduction of the relapse rate, 76% reduction of the number of new/growing T2-weighted lesions as well as stopping the progression of disability. At the same time, dimethyl fumarate has a good safety profile. During the clinical trials a small proportion of patients reported adverse reactions. Similarly to second-line drugs, dimethyl fumarate requires blood lymphocyte level monitoring. In the DEFINE and CONFIRM studies the total number of lymphocytes in patients treated with dimethyl fumarate decreased by 30% after one year and subsequently remained at a consistent level within the norm. In the majority of patients (76%) no lymphopenia was observed over the first 12 months of therapy. Only a small proportion of patients (2%) experienced severe lymphopenia for 6 months or longer. To date two cases of progressive multifocal encephalopathy were reported in patients treated with dimethyl fumarate who had chronic lymphopenia. This medicine is an attractive option for patients treated with first-line drugs.
Alemtuzumab is a humanized monoclonal antibody aimed against glycoprotein CD52, which causes the depletion (elimination) of circulating T and B cells. The recovery process for the two cell populations differs, leading to disturbances in the immune system. These changes result in a reduction in the disease activity. The efficacy of alemtuzumab has been confirmed in three clinical studies: one phase II – CAMMS223 study, and two phase III – CARE-MS I and CARE-MS II studies. They have shown the clinical effectiveness of intravenous alemtuzumab in patients with the remitting form of multiple sclerosis. Interferon beta-1a was administered subcutaneously as the comparator. CAMMS223 and CARE-MS I showed the drug to have significant impact on the decrease of the relapse rate as compared to interferon, whereas CAMMS223 and CARE-MS II showed it to slow down the increase of disability in patients. Treatment with alemtuzumab, however, has not been free of significant side effects, falling essentially into three major groups: side effects directly related to the administration of the drug, severe infections, and autoimmune disorders (idiopathic thrombocytopenic purpura, impaired thyroid function, and nephropathy). Alemtuzumab therapy can be both effective and safe, provided that an appropriate programme is maintained, aimed at monitoring the adverse events.
Multiple sclerosis is an inflammatory and demyelinating disease of the central nervous system. Impaired cell-mediated and humoral immunity play an important role in the pathogenesis of the disease. B lymphocytes play an important role in the presentation of own antigens to T lymphocytes and in the production of pro-inflammatory cytokines and autoantibodies. In primary progressive multiple sclerosis a degenerative reaction with axonopathy and neuronal damage are predominant features. A monoclonal antibody against CD20 B lymphocytes was used in clinical studies on relapsing multiple sclerosis (OPERA I and II studies) and on primary progressive MS (ORATORIO study). A statistically significant reduction of the annualised relapse rate, clinically defined progression and contrast-enhanced T2-weighted magnetic resonance imaging lesions was demonstrated for relapsing multiple sclerosis in the group of patients treated with ocrelizumab compared to patients receiving interferon beta-1a. A statistically significant reduction of clinically defined progression, T2-weighted lesions and changes in brain volume in magnetic resonance imaging was found for primary progressive multiple sclerosis in the group of patients treated with ocrelizumab compared to placebo. The safety profile of ocrelizumab was satisfactory and was not significantly different from the profile in the control groups. It seems that ocrelizumab affects CD20 B lymphocytes in a clinically beneficial way and that phase 3 clinical study results may be the basis for its registration and common use in clinical practice.