Side effects of immunomodulatory treatments

When we manipulate the immune system, we have to expect two major types of risk, namely the occurrence of more severe or unusual infections, or of cancer. It is therefore to these two types of side effects that we will be paying close attention during phase 2 and phase 3 clinical trials, as well as during the extension phases of these trials.

Beta interferons and Copaxone do not pose any specific infectious or neoplastic problems. They can even be continued without interruption during pregnancy. In some patients. Rare cases of severe allergic reactions have been reported with Copaxone. Toxicity of interferons on the bone marrow have also been observed.  Tecfidera may cause lymphopenia i.e. a decrease in the number of lymphocytes circulating in the blood, the mechanism of which is still poorly understood. The rule is not to continue this treatment if the lymphocyte count falls below 500/µL for more than 6 months. Very rare cases of PML have been reported with this product. It is generally stopped during pregnancy once the pregnancy test is positive. Aubagio may be responsible for allergic hepatitis during the first 6 months of treatment. This hepatitis is completely reversible when treatment is stopped, but requires an initial monthly blood test. The other side effects of Aubagio consist of diarrhoea and slight hair loss, which is reversible during the first 3 months, so they are therefore perfectly manageable. If you wish to become pregnant, you must first completely eliminate Aubagio by taking colestyramine (Questran) for 11 days.

In general, second-line "high efficacy " drugs may carry greater risks. The occurrence of herpes zoster (shingles) was described slightly more frequently than in people receiving placebo, but these herpes zoster were moderate and no more extensive than in normal subjects. Other rarer opportunistic infections have been described but the main danger comes from PML due to an infection of the brain by the JC virus, especially in people treated with Tysabri for more than 2 years and carrying high antibody levels. This antibody level is calculated on the basis of an index, and an index > 0.9 with a treatment duration > 2 years entails a risk of this type of encephalitis in one person in 100. This percentage is even higher in case of patients previously treated by immunosuppressive treatments (Imuran, Endoxan, Novantrone...). If pregnancy is desired, Tysabri can be stopped when the pregnancy test is positive or, in the case of potentially very active disease, continued during the first two quarters to avoid a rebound phenomenon of the disease. 

Gilenya induces a decrease in blood lymphocytes to not less than 200/µL. The very first intake may cause the heart rate to slow down and should be carried out under clinical supervision. This is not the case with the new derivatives, Zeposia, Ponvory and Mayzent. Gilenya and Zeposia must be stopped three months before starting a pregnancy. This is not the case with Ponvory, which has a shorter duration of action, with contraception needing to be extended by just one week.

Lemtrada can cause secondary autoimmune diseases usually occurring within 4 years of the last course of treatment. Almost a third of patients develop thyroid problems and, much more rarely, a drop in blood platelets and kidney problems. It is therefore necessary to carry out monthly biological checks for at least 5 years during and after treatment.

The side effects of Mavenclad are mild in the short term, but again, the possibility of rare side effects occurring several years after treatment is unknown. In principle, pregnancy is contraindicated during treatment and up to 6 months after the last dose. For this product alone, it is recommended that treated male patients avoid inducing pregnancy in their partners during the same period. However, the theoretical risk of the sperm carrying a malformation is very low. 

Ocrevus also has few immediate side effects during treatment except for a hypersensitivity reaction during the first infusion, which destroys a large number of B lymphocytes. This is why the first dose is divided in two, with two infusions 15 days apart, then a full dose every 6 months. What we do not know is the long-term side effects, particularly on blood antibody levels. In any case, this product generally reduces the effectiveness of vaccines apart from that of the flu vaccine. During the COVID-19 pandemic, people treated with Ocrevus had a greater risk of developing a severe form of the disease. For Kesimpta and Briumvi, which are also anti-CD20 monoclonal antibodies, dosing will initially be progressive, and the same uncertainties remain regarding long-term side effects.

The choice of treatment will therefore always be a balance between the benefits, i.e. stopping and stabilising the disease, and the risks of sometimes serious side effects . This benefit-risk ratio must be discussed with each patient. Decisions are sometimes difficult to make. Some patients refuse or postpone treatments that could nevertheless be beneficial for fear of a rare or exceptional side effect. It is also important to be aware of the seriousness of MS and its "vicious" side, as it can continue to progress quietly, accumulating lesions without the patient noticing immediately, with particular consequences for the cognitive function in the medium and long term. It is up to the neurologist to explain the potentially serious course of the disease and clearly describe the side effects of the proposed medication, without making a fuss, but with lucidity. It is a contract of trust that must be established, to reconcile the patient's wish to see his or her disease stabilised with the least possible risk, and the neurologist's desire to protect his or her patient's brain as best and as long as possible. A positive message is that we currently have enough molecules to be able to change treatments and find the one that is best suited to each patient, without running disproportionate risks of accelerating the disease.