Immunomodulatory treatments for relapsing-remitting MS

With the exception of symptomatic treatments directed against specific symptoms of the disease, and paramedical treatments such as physiotherapy, speech therapy and occupational therapy, all treatments currently used in MS have a direct action on the immune system with the aim of partially deactivating it, normalising its function if possible, and preventing aggressive auto-reactive lymphocytes from entering the CNS. This is true both for cortisone derivatives used to treat relapses and for long-term treatments known as immunomodulators.

In the event of a relapse with significant impact on activities of day-to-day life, the treatment of choice is based on a synthetic cortisone derivative generally given in high dose intravenously, i.e. 1 g of methylprednisolone per day for 3 to 5 days, sometimes 7 and up to 10 days in the case of very severe relapses. Some authors use the same product in the same doses but orally, with results that are broadly similar to those obtained intravenously. Cortisone causes the death of activated lymphocytes and reduces the synthesis of an enzyme enabling these lymphocytes to cross the blood-brain barrier and enter the CNS. High-dose but brief treatment avoids the side effects most often encountered with prolonged oral treatment. However, it must be taken under medical supervision, as it can cause blood ion disorders, blood pressure problems, heart palpitations, nervousness, insomnia and, after treatment has been stopped, tendon or muscle pain and severe fatigue. While active plaques take up MRI contrast for an average of 6 to 8 weeks, treatment with methylprednisolone inhibits this contrast uptake in around ten days. Note that this product does not cross the placental barrier and can therefore be used in the event of flare-ups occurring during pregnancy. Cortisone has no preventive action on the occurrence of subsequent relapses.

Long-term immunomodulatory treatments are used in forms with relapses and remissions and in active secondary progressive forms. These treatments can be divided into 4 categories according to their mode of action:

1° drugs modulating the immune system function to improve regulation: beta interferons (Betaferon, Rebif, Avonex, Plegridy); glatiramer acetate (Copaxone); dimethyl fumarate (Tecfidera).

2° drugs inhibiting the multiplication and proliferation of activated lymphocytes in a targeted manner: teriflunomide (Aubagio); cladribine (Mavenclad)

3° drugs interfering with lymphocyte circulation: natalizumab (Tysabri); fingolimod (Gilenya); ozanimod (Zeposia); siponimod (Mayzent); ponesimod (Ponvory).

4° drugs destroying a particular population of lymphocytes: alemtuzumab (Lemtrada), ocrelizumab (Ocrevus), ofatumumab (Kesimpta), ublituximab (Briumvi).

These drugs are further divided into first-line drugs (all those in the first group as well as Aubagio, Zeposia and Ponvory) and into second-line drugs (Tysabri, Gilenya and Mayzent in group 3, drugs in group 4 and Mavenclad). Second-line drugs are only used in the event of failure of first-line drugs, OR from the onset of the disease and its diagnosis, in cases of highly active and aggressive forms with frequent relapses and at least one active lesion on MRI. This distinction between first- and second-line treatments is disputed, and we currently prefer to talk about moderately or highly effective drugs.

At present, we cannot predict whether an individual patient will be a good or poor responder to any of these treatments, nor can we predict whether they will develop significant side effects. All these treatments therefore require ongoing monitoring, both in terms of efficacy and potential side effects. These will be discussed in the next chapter.

The beta interferons are natural substances that we all produce and which have antiviral properties because they "interfere" with viral replication. Beta interferons are gamma interferon antagonists and have been studied in MS because a clinical trial with gamma interferon resulted in an increase – not a decrease! -- in the number of relapses. Betaferon was launched in Belgium in 1996 and Rebif in 1998. These products have not caused any undesirable long-term side effects. Plegridy is a long-acting delayed interferon that only requires a single subcutaneous injection every 14 days. Interferons have an extremely polymorphic action on the immune system because they interact with not less than 3000 genes either by increasing their expression or inhibiting them.

 Copaxone is the only medication that has been specifically synthesised and applied to the treatment of MS. It is a small polymer composed of different amino acids originally synthesised to cause autoimmune encephalitis in mice. The results observed were the opposite of what was expected, as the polymer protected the mice from encephalitis! Based on this observation, the molecule was synthesised and clinically tested by the subcutaneous route (the oral route is ineffective). It acts as a false target for activated lymphocytes and deviates the pro-inflammatory immune response towards an anti-inflammatory response. The lymphocytes activated against Copaxone have immunoregulatory properties that reduce the inflammatory reaction within the CNS. This product has been in use since 1995 and has been shown to have no long-term side effects.

Aubagio is a drug that inhibits specifically the proliferation of activated lymphocytes. It is a derivative of a product used in rheumatology. It can accumulate in the body but can be eliminated in the faeces in around ten days using a specific antidote. It is taken at a dose of one tablet a day.

Tecfidera is derived from a product used for many years against psoriasis in Germany. This medicine is taken at a dose of 2 tablets a day. It stimulates antioxidant enzymes that limit brain inflammation, but not all its mechanisms of action are yet known.

Tysabri is a monoclonal antibody that is given as intravenous infusion or subcutaneous injection every 4 to 6 weeks, and which blocks a protein on the surface of activated lymphocytes, preventing them from crossing the blood-brain barrier and moving from the blood into the brain or spinal cord. This medication is rapidly very effective, but it prevents normal immune surveillance of the brain, which increases the risk of a possible viral encephalitis called Progressive Multifocal Leukoencephalitis (PML) (see next chapter).

Gilenya is an oral drug at a dose of one tablet/day, which blocks certain lymphocyte populations, including activated lymphocytes, in lymph nodes and prevents them from circulating in the blood and therefore potentially crossing the blood-brain barrier into the CNS. It was first tested against transplant rejection. However, this drug allows the normal circulation of "memory lymphocytes" which protect the body against reinfection by previously encountered infectious agents. Subsequently successfully tested and marketed, in this same family of molecules, were Zeposia, Ponvory and Mayzent. The latter is only indicated in secondary progressive forms with relapses.

Lemtrada is a monoclonal antibody that causes the destruction of many lymphocytes during the 5 days of intravenous infusion during the first week of treatment. This is completed a year later with an infusion of 3 new doses. This treatment has also been used for leukaemia. The immune system is then significantly altered by the destruction of these lymphocytes, but gradually rebuilds itself over the following months and 2-3 years. This treatment can bring 50% of patients into remission for several years without further medication.

Ocrevus is a monoclonal antibody directed against a particular protein called CD20 present on the membrane of B lymphocytes. It therefore destroys B lymphocytes, which represent around 10% of total lymphocytes. It leaves intact the mature B lymphocytes (plasma cells) that synthesise antibodies, as they lack this CD20 molecule. Its effectiveness against flare-ups is remarkable. It is administered intravenously or subcutaneously every 6 months, but studies are underway to further evaluate the efficacy of the subcutaneous route and to assess whether infusion intervals can be extended beyond 6 months, depending on the reappearance of B lymphocytes in the blood.

Kesimpta is also an anti-CD20 monoclonal antibody directed against B lymphocytes, with comparable efficacy to Ocrevus. It is administered subcutaneously with one injection every 4 weeks.

Mavenclad is a drug taken orally for the first 5 days of treatment, then for 5 days the following month, then a year later in a second course of 2 x 5 days. It has a prolonged effect on the proliferation of activated lymphocytes and is therefore likely to induce long-term remission. This product was first used intravenously in the treatment of leukaemia. Studies have shown that it is remarkably effective, but long-term recurrences are possible.

It should be noted that Lemtrada and Mavenclad, and these alone, are supposed to be "immune reconstitution" treatments. After two years of administration, it is hoped that the "new" immune system, which is reconstituted, no longer has an autoimmune component and that the disease can be put into remission for a long period. A "wait and see" attitude is therefore adopted, and treatment is resumed only if the disease progresses further (clinically or radiologically).

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Beta interferons

• Administration method: Subcutaneous or intramuscular injections
• Dosage: Frequency varies depending on the molecule

Copaxone®

• Administration method: Subcutaneous injections
• Dosage: Frequency varies according to dosage
• Generic: Glatiramyl Viatris

Aubagio®

• Administration method: Oral use
• Dosage: 1 tablet per day
• Generic: Teriflunomide Viatris

Tecfidera®

• Administration method: Oral use
• Dosage: 2 tablets per day

Tysabri®

• Administration method: Intravenous infusions (or subcutaneous injections)
• Dosage: Once every 4 to 6 weeks

Gilenya®

• Administration method: Oral use
• Dosage: 1 tablet per day
• Generic: Fingolimod Viatris

Zeposia

• Administration method: Oral use
• Dosage: 1 tablet per day

Ponvory

• Administration method: Oral use
• Dosage: 1 tablet per day

Mayzent

• Administration method: Oral use
• Dosage: 1 tablet per day

Lemtrada®

• Administration method: Intravenous infusions
• Dosage: 5 days (5 doses) at the start of treatment, then 3 days (3 doses) 1 year later

Ocrevus™

• Administration method: Intravenous infusions
• Dosage: 2 half-doses 15 days apart, then a full dose every 6 months

Ocrevus™

• Administration method: Subcutaneous infusions
• Dosage: Every 6 months

Kesimpta®

• Administration method: Subcutaneous injections
• Dosage: Once every 4 weeks

Mavenclad®

• Administration method: Oral use
• Dosage: 2 times 5 days at the start of treatment (1 month apart), then 2 times 5 days 1 year later

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NEDA" status, which stands for "Non Evidence of Disease Activity", has become the goal to be achieved in the treatment of relapsing-remitting MS. NEDA is defined by several clinical and radiological components:

The first component (" NEDA 1 ") is the absence of any relapse of the disease over the time interval considered.

NEDA 2 is the absence of progression of the disease as defined by the EDSS and additional tests, over a minimum period of 6 months.

NEDA 3 is the absence of new lesions on magnetic resonance, the absence of an increase in volume of an old lesion of more than 10%, and the absence of active inflammatory lesions taking up contrast.

NEDA 4 is used in clinical trials and is not yet available in everyday practice. This is a measurement of brain volume , which decreases on average by 0.2% per year in normal subjects, but in MS can decrease by more than 0.4% per year. NEDA 4 is obtained if the annual cerebral atrophy is less than this figure of 0.4%.

It should be noted that these 4 components are not independent of each other. A relapse of the disease will often be accompanied by a new lesion taking up the contrast medium, and an increase of the EDSS may correlate with an excessive reduction in cerebral volume.

Having "NEDA status" means that our current methods of detecting disease activity are negative, and that the disease can be considered inactive and stabilised. This is, of course, the aim of our treatments: to achieve a good-quality, long-term remission, but not yet to repair existing lesions.

Some people suffering from MS can spontaneously develop NEDA status without treatment. This has been observed in studies with placebo groups. In fact, 10 to 15% of people who receive no active treatment, but only a placebo, show no signs of active, progressive disease and spontaneously go into NEDA. On the other hand, a very good responder to treatment will enter NEDA status thanks to it. The paradox of NEDA status is therefore that it can be observed both in people with an inactive form of the disease requiring no treatment and in people responding excellently to their treatment.

The NEDA concept is an evolving concept. NEDA status can be lost after a few years because the disease becomes more active again or because the current treatment is no longer sufficient. It can therefore be used either to initiate treatment or to change treatment on a more objective basis.

However, the definition of NEDA status is still too demanding compared with most of our current treatments. It is therefore a question of defining the minimum tolerance threshold that we can accept in disease activity. The appearance on MRI of 2 small millimetre lesions within one year, without relapse or increased disability, does not mean that the current treatment has failed, and does not always justify a change of treatment. This is known as Minimal Evidence of Disease Activity (MEDA) status. However, if the signs of disease activity are more serious, it may be appropriate to switch from a moderately effective treatment to a highly effective one, or to change to another highly effective treatment if you are already receiving one.

Is it possible to stop a treatment completely and remain untreated? There is no definitive answer to this question. Most experts believe that after the age of 65, the risk of relapses becomes minimal. Furthermore, if the disability limits walking to just a few steps with double support (EDSS at 7), our current treatments are no longer useful and the risks outweigh the potential benefits. If it has been possible to maintain NEDA status for at least 5 years, an attempt can also be made to stop all treatment, but under close supervision, for example by an MRI scan six months later. Stopping treatment with Tysabri or Gilenya is more risky because it is regularly accompanied by a resumption of disease activity.