Secondline therapy

Second-line drugs that target RRMS include Fingolimod, Alemtuzumab and Natalizumab. These drugs are used in patients who, despite first-line therapy, continue to have many attacks or deteriorate rapidly. In general, these drugs are more effective than first line therapies, but have more severe side effects.

Fingolimod

One of the most well-known drugs used in MS is Fingolimod. When fingolimod enters the body, it is phosphorylated to fingolimod-phosphate. This substance is structurally comparable to s sphingolipid, called sphingosine-1-phosphate (S1P), an extracellular mediator.

Fingolimod-phosphate prevents the binding between S1P and the corresponding receptor S1P receptor of which there are a total of five species (S1PR1-5). This leads to internalization and ultimately the degradation of these cell surface receptors. S1PR1-5 receptors are found on lymphocytes and in other organs. Normally the binding between S1P and S1PR1-5 ensures the regulation of lymphocyte maturation, migration and trafficking. In short, fingolimod prevents the outflow of lymphocytes from the lymphoid tissue into the bloodstream.

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This spares the central nervous system from attacks by myelin-reactive lymphocytes (Mandal, Gupta, Fusi-Rubiano, Keane, & Yang, 2017).

Fingolimod is a slowly but efficiently absorbed in the body after oral administration. The maximum intake is approximately between 12 and 16 hours, with a bioavailability about 93% (Thomas, Proschmann, & Ziemssen, 2017). Each year, fingolimod costs ˆ22.487, based on a once daily oral dose of 0.5 mg, with 28 doses per package. However, these costs are still rising because a decrease in heart rate may occur with the first administration that must be monitored in the hospital.

Furthermore, a number of tests must be conducted in advance to identify risk factors, such as diabetes (Piena, Heisen, Wormhoudt, van Wingerden, & Frequin, 2018).

Research from Calabresi et al. (2014) has shown that administration of 0.5 mg fingolimod results in less brain volume loss, 48% fewer relapses, the time until the first relapse was delayed and all the MRI-inflammatory disease activity were lower in RRMS patients compared to the placebo group.

Because S1PR1-5 receptors are not only in lymphocytes but also in other organs, some side effects can occur. There are S1PR1 receptors on the heart, especially on atrial myocytes, to which fingolimod will bind. This can lead in heart rate reductions, symptomatic bradycardia and first or second degree AV block. However, due to compensation processes, these side effects often last between the one and six hours after the administration of fingolimod. During these six hours there is a strict monitoring of the heart in the patients. Furthermore, there may be effects on the heart from binding to S1PR3 receptors on vascular smooth muscle cells resulting in vasoconstriction. S1PR1 is also expressed on retinal cells and macular vascular endothelial cells, which can cause macular edema in 0.5% of the patients treated with fingolimod. Macular edema is an accumulation of fluid in the yellow spot of the retina which can be caused by a leak in the blood vessels in the eye. Furthermore, during the treatment of fingolimod there have been some reports of asymptomatic elevation of liver enzymes, basal cell carcinoma, melanoma and acute neurological deterioration caused by stronger demyelination leading to more MS lesions. These side effects generally disappear after a few months after stopping the fingolimod treatment (Thomas, Proschmann, & Ziemssen, 2017).

Alemtuzumab & Natalizumab

In MS patients there is a primary attack of T cells on oligodendrocytes in the central nervous system leading to neuro-inflammation followed by demyelination and axonal degeneration. Before this can happen T cells must first pass the blood brain barrier (BBB). The BBB limits and prevent the entry of xenobiotics, toxic metabolites and immune cells into the central nervous system (CNS). If the BBB no longer succeeds in keeping lymphocytes out of the brain, there can be serious consequences, such as MS. In MS, dysfunction of the BBB can occur resulting in that T cells, among other things, can penetrate the CNS, which causes lesions. First leukocytes contact the vessel wall and attach to it before it can enter the CNS. The attachment takes place through selectins and their ligands. They then roll over the vessel wall, which causes an inflammatory reaction. Because of more binding of selectins to their ligand (also known as integrins), they will eventually stop rolling and become completely attached to the vessel wall. Therefore, the endothelial cells have to shift to form a passage for the leukocytes. Molecules involved are cell adhesion receptor (VCAM) and intercellular adhesion molecules (ICAM), which are primarily present on the endothelial cells, alpha4 integrin (VLA-4) and functional leukocyte antigen (LFA) that are expressed on T cells (Ortiz et al., 2014).For MS, a number of drugs have been developed that prevent the T cells from coming through the endothelial layer of the vascular vessel. This ensures that the T cells cannot cause lesions in the brain. Examples of these drugs are Alemtuzumab and Natalizumab. These drugs are antibodies against the integrines of the T cells or against other surface proteins.

Alemtuzumab is a humanized igG1-kappa monoclonal antibody directed against the surface glycoprotein CD52. This is a protein that occurs to a large extent on the cell wall of both T cells and B cells. By binding of alemtuzumab to CD52 causes cell death in the relevant cells. These cells are affected in MS, causing lesions in the brain. By inactivation of these cells there is a significant reduction in exacerbations in the patients. After a few months, new B and T cells are created again from unaffected hematopoietic progenitor cells. These precursor cells have no extracellular CD52 and will therefore not be affected by alemtuzumab. Furthermore, due to the absence of CD52, they can no longer pass the BBB without reason. (Ruck, Bittner, Wiendle, & Meuth, 2015).

Another drug used in MS treatment is Natalizumab, a humanized monoclonal anti-4 integrin antibody. When the A4 integrin chain (CD49d), bound to the outside of the T-cells, is activated by a chemokine trigger, it binds to vascular cell adhesion molecule-2 (VCAM-1). These VCAM-1 are expressed on the endothelial cells of the BBB and ensure that the T-cells can pass through the BBB. Natalizumab contains CD49d antibodies which binds to the CD49d presented proteins on the T cells, this will prevent VCAM-1 from binding. This ensures that the T-cells can no longer enter the central nervous system, so that they can no longer attack the oligodendrocytes. In addition, the CD49d antigen inhibits cell renewal and mobilization of lymphoid (pre-B) and lymphoid/myeloid progenitors from the bone marrow (Ghandi et al., 2016).

Both drugs are given intraveneus. With alemtuzumab treatment, one infusion is given for five days. After 12 months there is a second treatment in which one infusion is given for three days. These infusions are given in the hospital. The costs for these two treatments are ˆ 56,000 in total, based on five 12 mg infusions during the first treatment and three infusions during the second treatment. In addition, the hospital costs of ˆ 4.554 are added. These can be increased by a possible third treatment and the test that must be done primarily to reduce any risks (Piena et al., 2018). With natalizumab one infusion is given once every four weeks, so thirteen times a year (7,8). This cost ˆ 21.450 per year, based on 300 mg intravenous administration. Natalizumab is not administered in the hospital, which reduces costs. However, the test that have to be done in advance, just as with alemtuzumab, can still entail costs (Piena et al., 2018).

Research by Tuohy et al, 2017 has been shown that alemtuzumab can result in an improved or unchanged disability in 67.8% of the patients. Furthermore, an area under the curve analysis showed that there was an overall improvement in invalidity stability in 59.9% of the patients. Research into natalizumab in patients with highly active form of MS has shown that natalizumab provides a reduction in relapse rate of 73% compared to the treatment period for natalizumab (Octurai et al., 2009).

Against the efficacy of these drugs are also some side effects. The side effect that occurs in more than 90% in patients treated with alemtuzumab are infusion associated reactions (IAR). These are side effects that occur within 24 hours after the infusion, such as headache, rash, pyrexia and nausea. This is probably caused by the sudden release of cytokines caused by cell death. Furthermore, many infections occur with these treatments, especially in the respiratory and urinary tract, which can vary in severity. Other side effects are an increased risk of developing other autoimmune diseases, thyroid disorders and certain kidney disorders (Ruck, Bittner, Wiendl, & Meuth, 2015)

The most fatal side effect that can occur with Natalizumab treatment is the brain infection called Progressive Multifocal Leukoencephalopathy (PML). PML is caused by the JC virus. About 50% of the MS patients are carriers of this virus, which can be seen by the JC antibody present in the blood. Usually this virus is harmless, but in combination with natalizumab there is a chance that it will lead to PML. Other less serious side effects are urinary tract infections, sore throat, rash with itching, headache, nausea, joint pain and fever (Ghandi et al., 2016).