1. Pharmacotherapy of multiple sclerosis
Domina Petric, MD

2. Types of MS
Relapsing-remitting MS (RRMS) is characterized by relapses followed by remission (85%).
Secondary progressive MS (SPMS) develops over time following diagnosis of RRMS.
Primary progressive MS (PPMS) is characterized by gradual continuous neurologic deterioration (8-10%).
Progressive relapsing MS (PRMS) is similar to PPMS, but with overlapping relapses (5%).

3. Interferon (IFN)
IFN type 1 consists of a group of IFNs which help regulate the immune system.
IFN-β is primarily produced by fibroblasts.
NK cells, B cells, T cells, macrophages also secrete IFN-β.
IFN-β has anti-viral and anti-tumor activity.
It is also effective in reducing the relapse rate in patients with MS.

4. Interferon (IFN)
IFN-β balances the expression of pro- and anti-inflammatory cytokines in the brain.
It decreases the number of inflammatory cells crossing the blood brain barrier.
IFN-β decreases inflammation of neurons, increases nerve growth factors and improves neuronal survival.

5. Interferon (IFN) IFN-β reduces Th17 population and IL-17 cytokines.
IFN-β injection subcutaneously or intramuscularly to patients with RRMS aims to decrease the relapse rate, duration and severity.
There is lack of efficacy to long-term disability.

6. Interferon (IFN) IFN-β approaches: IFN-β1a in a low dosage (Avonex)
IFN-β1a in a high dosage (Rebif)
IFN-β1b in a high dosage (Betaseron, Extavia)
peg IFN-β-1a (Plegridy) has polyethylene glycol linked to IFN-β1a allowing it to be active for longer in the body.

7. Interferon (IFN) IFNs have no direct neuroprotective effects.
They have direct effect on CD4+ Th1 cells: decreased demyelination of neurons, prevention of further neuronal damage.

8. Side effects suicidal thoughts hallucinations seizures
local body aches
skin reactions (swelling, redness)
fever
myalgia
flu-like symptoms
suicidal thoughts
hallucinations
seizures
heart and liver problems

9. Glatiramer Acetate (Copaxone)
Glatiramer acetate (GA) is a synthetic 4-mer peptide: L-glutamic acid, lysine, alanine, tyrosine.
GA competes with short antigenic myelin basic protein (MBP) peptides in complex with MHC class II.
GA diverts Th1 cells to Th2 cells, that supress inflammatory responses, and activates Tregs in the periphery.

10. Glatiramer Acetate (Copaxone)
GA can significantly reduce disease symptoms and development of new lesions by up to 30% in RRMS.
It showed no improvement in long-term efficacy on progression of disability.
GA injection results in side effects ranging from minor (fever, chills) to more serious (cardiovascular, digestive, muscular, respiratory issues).

11. Dimethyl fumarate (Tecfidera)
Dimethyl fumarate (BG-12) is a methyl ester of fumaric acid that modulates immune responses.
BG-12 can reduce relapse rate and increase the time to disability progression in patients with RRMS.
BG-12 reduces the migration of inflammatory cells through the blood brain barrier and activates nuclear factor erythroid 2-related factor (Nrf2).

12. Dimethyl fumarate (Tecfidera)
Nrf2 regulates anti-oxidative proteins that protect cells against oxidative damage and inflammation.
BG-12 protects neuronal cells from oxidative stress by increasing glutathione levels and suppressing pro-inflammatory cytokines from splenocytes in vitro.
Side effects: diarrhea, abdominal pain, nausea, abnormal liver enzymes, decreased lymphocyte counts.

13. Teriflunomide (Aubagio)
Teriflunomide is an active metabolite of leflunomide.
Leflunomide is an immunosuppressive disease-modifying drug used for rheumatoid arthritis.
Teriflunomide inhibits the enzyme dihydroorotate dehydrogenase and inhibits the proliferation of B and T cells.

14. Teriflunomide (Aubagio)
Teriflunomide exerts anti-inflammatory properties by inhibiting IFN-γ producing T cells.
IL-4 and IL-10 producing T cells are unaffected.
Oral administration of teriflunomide reduced relapse rates, MS lesions and also decreased disability progression.
Permanent discontinuation due to side effects is less common compared to IFN-β1a.

15. Side effects reduced white blood cell count alopecia hepatic effects
nausea
diarrhea
numbness in hands and feet
allergic reactions
breathing issues
increased blood pressure

16. Fingolimod (Gilenya)
Fingolimod is a sphingosine 1-phosphate (S1P) receptor modulator.
It acts as a super agonist of S1P receptors causing receptors internalization and leading to reduced infiltration of potentially auto-reactive lymphocytes into the CNS.
Auto-reactive lymphocytes remain localized in the lymph nodes.

17. Fingolimod (Gilenya)
Secondary beneficial effects of fingolimod is that it targets S1P receptors on glia cells in the CNS, activating signaling pathways within the CNS.
It is available as oral therapy 0,5 mg once daily for patients with relapsing forms of MS.
Side effects: bradycardia (within 6 h after treatment initiation), blurred vision, diarrhea, back pain, headache, cough and vomiting.

18. Mitoxantrone (Novantrone)
Mitoxantrone is a type-II topoisomerase inhibitor.
It disrupts DNA synthesis and DNA repair of cancer cells, but normal cells are also affected.
It is a potent immune suppressant: suppresses T cells, B cells and macrophages.
It reduces pro-inflammatory cytokines: IFN-γ, TNF-α and IL-2.

19. Mitoxantrone (Novantrone)
In patients with SPMS, iv. injection of mg/m2 of mitoxantrone every 3 months up to 2 years resulted in reduced disability progression by 84%.
Side effects: nausea, vomiting, hair loss, cardiotoxicity, leukemia, infertility, infection, leukopenia and thrombocytopenia.
There is a limit on the cumulative lifetime doses!

20. Natalizumab (Tysabr)
Natalizumab is a humanized monoclonal antibody against the cellular adhesion molecule α4-integrin.
Integrins are transmembrane receptors that enable cell-extracellular matrix adhesion activating cell signaling: regulation of cell growth, division, survival differentiation and migration.

21. Natalizumab (Tysabr)
Integrins are expressed on T cells, B cells, monocytes, macrophages, NK cells, DC, neutrophils and eosinophils.
Interfering or blocking α4-integrin affects immune cell migration across the blood brain barrier (BBB).
By blocking the interaction between α4-integrin and vascular endothelial adhesion molecule-1, natalizumab inhibits transendothelial migration to the CNS.

22. Natalizumab (Tysabr)
Natalizumab is administered iv. once a month: reduction of activated T cells within the CNS, anti-inflammatory responses, neuroprotective effects.
Side effects: hepatotoxicity, allergic reactions, increased risks of infection, PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (rarely).

23. Ofatumumab (Arzerra)
Ofatumumab (OMB157) is the first fully human type 1 IgG1 kappa monoclonal antibody.
B cells play a role in the pathogenesis of MS.
B cells have essential functions in regulating immune response, by activating CD4+ T cells and regulating T cell responses via the secretion of cytokines and antibodies.
B cells are present at demyelinating areas and in cerebrospinal fluid of patients with MS.

24. Ofatumumab (Arzerra)
CD20 is a marker and present on the cell surface of all B cells.
Ofatumumab binds to 2 unique novel epitopes on the CD20 molecule, induces B cell depletion via complement dependent cytotoxicity and antibody-dependent cell-mediated cytotoxicity causing B cell apoptosis.

25. Ocrelizumab (Ocrevus)
Approved for PPMS.

26. Alemtuzumab (Lemtrada)
It is a humanized monoclonal antibody against CD52.
CD52 is a cell surface molecule expressed on B and T cells.
It is generally used in patients with RRMS who have used 2 or more MS drugs and have failed to work.

27. Side effects immune trombocytopenia kidney problems
serious infusion problems (trouble breathing, swelling, chest pain, irregular heart beat)
cancers (blood cancers, thyroid cancer)
cytopenia
serious infections

28. Daclizumab (Zinbryta)
Daclizumab is a humanized monoclonal antibody against CD25, the IL-2 receptor expressed on the surface of T cells.
It blocks the IL-2 receptor on T cells, preventing the activation of T cells.
In patients with RRMS, it is injected subcutaneously once a month.
Side effects: infections, skin rashes, liver complications.

29. New immunotherapeutic strategies
STEM CELLS
DNA VACCINE
NANOPARTICLES
ALTERED PEPTIDE LIGANDS
CYCLIC PEPTIDES
MANNAN AS CARRIER TO MODULATE IMMUNE RESPONSES

30. Treatment of MS relapses
CORTICOSTEROIDS IV.
PLASMA EXCHANGE
ADRENOCORTICOTROPIC HORMONE INJECTIONS

31. Literature
Dargahi N, Katsara M, Tselios T et al. Multiple Sclerosis: Immunopathology and Treatment Update. Brain Sci. 2017;7:78.