MS Treatment

INTERFERON-β

Three interferon-β (IFN-β) formulations are approved for relapsing-remitting MS (RRMS). These are IFN-β-1b (Betaseron) subcutaneously every other day, IFN-β-1a (Rebif) subcutaneously three times weekly and IFN-β-1a (Avonex) intramuscularly weekly. The earlier that treatment is initiated, the better the result.

IFN-β is a hydrophobic short-range molecule; little crosses into the CNS. Interferon-β reduces MHC class II molecule and immune system–activating co-stimulatory molecule expression on dendritic cells (DCs) and monocytes/macrophages. These actions inhibit processing and presentation of antigen to CD4⁺ T cells. IFN-β increases tolerance-inducing cytotoxic T lymphocyte antigen-4 (CTLA-4) and immunoglobulin-like transcript 3 (ILT3) production and restores deficient CD8⁺CD28⁻T_S-cell function. These actions further inhibit T-cell activation and proliferation within lymph nodes (LNs). In addition, IFN-β increases soluble vascular cell adhesion molecule-1 (VCAM-1) production. The very late antigen-4 (VLA-4) adhesion molecule expressed by CD4⁺ T_E cells is captured by soluble VCAM-1 so that VLA-4 binding to endothelial cell surface–expressed VCAM-1 is reduced, and CD4⁺ T_E-cell adhesion to cerebral venular endothelium and subsequent cell translocation across the blood-brain barrier (BBB) (step 2) is lessened. IFN-β inhibits matrix metalloproteinases (MMP) activity and hence leukocyte migration across the glia limitans into CNS parenchyma (step 5). IFN-β facilitates apoptosis of autoreactive T cells (step 8), down-regulates proinflammatory cytokine production by activated T cells, and up-regulates anti-inflammatory cytokine production by T cells and mononuclear cells, IFN-β modestly increases brain-derived neurotrophic factor (BDNF) production by immune system cells pointing to a putative neuroprotective role (step 9 of the MS relapse and see later).

One third of patients receiving high-dose IFN-β subcutaneously develop neutralizing antibodies to the agent. Antibody positivity is transient in many patients but persists in others and more so in those with hightiter antibody. In two recent studies, high antibody titer was associated with increased magnetic resonance imaging (MRI) activity (i.e., with a deleterious impact on MRI outcomes), whereas in a seeming paradox, no discernable deleterious effect on any clinical outcome by any statistical analysis was detected.

GLATIRAMER ACETATE

Glatiramer acetate (GA) (Copaxone) is approved for treatment of RRMS. How it acts is imperfectly understood. GA, a random polymer of glutamic acid, lysine, alanine, and tyrosine, is highly basic and does not cross the BBB. GA modulates antigen-presenting cells (APC) function such that T cells shift from the Th1 dominance of MS relapses to Th-2 dominance. Perhaps this is why attack frequency lessens.

GA reduces expression of APC-derived inflammatory mediators. APC-derived interleukin (IL)-12p70 drives proinflammatory IFN-γ production by Th1 cells. GA reduces IL-12p70 levels and reduces secretion of proinflammatory TNF-α while concomitantly increasing production of anti-inflammatory IL-10 and transforming growth factor-β (TGF-β). In addition, APC-derived IL-10 and TGF-β augment Th2 cell production of anti-inflammatory IL-4 and IL-10. Release of cytokines that participate in Th17 cell differentiation is also reduced. Although GA binds rapidly and efficiently to APC-expressed MHC class II molecules, its effect on the Th1 to Th2 shift appears to be independent of this binding.

GA stimulates polyclonal proliferation of CD4⁺ T cells. Proliferation declines over time. In contrast, CD8⁺ T-cell proliferative responses of patients, initially deficient, versus CD8⁺ T cells of controls, rise over time on drug, and CD8⁺CD28⁻ T_S-cell function, also defective initially, corrects to levels observed in controls. The CD8⁺CD28⁻T_S-cell population is clonally restricted, indicating antigen specificity. Response is confined to antigen presented by HLA-E, an HLA class1 molecule with a limited antigenic repertoire. Of interest, CD8⁺ T cells in MS brain parenchyma are likewise clonally restricted. Patients receiving GA invariably develop anti-GA antibodies. These antibodies do not appear to interfere with efficacy.

There is interest in a neuroprotective role for GA. Neurotrophins are polypeptide growth factors essential for development and maintenance of the vertebrate nervous system. BDNF, a neurotrophin that encourages neuronal and axonal survival and regulates neurotransmitter release, is made within the CNS chiefly by neurons but is also synthesized by stimulated T cells and monocytes/macrophages. BDNF is seen within invading cells in MS plaques, and its receptor is expressed by neurons and astrocytes in MS brain lesions. GA substantially increases BDNF production by immune system cells, and this action might favorably alter step 9 of MS relapses.

NATALIZUMAB

Natalizumab (Tysabri) is a humanized (>90% human components) monoclonal antibody (MAb) directed against the α4 subunit of VLA-4, an adhesion molecule expressed by T cells, B cells, and activated macrophages. Natalizumab blocks adhesion between VLA-4–expressing immune cells and VCAM-1 expressed by endothelial cells at sites of inflammation. Blocking of adhesion prevents immune cell extravasation across CNS parenchymal venules (step 2 of an MS relapse).VLA-4–mediated events help up-regulate monocyte-induced MMP expression so that natalizumab may also impede step 5 of an MS relapse.

Natalizumab is approved for treatment of RRMS. Natalizumab reduced MS relapse rate by 68% compared with placebo. Its ability to markedly reduce lymphocyte migration into the CNS is counterbalanced by a reduction in CNS surveillance and increased risk for progressive multifocal leukoencephalopathy (PML), a serious opportunistic infection caused by the JC virus that can kill. Natalizumab is generally reserved for patients who fail first-line therapies. The drug is administered monthly intravenously. The 10% of patients who develop antibodies to natalizumab lose efficacy. Natalizumab has a half-life of 11 days. Should PML be suspected, accelerated clearance of natalizumab via plasma exchange has been proposed as a way to accelerate restoration of immune function. Because 50% of MS patients test negative for anti-JC virus antibodies at screening, they may be at reduced risk for PML, but conversions to positivity during treatment do occur.

FINGOLIMOD

Fingolimod (Gilenya) is the first oral agent approved for treatment of MS; this reduces MS relapses by 53%. Fingolimod is a sphingosine-1-phosphate (S1P) receptor modulator that regulates lymphocyte trafficking and exerts pleiotropic actions on OGCs, other neural cells, and endothelium. Fingolimod is phosphorylated in vivo. Fingolimod-phosphate, the active moiety, binds to S1P receptors. When a recirculating CCR7⁺ CD4⁺ T_CM cell within a LN encounters an APC bearing its cognate antigen, the T cell stops moving. Shut-down requires internalization of S1P-1. Arrested T cells undergo clonal expansion, after which S1P-1 receptor expression is restored and movement resumes. LN exit requires signaling between newly restored S1P-1 receptor and its endogenous ligand S1P. Fingolimod-phosphate causes S1P-1 receptors to be internalized and degraded. Consequently, T cells are trapped in the LNs. Th1 and Th17 cells are trapped preferentially. CD8⁺ T cells are largely spared because the circulating CD8⁺ T-cell pool consists primarily of cells that do not enter LNs. CD4⁺ T_EM cells also remain in the periphery. Fingolimod-phosphate does not interfere with T-cell function. Hence CD4⁺ T_EM cell defense against previously encountered organisms remains largely intact. However, circulating CD4⁺ T_N and CD4⁺ T_CM cell numbers fall, and because T_CM cells initiate step 1 of an MS relapse, their entrapment in LNs lessens MS relapse likelihood. Circulating lymphocyte counts revert to normal within 4 to 8 weeks of stopping the drug.

Fingolimod crosses the BBB. Disturbed sphingolipid metabolism within normal-appearing white matter occurs in MS. Phospholipid content shifts upward and sphingolipid content downward. Such shifts should increase repulsive forces between apposed lipid bilayers and loosen myelin structure. Fingolimod accumulating within CNS white matter might, over time, correct this abnormality. Fingolimod lessens toxin-triggered CNS myelin breakdown, lessens toxin-induced injury to OGCs, and spares axons. Fingolimod also increases endothelial integrity, possibly lessening CNS vascular leakage.

Fingolimod has risks. Infections have included fatal herpes virus infections. Macular edema has occurred during early months on treatment. Bradycardia, possibly serious, can occur with the first dose.

TERIFLUNOMIDE

Teriflunomide (Aubagio), the second oral agent approved for treatment of MS, reduced relapse frequency by 31% at doses of 7 or 14 mg daily. GD- positive lesions were reduced by 57% (7 mg) and 80% (14 mg). Disability progression was reduced significantly at the higher dose.

Teriflunomide blocks dihydroorotate dehydrogenase (DHODH), the rate limiting enzyme for the de novo pyrimidine synthesis required for rapid clonal expansion of T and B cell blasts. Pyrimidine can be salvaged from food and by recycling. This DHODH independent path suffices for day to day needs. Thus the agent is highly specific for rapidly dividing immune system cells. Its antiproliferative effect is reversed by exogenous uridine.

Some actions of teriflunomide are not reversed by uridine. Included are impaired proinflammatory cytokine and surface molecule expression, deficient T cell migration, and reduced interactions of T cells with APCs or B cells. A Th1 to Th2 shift occurs with increased expression of antiinflammatory IL-10.

Side effects, seen in a minority of patients include GI upset, mild hair thinning that reverses spontaneously, asymptomatic liver enzyme elevations, and mildly elevated blood pressure. Discontinuation for these reasons is rare. The overall safety profile is favorable. A prodrug, with teriflunomide the active moiety, has been used to treat rheumatoid arthritis since 1998.

Teriflunomide has a long half-life, but because it recycles through the gut it can be cleared rapidly by oral polystyramine daily for 11 days. The drug is contraindicated in pregnancy, in which case clearance should be prompt.

MITOXANTRONE: (NOVANTRONE)

Mitoxantrone, a synthetic anthracenedione, intercalates into deoxyribonucleic acid (DNA), causing crosslinking and strand breaks that interfere with DNA repair. Mitoxantrone, primarily used as an antineoplastic agent, is approved for the treatment of secondary progressive MS (SPMS), progressive relapsing MS, and rapidly worsening RRMS. Mitoxantrone inhibits monocyte and lymphocyte migration, decreases secretion of proinflammatory cytokines, inhibits B-cell and DC-cell function and augments T_S-cell function. Mitoxantrone is usually given briefly to RRMS patients with overwhelming disease before introduction of a first-line anti-MS drug.

Complications include myelosuppression, cardiac toxicity (sometimes fatal), acute myelogenous leukemia (frequently fatal), and infertility. MS reactivates once drug is stopped.

DIMETHYL FUMARATE (BG-12)

This agent reduced MS relapse rate by 53%, disability by 38%, new GD-positive lesions by 90% and new/enlarging T2 lesions by 85%. Adverse events include early flushing and gastrointestinal upset. BG-12’s mode of action is imperfectly understood; it may activate the nuclear factor (erythroid-derived 2)–like 2 (Nrf2) transcription pathway that has antioxidant effects, may have NF-κB–inhibiting effects that reduce levels of proinflammatory IL-1β, TNF-α, and IL-6 and may shift DC differentiation along a tolerance-promoting path.

ANTI–B-CELL AGENTS

Rituximab (Rituxan) is a chimeric (two thirds human and one third murine) anti-CD20 monoclonal antibody (MAb) approved for treatment of B-cell lymphomas and rheumatoid arthritis (RA). Ocrelizumab is a humanized (>90% human components) anti-CD20 MAb thought less likely than rituximab to provoke production of efficacy-blocking antibodies. In pilot trials in RRMS, both drugs reduced relapse frequency and the number of new GD-positive lesions. Neither is approved for treatment of MS, but data at hand indicate a clear-cut role for B cells in MS pathogenesis.

CD20 is expressed by mature naïve B cells and by memory B cells but not by the plasma cells that produce most of the antibody. Although CD20-positive cells are totally depleted within days of agent administration and remain so for 6 months, total immunoglobulin levels are little reduced, and most protective antibodies remain unchanged. B cells do not simply make disease-relevant antibodies in MS. Rather, a role in antigen presentation to T cells, at which B cells are highly efficient, seems likely. Several cases of PML in systemic lupus erythematosus (SLE) patients given rituximab, and opportunistic infections (some fatal) in rheumatoid arthritis patients given ocrelizumab are reported. To date, such infections have not been reported in MS.

Only gold members can continue reading. Log In or Register to continue