4. Relapsing Remitting Multiple Sclerosis Treatments

Multiple Sclerosis (MS) is a central nervous system (CNS) autoimmune disease where axons are targeted by the immune system leading to degradation of the myelin sheaths around them. By destroying these sheaths, the axons of the CNS become far less capable in their ability to transmit signals, causing faulty or absent communication between neurons. In the majority of MS cases, an initial phase of the disease is experienced, followed later by a series of relapses and remissions, this form of MS is aptly named Relapsing-Remitting MS (RRMS)[1]. In the relapse events of RRMS, demyelination occurs in an inflammatory autoimmune attack in the CNS which may cause lasting damage, and having many of these events over years can lead to a variety of disabilities[1]. It is clear that treating these relapse events as effectively as possible is critical to improving a patient’s long-term health and functionality. As a first line of treatment for RRMS relapses several medications are available, though the main ones used are interferon-βs and glatiramer acetate[1]. Both of these medications serve a similar function in the attempt to remedy the autoimmune attack, and that is by decreasing inflammation in a variety of ways, mainly through interactions with the body’s T-cells[1]. The precise mechanisms of the pathways involved in these treatments are not fully known though, and research on their effectiveness and treatment regimens continues to be done.

4.1 Glatiramer Acetate

4.1.1 Mechanism

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Figure 1. Diagram illustrates how GA-activated T cells partake in the bystander suppression effect.
Image source: Neuhaus, Farina, Wekerle, and Hohlfeld (2001)

Glatiramer acetate, a randomized heterogeneous mixture of polymerized glutamic acid, tyrosine, alanine and lysine, is widely used as a treatment for RRMS, though the medication’s exact biological pathways of function have not been completely elucidated[2]. What is currently known is glatiramer acetate’s suggested mechanism of function in RRMS treatment, the specifics of which are still unclear[3]. Glatiramer acetate has been shown in vitro to be primarily affecting immune cells, particularly those that are myelin basic protein (MBP) specific as glatiramer acetate competes with MBP for major histocompatibility complex binding[3]. In vivo, glatiramer acetate has been shown to target regulatory T cells, inducing T-helper 2-(TH2)-type cells, evident in a study in which mice had spleen cells transferred to them from glatiramer acetate-treated mice, which ended up providing protection to EAE (experimental autoimmune encephalomyelitis)[4]. This induction of TH2 cells is particularly important in RRMS, since down-regulatory, anti-inflammatory cytokines are produced by TH2 cells4. One effect of glatiramer acetate treatment is a conversion of TH1 cells, which produce proinflammatory cytokines that worsen the relapse events in RRMS, to TH2 cells[5]. These TH2 cells then migrate into the central nervous system, where they produce and increase serum levels of anti-inflammatory cytokines such as interleukin-10 and TGF-beta[4] [6]. This production of anti-inflammatory cytokines leads to what is known as bystander suppression of the T cells that are auto-reactive, which as shown in Figure 1 acts to suppress the other T cells in the TH2 cell’s proximity[4]. TH2 cells also have been found to suppress mRNA production of proinflammatory TNF-α[4] [6]. Glatiramer acetate has also been found to have effects on oligodendrocyte precursor cells by increasing their survival, proliferation and differentiation, allowing them to have a larger impact on repair and remyelination of lesions caused in MS[4]. A final function of glatiramer acetate is to reduce the migration of lymphocytes in comparison to untreated individuals, accomplishing this through an indirect pathway that is of yet unknown[3].

4.1.2 Treatments and Effectiveness

Glatiramer acetate’s most common treatment in RRMS is to administer 20mg subcutaneously injected once daily, though it has been shown that three times weekly 40mg subcutaneous injections of glatiramer acetate is just as effective in all areas[7] [2]. This drug has been shown to have an impact on relapses, reducing them by approximately 30% in treated patients, with brain MRIs also indicating a reduction in active brain lesions[7]. Those treated with 40mg glatiramer acetate three-times-weekly had a 34% reduction to their risk of confirmed relapse, a 10% greater number of patients that were relapse free, severe relapse rates reduces by 35%, and a massive 45% and 35% reduction in total T1and T2 lesions respectively, all compared to placebo[2]. Glatiramer acetate has also shown to significantly delay progression from RRMS to clinically definite MS[2].

4.2 Interferon-β

4.2.1 Mechanism

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Figure 2. This image illustrates the proposed function of IFN-β in decreasing
inflammation and protecting myelin in RRMS patients.

Image source: Kieseier (2011)

Though IFN-β is widely accepted and used for RRMS treatment, the exact pathways of its function are not completely known or understood, but the treatments overall effects can be seen. IFN-β has three main ways that it combats the negative aspects of RRMS, the first of which is by increasing anti-inflammatory cytokine production[8]. In the CNS, IFN-β is capable of increasing levels of cytokines such as IL-10, an anti-inflammatory agent[8]. By increasing anti-inflammatory agents in the CNS, damage caused by relapse events and the inflammatory CNS environment associated with it can be lessened[9]. The second way in which IFN-β combats RRMS has been shown in vitro and in vivo, by down-regulating the production of certain proinflammatory cytokines such as osteopontin and IL-17[10]. IFN-β accomplishes this downregulation by three potential methods, including: inhibiting osteopontin translation, inhibiting IL-17 secretion, and regulating T cell expression of IL-17 and osteopontin directly through IFN receptor-mediated activation[10]. The final way in which IFN-β acts in RRMS treatment is by limiting the ability of leukocytes to travel across the blood-brain barrier (BBB)[11]. IFN-β limits the leukocyte migration by indirectly decreasing the quantity of adhesion molecules present on the cell surface of endothelial cells; by altering these to be less adhesive than normal, the leukocytes are then less capable to interact and adhere to the cells that comprise the BBB[11]. Along with down-regulating adhesion molecules, chemokines and matrix metalloproteinases are down-regulated as well, further decreasing leukocyte ability to migrate[9]. Without an effective adhesion, these leukocytes cross the BBB much less, and therefore are less able to induce the inflammatory environment that they are capable of creating in RRMS.

4.2.2 Treatments and Effectiveness

There are two IFN-βs that are used in the treatment of RRMS, IFN-β-1a 44μg three times per week and IFN-β-1b 250μg every 2 days, both injected subcutaneously[12]. While IFN-β-1a may be administered intramuscularly, it is more commonly given subcutaneously[12]. It has been shown that interferon treatment for RRMS is effective for both IFN-β-1b and IFN-β-1b in comparison to patients that received no treatment, able to significantly reduce disability progression[13]. Along with reducing disability progression, IFN-β treatment also has been shown to reduce relapses by approximately 30% and brain MRIs reveal reduced brain lesions in treated patients as well[7]. IFN-β treatments also delay RRMS’ progression to clinically definite MS[7]. One of the leading reasons behind the treatments effectiveness is the finding that IFN-β induces a strong IL-10 response in the T cells of RRMS patients[12]. IFN-β-1a and IFN-β-1b serve the same functions during treatment, yet different dosages and treatment schedules are used for each which in turn have different efficacy in treating RRMS[12]. In a study, two treatment schedules were compared to determine which was more beneficial, either an every-other-day treatment with IFN-β-1b or a once-weekly IFN-β-1a treatment[12]. What was found was that the every-other-day IFN-β-1b treatment was more effective in most categories under examination[12]. IFN-β-1b every-other-day had a significantly lower number of relapse rates, significantly lower annualised average relapse events, lower proportion of disability progression in patients, and finally significantly fewer instances of new T2 lesions[12]. The only real benefit that IFN-β-1a once-weekly has over IFN-β-1b every-other-day is that it is administered once per week, and as such is more convenient and provides less injection adverse events[12]. Though IFN-β treatments are effective at delaying disease progression, it must be noted though that the disease still progresses and that this is not a cure, but merely postponing the inevitable late phases of MS[14].

4.3 Benefit of Earlier Interferon-β Treatments

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Figure 3. Here, the benefit of early treatment of RRMS with IFN-β with regard to EDSS progression is made clear.
Image source: Kappos et al (2007)

While it has been shown that IFN-β treatments are effective when administered to RRMS patients, it has also been found that the earlier that treatment with IFN-β is started the more effective it is for the patient[15]. It is known that MS shifts from early stages of inflammatory processes to late stages of predominantly degenerative activity[16]. It has been found that one of the earliest events in MS is damage to axons in lesions and in the white matter, and this axonal damage is most principally due to inflammation[15]. Since this event of axonal damage is early in the MS disease progression, anti-inflammatory treatments such as IFN-β which function through anti-inflammatory processes are much more effective the earlier they begin to be used, with very early treatments of IFN-β showing significant lowered proportion of individuals that progressed to clinically definite MS and overall reduced relapse rates[15]. With this knowledge of earlier treatment being more beneficial, once study has tried to determine if treating with IFN-β to patients that are not yet found to have MS, but have just had a first clinical event that is suggestive of MS, is beneficial to disease treatment[17]. In this study, IFN-β-1b was administered 250μg every-other-day subcutaneously and found that this treatment had a 40% reduction in the risk of confirmed EDSS progression, and a 41% reduction to the risk for developing clinically definite MS[17]. Even a delay of treatment from the first to the second clinical event suggestive of MS showed to have an effect on disability accumulation later in the course of disease progression[17].

4.4 Side Effects and Drawbacks

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Figure 4. An image of a typical, mild injection-site raction, the most
common symptom in glatiramer acetate and IFN-β treatments.

Image source: http://theroadislife.net/2010/02/

For IFN-β, flu-like symptoms are the most commonly reported side effects, including fever, back pain, chills, muscle aches, fever etc, all beginning roughly 2 to 8 hours after administration of treatment and ending in approximately a day[16]. IFN-β-1b has a higher incidence of flu-like symptoms in patients compared to IFN-β-1a, they being roughly 75% and 50% respectively[16]. For glatiramer acetate, the most common side effects are also very short-lived symptoms just after injection, including anxiety, flushing, palpitations, chest pain, constriction of the throat and dyspnea[4]. Since both of these treatments are administered subcutaneously though, their patients both experience injection-site reactions as well, which are mild and include pain, swelling, redness, and itching[18]. Drawbacks to these treatments include being expensive and inconvenient, needing to receive injections repeatedly[2].

4.5 Compared Efficacy

In a study, the effectiveness of 20mg subcutaneous glatiramer acetate once-per-day and 44μg subcutaneous IFN-β-1a three-times-per-week were compared with each other in order to determine which is most effective in treating patients with RRMS[18]. What was found was that there is in fact no significant difference between the two treatment methods for a multitude of criteria, including: time to first relapse, proportion relapse free, relapse rate, and disability progression[18]. Some of the only evidence indicative of one treatment being more effective than the other shows that IFN-β-1a treatment was better able to reduce BBB disruption than glatiramer acetate treatment[18]. This, of course, was only a comparison of two treatment methods; many variations of treatment doses and injection schedules are available and it is important that the needs of individual patients are taken into consideration when determining which treatment regimen to undertake[18].

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2. Khan, O., et al. Three times weekly glatiramer acetate in relapsing-remitting multiple sclerosis. Ann Neurol 73, 705-713 (2013).
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