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Disease-Modifying Therapies in Multiple Sclerosis
P.B.Vani
1, Dr. V.Chitra
2*
1, 2 Department of Pharmacology, SRM College of Pharmacy, SRM Institute Of Science and Technology, Kattankulathur, Tamil Nadu- India; PO Box: 603203
ABSTRACT
Background: Multiple sclerosis (MS) is a demyelinating condition resulting from the damage of the insulating covers of the brain nerve cells and the spinal cord. The damage affects the ability of the nervous system to transmit signals, and affected individuals end up experiencing physical, mental, and psychiatric problems. Specific symptoms of multiple sclerosis include one-sided blindness, double vision, trouble with sensation and coordination, and muscle weakness. Disease-modifying therapies (DMTs) are preferred for managing relapsing MS and preventing associated disabilities. Their mechanism of action determines how they initiate the therapeutic effect. Besides, each class of DMTs may cause adverse effects to the patients, so they need to be monitored frequently. They exist in injectable, oral, and infusion forms. The purpose of the study was to research the efficacy, efficiency, and tolerability of the mentioned forms of DMTs in managing MS and its complications. Methods: Systematic review and meta- analysis of peer-reviewed articles using databases such as PubMed, MEDLINE, and Cochrane library. Randomized controlled trials were considered. Articles published in the past 20 years were selected as long as they related to the study objectives.
Literature search entailed the use of key terms such as "management of multiple sclerosis,” "injectable disease-modifying therapies,” "oral disease-modifying therapies,” "infusion disease-modifying therapies," and "randomized controlled trials." Data extraction was based on study characteristics such as the title, publication year, number of participants, and the study duration.
Data presentation was done using tables. Results: 24 out of 99 sources met the study requirements. Among them, those that investigated injectable DMTs were 8, oral DMTs, were 11, and infusion DMTs were 5. In the injectable DMT group, interferon beta-1a was the most tested injectable DMT such that it appeared in all 8 studies. Secondly, the 6 studies in the oral DMTs group used oral fingolimod as a major drug, 4 studies used Oral teriflunomide, and the remaining 2 studies used ozanimod and cladribine. 2 studies in the infusion DMTs group tested Ocrelizumab, and the remaining study measured natalizumab and Alemtuzumab. In injectable DMTs, Avonex® (interferon beta-1a) showed the highest efficacy than Betaseron® (interferon beta- 1b). Aubagio® (teriflunomide), Gilenya® (fingolimod), Mavenclad® (cladribine and Zeposia® (ozanimod) were the most common oral DMTs in the identified studies. Lastly, Lemtrada® (alemtuzumab), Ocrevus® (ocrelizumab), and Tysabri®
(natalizumab) were the most investigated infusion DMTs. Conclusion: Findings of the identified studies show that several disease-modifying therapies can prevent the relapse of multiple sclerosis. Although some of the DMTs have adverse effects, selecting therapies with maximal efficacy and minimal adverse effects can help patients to tolerate DMTs well and achieve quality outcomes. Therefore, injectable, oral, and infusion disease-modifying therapies can be administered to patients with multiple sclerosis to prevent relapse and associated complications and disabilities.
Keywords
Multiple sclerosis, Disease –modifying therapies(DMTs),Interferon beta-1a,Fingolimod, Alemtuzumab
1.Introduction
Multiple sclerosis also referred to as encephalomyelitis disseminate, is a demyelinating condition that results due to the damage of the insulating covers of the brain nerve cells and the spinal cord [1]. The damage affects the ability of different parts of the nervous system to transmit signals that control thinking and other body functions. The affected individuals may experience physical, mental, and psychiatric problems in severe cases of the diseases. Specific symptoms of multiple sclerosis include one-sided blindness, double vision, trouble with sensation and coordination, and muscle weakness [1]. The disease presents in either relapsing or progressive forms. The relapsing form is characterized by isolated attacks that appear and disappear after some time while the progressive form develops over time into the severe stage of the disease. Although symptoms of multiple sclerosis disappear in between attacks, the damage on the nervous system remains unchanged and it may cause further complications to parts of the body that depend on nerve signals.
Multiple sclerosis lacks an established cure. However, disease-modifying therapies have been made available to lower the relapse rate of multiple sclerosis, slow down the rate of damage that results during the relapse, and prevent the disease symptoms. Several disease-modifying therapies are available such that healthcare professionals can assess and determine the specific therapy to administer to patients presenting with the condition. The disease- modifying therapies (DMTs) come in injectable, oral, and infusion forms and are administered based on the patient's condition. Common DMTs include interferon beta-1a, interferon beta-1b, teriflunomide, alemtuzumab, and mitoxantrone, among others [ 1, 2, 3, 4]. The mentioned DMTs belong to various classes of medications that function differently to induce a therapeutic effect. Also, each class of DMTs has adverse effects that may prevent its administration to patients that report non-compliance. To prove the pharmacological well-being of DMTs, several clinical trial studies have been done. As such, the purpose of this paper is to discuss several DMTs used to manage multiple sclerosis, their mechanism of action, and adverse effects. Also, the paper will include a method section that will discuss clinical trial studies done regarding the use of DMTs in managing multiple sclerosis (MS). More so, the paper will discuss the results of the respective clinical trials.
1.1 Injectable DMTs
Injectable DMTs include Avonex® (interferon beta-1a), Betaseron® (interferon beta-1b), Copaxone® (glatiramer acetate), Extavia® (interferon beta-1b), Glatiramer Acetate Injection (glatiramer acetate –generic equivalent of Copaxone 20 mg and 40 mg doses) Glatopa® (glatiramer acetate – generic equivalent of Copaxone 20mg and 40mg doses) Kesimpta® (ofatumumab) Plegridy® (peginterferon beta-1a) Rebif® (interferon beta-1a) [5] .Avonex® is a 166-amino acid glycoprotein that was approved by the FDA for use in 1996 as a treatment for relapsing MS. The drug is an interferon that induces a therapeutic effect by balancing the expression of pro- and anti-inflammatory agents in the human brain [2]. A reduction of inflammatory cells in the brain that intrude the blood-brain barrier reduces neuronal inflammatory. Also, the drug increases the release of nerve growth factor that contributes to neuronal survival. The drug is well tolerated after injection. Adverse effects include skin reactions at the injection site, dizziness, stomach pain, mood changes, and weight change, among others [5].Betaseron® is another injectable DMT that was approved by the FDA in 1993. The drug is also in interferon and works in a similar way as Avonex®
to prevent MS relapse. Adverse effects include injection reactions, abdominal pain, body weakness, unexplained weight change, and ease bleeding.
Glatiramer Acetate Injection is also recommended for managing MS. The drug was approved by the FDA in 1996 as a reliable therapy for MS. Approval of dosage increase to 40 mg was done in 2014 for managing MS. Its mechanism of action involves modification of the immune processes involved in the pathogenesis of MS [5]. As a result, the population of T cells from the pro-inflammatory Th1 T-cells shift to regulatory Th2 T-cells, leading to the suppression of the immune response. Adverse effects after the injection may include the formation of a lump at the injection site, fever, and chills [5]. Patients may also experience severe side effects on the body systems, including the cardiovascular, respiratory, nervous, and urogenital systems. Another injectable medication for MS is Kesimpta®. It was approved in 2009 as a DMT for MS. The drug induces a therapeutic effect by binding to the CD20 cell antigen that is found on pre-B and mature B lymphocytes. This results in antibody-dependent cellular cytosis and complement-mediated lysis
1.2 Oral DMTs
Oral DMTs include Aubagio® (teriflunomide), Bafiertam™ (monomethyl fumarate), Dimethyl Fumarate (dimethyl fumarate - generic equivalent of Tecfidera), Gilenya® (fingolimod), Mavenclad® (cladribine), Mayzent®
(siponimod), Tecfidera® (dimethyl fumarate), Vumerity® (diroximel fumarate), and Zeposia® (ozanimod) [6,7,8,9].
Firstly, Aubagio® is a commonly used oral therapy for MS. The drug was approved by the FDA in 2012 for MS management. Aubagio® is an immunomodulatory drug that prevents rapid cell division, including activated T-cells that drive the development process of MS [6]. The drug is linked with several adverse effects including nausea, diarrhea, influenza, and liver problems.Secondly, Bafiertam was approved by FDA in 2020 as an oral DMT for multiple sclerosis. Its mechanism of action involves the activation of the nuclear factor (erythroid-derived 2)-like the 2-factor pathway. The drug is also associated with several adverse effects such as flushing, itchiness, indigestion, nausea, vomiting, and diarrhea.
Another oral drug for relapsing MS is Gilenya®, which was approved by the FDA in 2010. The drug reduces the immune system attack on the central nervous system by retaining white blood cells in the lymphocytes [7]. In this case, the disease process is delayed preventing further damage and complications. Adverse effects associated with
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MS include headache, abdominal pain, and abnormal liver tests. Mavenclad® is also an approved short-course oral therapy for MS. The drug was approved by FDA in 2019. The drug targets the B and T lymphocytes leading to a reduction and recovery of lymphocytes to the normal count. Adverse effects associated with the drug include upper respiratory tract infection, headache, back pain, insomnia, and lymphopenia.Lastly, Mayzent® can be administered orally to manage relapsing MS. The drug was approved by FDA in 2019 for use in managing MS. It is a selective sphingosine-1-phosphate receptor that prevents the migration of lymphocytes to the location of the inflammation.
Common adverse effects include headache, raised blood pressure, and abnormalities in liver function tests.
1.2 Infusion DMTs
Injectable DMTs include Lemtrada® (alemtuzumab), Novantrone® (mitoxantrone), Ocrevus® (ocrelizumab), and Tysabri® (natalizumab) [4]. First of all, Lemtrada® was approved by USFDA in 2014 for use in managing relapsing MS. It is a monoclonal antibody that induces a therapeutic effect by binding selectively to CD52 which is mostly expressed on T and B lymphocytes [4]. Adverse effects associated with the drug include skin rash, headache, fever, chills, urinary tract infection, and thyroid problems, among others. Secondly, Novantrone® can as well be infused to manage relapsingMS. The USFDA approved the drug for MS management in 2000. It initiates a therapeutic effect by inhibiting the replication of DNA and DNA-dependent RNA synthesis. This prevents cell division which then suppresses the proliferation of diseases causing cells. Common adverse effects include nausea, vomiting, diarrhea, stomach pain, and heavy menstrual bleeding, among others [4]. Ocrevus® and Tysabri® play the same roles as Lemtrada® since they belong to the same class of drugs. Ocrevus® was approved by USFDA in 2017 and Tysabri®
in 2004. Both drugs may present with common adverse effects including upper respiratory infections, infusion reactions, and skin infections, among others.
2. Methods 2.1 Criteria for Study Inclusion
The study applied a systematic review and meta-analysis design. Databases such as PubMed, MEDLINE, and Cochrane library were researched to identify peer-reviewed articles that were published after performing randomized controlled trials. A trial was termed eligible if it measured the application of DMTs in managing participants with multiple sclerosis. Also, only articles published in the past 20 years were selected as they mostly entail current therapeutic approaches for MS. Eligible studies had to report the effectiveness of the DMTs used to manage the study participants.
2.2 Literature Search and Study Selection
An electronic search of peer-reviewed articles on PubMed, Cochrane Library, and MEDLINE was performed to identify articles that had been published between 2010 and 2020. The search strategy applies major terms such as
"management of multiple sclerosis,” "injectable disease-modifying therapies,” "oral disease-modifying therapies,”
"infusion disease-modifying therapies," and randomized controlled trials." All searches were focused on human studies with much consideration of studies published in the English language.
2.2 Data Extraction and Risk of Bias
Data was strictly extracted from the selected peer-reviewed articles and the risk of bias was assessed to determine any deviations from normal expectations of the study purpose. Extracted data included study characteristics such as the title, authors, publication year, number of participants, setting, and study duration. Also, patient characteristics such as age, gender, treatment outcomes, overall health status, and intervention comparisons were extracted. Study methods used in the selected articles were extracted as well, including the study design and random sequence generation. Lastly, the risk of bias was assessed using the Cochrane Collaboration's tool.
2.3 Data Presentation and Analysis
Data collected from the selected studies were presented in tables for easier understands. Besides, quantitative and diagnostic data analysis was done to ensure that all information from the randomized controlled trial can help understand the treatment outcomes of the administered medications.
3. Results
The electronic search identified 99 sources after search PubMed, MEDLINE, and Cochrane Library using the key terms. However, only 24 sources met the requirements for the paper and so they were isolated and analyzed carefully. To promote efficient data analysis, the selected studies were divided into injectable, oral, and infusion DMTs. In this case, studies that analyzed injectable DMTs were 8, oral DMTs, 11, and infusion DMTs 5.
Furthermore, the grouped studies were analyzed based on the specific DMTs therapies administered to the participants. In the injectable DMT group, interferon beta-1a was the most tested injectable such that it appeared in all the 8 studies. Secondly, the 6 studies in the oral DMTs group used oral fingolimod as a major drug, 4 studies used Oral teriflunomide, and the remaining 2 studies used ozanimod and cladribine. Lastly, 2 studies in the infusion DMTs group tested Ocrelizumab, and the remaining study measured natalizumab and Alemtuzumab.
3.1 Injectable DMTs
All 8 studies identified during the literature search measured the effectiveness of interferon-beta-1a in managing relapsing MS. A total of 1127 participants who had been diagnosed with MS were involved in the 8 studies.IM interferon beta-1a was the most administered drug and it resulted in positive outcomes. One study that had eighty participants and was carried out for 12 months led to a decrease in the relapse rate from 0.95 +/- 0.41 to 0.60 +/- 0.67 [10].The study was done in a period of one year which is enough to deliver reliable outcomes. Although some studies did not indicate of ages of participants, two of them measured the outcomes among participants with an average age of 16 years [2,11]. One of the two studies also measured the prevalence of adverse effects among the young population and the findings indicated that all participants tolerated interferon beta-1a without any outstanding adverse effects [11]. Also, the studies measured the ability of interferon beta-1a to prevent the progressive disability that is mostly witnessed among patients with MS. The drug showed its capability to perform the function after 25 patients with MS reported a lack of continuous disabilities after taking the drug for 21 months [12].
One study that involved 521 participants who were subjected to IM interferon beta-1a at different periods after diagnosis measured the importance of early treatment. Among the participants, 171 of them who were subjected to early treatment reported better outcomes than those who later began the treatment [13]. The rate of relapse among the participants was low after taking the drug for 3 to 5 years. Since MS causes both physical and mental symptoms, one study aimed to assess the ability of injectable DMTs to manage both classes of symptoms. After administering Avenox, Betaferon, and Rebif for 12 months, the participants showed an improvement in both physical and mental symptoms [14].The rate of recovery among the participants was determined by the adherence to the medications, especially among participants who used autoinjectors [15,16]. In all the mentioned studies, the risk of bias was assessed by reviewing similar studies that applied similar research methods. Table 1 below summarizes information from the discussed studies.
Table 1.
Injectable DMTs.Study Number of
participants
Intervention Duration Age of participants
Sex Measurement outcomes Kalanie
2004
80 IM interferon
beta-1a
12 months - Males
and females
Relapse rate decreased from 0.95 +/- 0.41 to 0.60 +/- 0.67 Pakdaman
2006
16 IM interferon
beta-1a
4 years Under 16 years
Male and female
Treatment with IM interferon beta-1a was well-tolerated
with no
significant adverse effects Motamed
2007
25 interferon
beta-1a
21 months - Males
and females
DMTs reduce relapses and prevent
progressive
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disability Bermel
2010
122 IM interferon
beta-1a
2 years Average of 15 years
Males and females
Lower mean expanded Disability Standard Scale Score (p=0.011) Baranzini
2015
180 interferon
beta-1a
1 year - Males
and females
Positive
response to interferon beta- 1a
Mokhber 2015
90 Avenox,
Betaferon, Rebif
12 months - Males
and females
Physical and mental
improvements in
all three
interventions Coyle 2017 521 Interferon-
beta-1a
2 years - Males
and females
Early treatment of led prevented relapse of MS in 3 to 5 years
Wray 2017 97 S/C interferon
beta-1a
4 weeks - Males
and females
Most patients preferred using autoinjectors
3.2 Oral DMTs
3.2.1 Oral Teriflunomide
4 of the 11 studies focused on investigating the efficacy of oral teriflunomide in managing relapsing MS. A total of 2,910 participants participated in the 4 studies [6,7,8,9]. Four studies showed that patients who were subjected to oral teriflunomide reported a reduction in the risk of MS relapse [6,8,9]. Dosage adjustment in the respective studies up to the maximum dose improved the quality of outcomes. The three studies also measured the prevalence of adverse events among participants following the continuous use of oral teriflunomide. Minimal adverse effects were witnessed among those who were given a continuous dosage of 7 mg. Adverse effects such as increased alanine aminotransferase, hair thinning, diarrhea, urinary tract infections, paresthesia, and diarrhea [6,8,9]. One study compares the efficacy and safety of oral teriflunomide with interferon beta-1a when co-administered as an add-on therapy. The drug was administered in 7 and 14 mg dosages for 24 weeks. The findings showed that oral teriflunomide was well tolerated such that incidences of adverse effects were minimal and the rate of relapse of MS reduced [8]. The efficacy of teriflunomide in managing early MS was investigated in one of the studies whereby the findings revealed that the drug has a beneficial effect [6]. The other studies focused on relapsing MS, and the results showed a reduction in the relapse rate among participants [7, 8, 9]. Table 2 below summarizes information from the discussed studies.
Table 2: Oral Teriflunomide
Study Number of
participants
Intervention Duration Age of
participants
Findings
O' Connor 2011 1088 Oral
teriflunomide
108 weeks 18 - 55 years The reduced annualized relapse rate of MS
Confavreux 2012
118 Oral
teriflunomide
24 weeks - Low incidents of
treatment-related adverse events
Vermersch 2013 1086 Oral 30 days - Teriflunomide
teriflunomide reduced
annualized rates of MS relapses
Miller 2014 618 Oral
teriflunomide
108 weeks 18 - 55 years 7 mg and 14 mg
of oral
teriflunomide reduced the risk of MS relapse among
participants.
3.2.2 Oral Fingolimod
5 out of the 11 studies investigated the efficacy and tolerability of oral fingolimod in managing relapsing MS [17, 18, 19, 20, 21]. One study revealed that initiating treatment with oral fingolimod improved the quality of outcomes among the participants and reduce the cost of managing MS relapse. In the study which took a period of 12 months, participants who were subjected to early treatment using oral fingolimod spend approximately $83,123, and those who delayed treatment spend approximately $103,624 [17]. Another study showed that oral fingolimod is associated with minimal adverse effects and a low annualized relapse rate (0.2/relapses per year) [18].Still, another study compared the effectiveness of switching from interferon beta-1a to oral fingolimod. Fingolimod 0.5 and 1.25mg proved to prolong the time to relapse (median of 5.07 years) compared to interferon beta-1a [20]. Another study showed that the retention rate was higher with oral fingolimod (80.6%) than in injectable DMTs (30.4%) [21]. Also, patient satisfaction was greater with oral fingolimod than injectable DMTs [21]. MS is also associated with mental symptoms such as depression. In this case, a study involving 1053 patients that were done in a period of 6 months showed that oral fingolimod improved recovery in MS-related depression [17]. Table 3 below shows the information on the discussed studies.
Table 3: Oral Fingolimod
Study Number of
participants
Intervention Duration The average age of participants
Results Agashivala
2012
- Oral fingolimod 12 months - Early initiation
of fingolimod reduced the cost of managing relapse. Early initiation cost
$83,123 and delayed
initiation cost
$103,624
Izquierdo 2014 140 Oral fingolimod 6 months Low annualized
relapse rates (0.2
relapses/year.
No safety issues reported
Meng 2015 Switching
interferon beta- 1a to oral fingolimod
- - Fingolimod 0.5
and 1.25mg prolonged time to relapse to a median of 5.07 years
Hunter 2016 1053 Oral fingolimod 6 months - Switching to
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oral fingolimod improved recovery from MS-associated depression.
Reduced rate of MS relapse
Cascione 2018 141 Oral
fingolimodand injectable DMTs
48 weeks 18 – 65 years The retention rate was higher
with oral
fingolimod (80.6%) than in injectable DMTs (30.4%).
Patient
satisfaction was greater with oral fingolimod than injectable DMTs
3.2.3 Other Oral DMTs
The remaining studies among the 11 investigated several oral DMTs including cladribine and ozanimod. One study involving 1,326 participants that 96 weeks monitored adverse events and tolerability of cladribine tablets in managing MS. Common adverse events witnessed included lymphopenia, herpes zoster infections, uterine leiomyomas, and pre-malignant cervical carcinoma [22]. Another study investigated the efficacy, tolerability, and safety of Ozanimod. 223 participants underwent the treatment test using different doses of the drug for 2 years.Tolerability, safety, and efficacy were high in most of the patients. Also, no adverse events or adverse effects such as atrioventricular block or opportunistic infection were reported [23].
3.3 Infusion DMTs
As shown earlier, 4 of the 23 studies investigated the efficacy of infusion DMTs in managing relapsing MS. A comparison between alemtuzumab and interferon beta 1a showed that 51% of participants in the interferon beta 1a group relapsed compared with 35% in the alemtuzumab group [24]. A study on the efficacy of natalizumab showed that discontinuation Natalizumab discontinuation therapy resulted in the development of new T2 lesions in 6-12 months [4]. More so, Ocrelizumab reduced the change in the Nine-Hole Peg Test and the risk for confirmed progression (CP) for primary progressive MS. However, comparison with interferon beta 1a showed that Infusion- related reactions (IRR) were highly reported in Ocrelizumab than in interferon beta 1a. Table 4 below shows the information on the discussed studies.
Table 4
:Infusion DMTs
Study No of
participants
Intervention Duration The average age of participants
Results
Coles 2012 202 Alemtuzumab and
interferon beta 1a
2 years 18 – 55 years 51% of
participants in the interferon beta 1a group relapsed compared with 35% in the alemtuzumab group.
Weinstock- 36 Natalizumab 12 months - Natalizumab
Guttman 2015 discontinuation therapy
discontinuation therapy resulted
in the
development of new T2 lesions in 6-12 months.
Fox 2018 - Ocrelizumab 120 weeks - Ocrelizumab
reduced the change in the Nine-Hole Peg Test and the risk for confirmed progression (CP) for primary progressive MS.
Mayer 2019 1651 Ocrelizumab and
interferon beta 1a
72 weeks - Infusion-related
reactions (IRR) were highly reported in Ocrelizumab than in interferon beta 1a
4. Discussion of Findings
Multiple sclerosis is a disease that can disable the brain and spinal cord resulting in several complications such as paralysis, muscle spasms, epilepsy, and mental changes. The disease relapses from time to time leading to worsening of the mentioned complications unless effective therapeutic measures are taken. Several studies have been done to determine effective disease-modifying therapies (DMTs) that need to be administered to patients to prevent relapses.
Injectable, oral, and infusion DMTs have all been found to be effective in managing relapsing MS. Most of the studies confirmed Avonex® (interferon beta-1a) as the most effective injectable DMT that can be administered to patients [2, 10, 11]. Administering the drug can prevent the worsening of disabilities and complications of MS. Still, one study confirmed that Betaseron® (interferon beta-1b) can as well prevent the relapse of MS if administered in the right regulations [14].
Some oral DMTs proved to have higher efficacy than interferon beta-1a, including Aubagio® (teriflunomide) and Gilenya® (fingolimod) [17, 18, 19]. Apart from inducing a therapeutic effect, the two drugs are associated with minimal adverse effects, and so they are likely to be tolerated well among patients. Another advantage of the mentioned oral DMTs is that dosage adjustments up to the maximum improve the quality of outcomes.Infusion DMTs also proved to be effective in managing relapsing MS. Lemtrada® (alemtuzumab), Ocrevus® (ocrelizumab), and Tysabri® (natalizumab) can all improve the outcome of MS. Alemtuzumab proved to have higher efficacy than interferon beta-1 [4]. Ocrelizumab is also a reliable infusion DMT. However, it is associated with adverse effects that can hinder its usage in the clinical setting.
One strength of the study findings is that all sources were obtained from reliable databases. As such, the validity and reliability of the information is a guarantee. Also, all the articles are peer-reviewed such the findings can be applied in academic and clinical settings. Still, one major limitation of the study is a lack of studies about other DMTs that could as well be used to manage MS. For example, studies about Betaseron® (interferon beta-1b) were limited.
5. Conclusion
Multiple sclerosis is one disease that needs to be managed effectively to prevent physical and mental complications and disabilities. Findings of the identified studies show that several disease-modifying therapies can prevent the relapse of multiple sclerosis. Although some of the DMTs have adverse effects, selecting therapies with maximal efficacy and minimal adverse effects can help patients to tolerate DMTs well and achieve quality outcomes.
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Therefore, injectable, oral, and infusion disease-modifying therapies can be administered to patients with multiple sclerosis to prevent relapse and associated complications and disabilities.
6. Acknowledgment
None to be declared.
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