Disease-modifying Treatments for Multiple Sclerosis - a Review of Approved Medications

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Eur J Neurol. 2016 Jan; 23(Suppl i): 18–27.

Disease-modifying treatments for multiple sclerosis – a review of approved medications

Ø Torkildsen

^aDepartment of Clinical Medicine, KG Jebsen MS Research Middle, Academy of Bergen, Bergen, Norway

^bDepartment of Neurology, Norwegian Multiple Sclerosis Competence Centre, Haukeland Academy Hospital, Bergen, Norway

Thou-M Myhr

^aDepartment of Clinical Medicine, KG Jebsen MS Enquiry Centre, University of Bergen, Bergen, Norway

^cSection of Neurology, Norwegian Multiple Sclerosis Registry and Biobank, Haukeland Academy Infirmary, Bergen, Norway

L Bø

^aSection of Clinical Medicine, KG Jebsen MS Inquiry Centre, University of Bergen, Bergen, Kingdom of norway

^bSection of Neurology, Norwegian Multiple Sclerosis Competence Middle, Haukeland University Hospital, Bergen, Norway

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Abstract

Background and purpose

There is nevertheless no curative treatment for multiple sclerosis (MS), but during the last 20 years eight dissimilar disease-modifying compounds have been approved for relapsing−remitting MS (RRMS).

Methods

A literature search was conducted on published randomized controlled phase III trials indexed in PubMed on the canonical medications until 21 May 2015.

Results

In this review the fashion of activity, documented handling effects and side furnishings of the approved MS therapies are briefly discussed.

Conclusions

Based on current knowledge of risk−do good of the approved MS medications, including factors influencing adherence, information technology is suggested that oral treatment with dimethyl fumarate or teriflunomide should be preferred as a starting therapy among the beginning-line preparations for de novo RRMS. In the case of breakthrough disease on showtime-line therapy, or quickly evolving severe RRMS, second-line therapy with natalizumab, fingolimod or alemtuzumab should be chosen based on careful risk−benefit stratification.

Keywords: disease-modifying, multiple sclerosis, review, treatment

Introduction

Multiple sclerosis (MS) is a common cause of disability in immature adults. Irreversible axonal damage occurs even in the primeval phases of affliction evolution ^ane. Although some people with relapsing−remitting MS (RRMS) have a 'benign' illness grade with minimal illness activity and impairment, most patients experience increasing disability over time and somewhen convert to secondary progressive MS (SPMS). There is still no curative treatment, but during the concluding twenty years eight different therapies have go available including interferon beta, glatiramer acetate, teriflunomide, dimethyl fumarate, natalizumab, fingolimod, alemtuzumab and mitoxantrone, and several new compounds are in development. All the approved medications have mainly anti-inflammatory effects and increasing evidence indicates that all of them are more constructive in the early on phases of disease development ^{ii , 3}. With the development of more effective treatments, the aim of treatment has changed dramatically in the concluding decades, from merely reducing relapse rates and slowing of disability progression to preventing all show of new disease activity ⁴. In the current review, the fashion of action and documented result of the current immunomodulatory MS therapies are briefly discussed.

Methods

The commodity is based on English language-language original clinical treatment trials and selected review articles, identified through a literature search in PubMed using the search term 'multiple sclerosis' combined with 'interferon beta', 'glatiramer acetate', 'teriflunomide', 'dimethyl fumarate', 'natalizumab', 'fingolimod', 'mitoxantrone' and 'alemtuzumab'. The search was terminated on 21 May 2015. Titles and abstracts accept been reviewed, and full-text versions of manufactures examined in the bulk of cases. Particular emphasis has been placed on randomized controlled stage III studies.

First-line medications

Interferon beta

Interferon beta is a naturally occurring polypeptide predominantly produced by fibroblasts. Its anti-inflammatory furnishings are largely believed to result from the inhibition of T-lymphocyte proliferation, a shift of cytokine response from an inflammatory response to an anti-inflammatory profile, and reduced migration of inflammatory cells across the blood–brain barrier ⁵. Interferon beta is available for MS handling in recombinant forms, as interferon beta-1a or interferon beta-1b. Interferon beta-1b is given as a dose of 250 μg subcutaneously every other 24-hour interval; interferon beta-1a is given as a dose of thirty μg intramuscularly once weekly or subcutaneously at doses of 22 or 44 μg three times a calendar week.

Phase III trials of all the interferon beta preparations take shown benign effects in reducing the annualized relapse rate (ARR) by about 30%–34%, reducing the progression of disability in RRMS likewise as magnetic resonance imaging (MRI) disease activity ^{6 – 9}. A recent report on peginterferon beta-1a, given in one case every 2 weeks, found comparable results, with a reduction in ARR at 36% ^x. Studies of all interferon beta preparations ^{11 – 14} accept likewise reported a reduced gamble of new illness activity amongst people with clinically isolated syndrome (CIS), every bit shown past a significantly prolonged time to a 2nd relapse and reduction in new MRI lesions, in some cases too a delayed progression of disability. All the interferon beta preparations have been evaluated in the treatment of SPMS. The first interferon beta-1b written report showed efficacy of the treatment equally measured past both relapse charge per unit and inability progression ¹⁵, just later studies of both interferon beta-1b and interferon beta-1a could only detect handling effects on the relapse rate ^{sixteen – 18}. Thus, information technology seems that only SPMS patients with superimposed relapses benefit from interferon beta handling ^{xv – xviii}. Interferons have non been documented to be effective in main progressive MS (PPMS) ¹⁹.

Well-nigh patients (50%–75%) experience flu-like symptoms, including muscle aches, fever, chills, headache and back pain, that usually announced 2–8 h afterwards an injection and resolve inside 24 h. Liver enzymes may be elevated and bone marrow function may be depressed, which warrants periodic surveillance of liver function and claret counts before starting therapy and every vi months thereafter ^{xi – fourteen}. Isolated cases of severe injection-site reactions involving infection or necrosis too as severe cases of acute liver failure and pancreatitis have been reported. Long-fourth dimension exposure to interferon beta does not seem to increase the risk of cancer ^{20 , 21} or infections.

Interferon beta treatment may induce formation of specific neutralizing antibodies (NABs). NAB germination is less likely during treatment with intramuscular interferon beta-1a ²². The NABs ordinarily announced within half-dozen–eighteen months of treatment, and evidence is accumulating that the efficacy of treatment is reduced in the presence of NABs. Accordingly, it is recommended to test all patients for the presence of NABs every 6 months during the first 2 years of therapy, and treatment should be switched in patients who are confirmed to exist NAB positive ²². In cases of clinically stable affliction, switches to other non-interferon first-line treatments are recommended, simply second-line handling should be considered in cases of quantum disease.

Glatiramer acetate

Glatiramer acetate is a puddle of synthetic peptides, resembling sequences of myelin basic protein, with an average length of 40–100 residues. The mechanisms of activeness have not been fully antiseptic just are probably largely related to anti-inflammatory effects past promoting Th2 difference under the development of Th2 glatiramer acetate reactive CD4+ T cells. These can accumulate in the primal nervous system (CNS) and promote eyewitness suppression by releasing anti-inflammatory cytokines ²³. Glatiramer acetate is administered as subcutaneous injections of twenty mg once a day.

Glatiramer acetate treatment trials in RRMS ²⁴ showed a meaning reduction in ARR (29%) and a reduction in gadolinium-enhanced MRI activity ²⁵. In a treatment trial of CIS with silent MRI lesions, glatiramer acetate treatment was found to significantly prolong time to a second relapse and to reduce the risk of new MRI lesions ²⁶. Glatiramer acetate has not been investigated for the treatment of SPMS and has non shown significant do good in PPMS patients ²⁷.

Glatiramer acetate is commonly well tolerated, just virtually patients (65%) feel injection-site reactions (hurting, erythema, swelling and pruritus). About 15% report a transient self-limited systemic reaction (immediately after injection) of facial flushing and chest tightness, accompanied at times past palpitation, anxiety and dyspnoea. Other reported side effects are lymphadenopathy, dyspnoea and lipoatrophy ^{24 – 26}. Lipoatrophy is permanent and is perhaps the most severe side effect. At that place have non been reports of increased cancer risk or increased risk of infections with prolonged employ of glatiramer acetate.

Teriflunomide

Teriflunomide is an immunomodulatory amanuensis that selectively and reversibly inhibits the mitochondrial enzyme dihydroorotate dehydrogenase, required for de novo pyrimidine synthesis. This leads to reduced proliferation of dividing cells that demand de novo synthesis of pyrimidine to expand. The therapeutic effect in MS is non fully understood but it is probably mediated by a reduced number of circulating lymphocytes ²⁸. Teriflunomide is administered as tablets, xiv mg once daily.

2 phase 3 trials in RRMS ^{29 , 30} showed that teriflunomide 14 mg once daily, compared to placebo, reduced the ARR by 31%–36%, the charge per unit of inability progression by 26%–27% and MRI gadolinium-enhancing lesions by about 80%. Some other stage Three trial of teriflunomide 14 mg once daily, compared to interferon beta-1a 44 μg subcutaneously three times weekly, showed similar furnishings on the ARR (0.26 and 0.22 respectively) and on time to a new relapse or termination of handling ³¹. Teriflunomide 14 mg once daily has been tested in a randomized, double-bullheaded, placebo-controlled trial of CIS patients with silent MRI lesions. Teriflunomide treatment was associated with significantly prolonged time to a 2d relapse and a reduction in new MRI lesions ³². Teriflunomide has not been studied for the handling of progressive MS.

Common adverse events include upper respiratory tract infection, urinary tract infection, paraesthesia, diarrhoea, nausea, hair thinning, alanine aminotransferase increase, reduction in claret leucocytes and increase in blood pressure ^{29 , thirty}. Relatively frequent (every second week) alanine aminotransferase screening during the first half dozen months of treatment is recommended and thereafter every second month ^{29 , thirty}. Teriflunomide treatment should be stopped if liver transaminase levels increase three times in a higher place upper normal levels. Regular measurements of claret pressure, white blood cells and platelet counts are also recommended. Teriflunomide has a long half-life. Elimination with cholestyramine or activated charcoal for eleven days tin can accelerate teriflunomide elimination, leading to more than than 98% subtract in teriflunomide plasma concentrations. Liver function needs to be carefully monitored during teriflunomide treatment, and discontinuation of therapy should be considered if a serum transaminase increase more than than three times the upper normal level is confirmed. Rare cases of pancytopenia have been reported with the utilize of leflunomide; this should also lead to treatment termination.

Dimethyl fumarate

Dimethyl fumarate is an immunomodulatory amanuensis with anti-inflammatory backdrop, but the mechanism of action in MS is just partially understood. Pre-clinical studies bespeak that dimethyl fumarate responses are primarily mediated through activation of the nuclear factor (erythroid-derived 2)-like ii (Nrf2) transcriptional pathway. Dimethyl fumarate has also been shown to upregulate Nrf2-dependent antioxidant genes in patients ³³. Dimethyl fumarate is administered as a 240 mg capsule twice daily.

2 phase Iii trials of RRMS ^{34 , 35} showed that dimethyl fumarate 240 mg twice daily, compared to placebo, reduced the ARR past 44%–53%, the charge per unit of disability progression by 22%–32% and MRI gadolinium-enhancing lesions by near 75%–94%. Compared to glatiramer acetate every bit an active comparator in i of the trials ³⁵, dimethyl fumarate 240 mg twice daily reduced the ARR by 24% and the rate of disability progression by 17%. These differences were not pregnant and the study was not powered to observe statistically significant differences in treatment outcome. The number of new and enlarging MRI T2 lesions was significantly reduced past about 36%. Dimethyl fumarate has not been studied for the treatment of CIS or progressive MS.

Mutual adverse events include flushing, nausea, diarrhoea and abdominal hurting ^{34 , 35}. The handling may also reduce white blood cell counts and requite elevations of hepatic transaminases; regular blood tests are therefore recommended ^{34 , 35}. Dimethyl fumarate should be stopped if liver transaminase levels increase iii times above upper normal levels. Recently, a case of John Cunningham virus (JCV) induced progressive multifocal leucoencephalopathy (PML) was reported in a patient who had received dimethyl fumarate ³⁶. An additional four PML cases have been previously reported in psoriasis patients who had received fumaderm ³⁷. Prolonged severe lymphopaenia (<500 cells per cubic millimetre) that persists for more than 6 months has been suggested every bit a gamble factor for PML. In the case of persistent lymphopaenia, dimethyl fumarate should exist terminated in JCV-positive patients.

Second-line medications

Fingolimod

Fingolimod is an oral sphingosine 1-phosphate receptor (S1PR) modulator that subsequent to its phosphorylation binds with high affinity to S1PR, which in turn leads to an internalization and degradation of the receptor in unlike tissues and prison cell types, including lymphocytes. As a consequence, fingolimod inhibits the power of autoreactive lymphocytes to egress from the lymph nodes towards the CNS. Fingolimod 0.5 mg capsules are given orally once daily ³⁸.

Ii phase Three trials in RRMS ^{38 , 39} showed that fingolimod 0.v mg one time daily, compared to placebo, reduced the ARR by 48%–55%, the rate of disability progression past 25%–30% and MRI gadolinium-enhancing lesions by more than than eighty%. Another study comparing fingolimod 0.5 mg one time daily to interferon beta-1a 30 μg intramuscularly one time weekly showed a reduced ARR by 52%, a reduced charge per unit of disability progression by 25% and a reduced number of MRI gadolinium-enhancing lesions by more than than fifty% amongst those who received fingolimod ^twoscore. Fingolimod is currently not documented to be effective confronting CIS, SPMS or PPMS.

Common adverse events include upper respiratory tract infection, headache, coughing, diarrhoea and back pain ^{38 , 39}. Fingolimod may also crusade a transient bradycardia and atrioventricular block. It is therefore recommended to monitor patients continuously with an electrocardiogram for six h after the first dose, and to extend the monitoring of patients who develop specific clinically relevant signs of heart arrhythmia (http://www.fda.gov/Drugs/DrugSafety/ucm303192.htm). More often than not, fingolimod should not be used by patients with known cardiac arrhythmias or patients using other medications known to induce bradycardia. Rare adverse events of elevated liver enzymes and macular oedema may occur, and regular claret sampling and a routine eye examination later on 3 months of treatment are therefore recommended. Ane decease due to a fulminant primary varicella zoster infection was reported in one of the phase Three trials ^twoscore. Therefore a blood sample for screening of previous varicella zoster infection is advised, and in the example of a negative screening test vaccination is recommended prior to treatment initiation.

Natalizumab

Natalizumab is a monoclonal antibody against α4-integrin, blocking the interaction with its ligands. The machinery of action is largely through preventing adherence of activated leucocytes to inflamed endothelium, thus inhibiting the migration of inflammatory cells into the CNS. Natalizumab is administered as a 300 mg intravenous infusion every iv weeks ⁴¹.

The pivotal phase III trial of RRMS showed that natalizumab monotherapy reduced the ARR by 68%, the rate of disability progression by 54% and MRI gadolinium-enhancing lesions by more than than 90% compared to placebo ⁴¹. Another written report ⁴² constitute that treatment with natalizumab added to interferon beta-1a was significantly more effective than interferon beta-1a alone in reducing ARR, new T2 lesions and disability progression. Natalizumab is currently not documented to be effective against CIS, SPMS or PPMS.

Although natalizumab is more often than not well tolerated, the treatment is associated with an increased run a risk of developing PML ⁴³. This is a potentially life-threatening CNS infection of oligodendrocytes by the JCV. Therefore all patients receiving natalizumab should be screened for previous JCV infection. The risk for PML in JCV-negative patients is low (<0.09/thou) and is probably associated with recent seroconversion (estimated as 2%–3% each year) or a false negative test. Amongst the JCV-positive patients the take chances of developing PML is influenced by treatment duration and previous immunosuppressive handling. The chance is relatively depression during the start 2 years of treatment and increases thereafter. The highest run a risk is found amongst JCV-positive patients who previously have too received immunosuppressive treatment after 2 years of handling (∼1/60) ⁴⁴. Anti-JCV antibody levels seem besides to differentiate PML risk in anti-JCV antibody positive patients with no prior immunosuppressant utilise ⁴⁵. Equally a general rule, it is recommended that JCV-positive patients who take been treated with natalizumab for more than 2 years should be switched to another 2d-line therapy. Based on current cognition, a washout time of 8 weeks seems to reduce the risk of rebound effect compared to longer washout periods. In the case of a depression JCV index (<i.5), natalizumab treatment may in some cases be continued after thorough information is given to the patient and under careful evaluation for new symptoms that may stand for PML ⁴⁴. Three-monthly JCV alphabetize evaluation and MR examination is then recommended. It is recommended to retest JCV-negative patients every 6 months and JCV-positive patients should be carefully informed about the risk for PML at handling initiation and after 2 years of handling.

Natalizumab treatment may induce an immune response, with the formation of persistent NABs (∼4%–half dozen%) confronting the preparation. NABs ordinarily appear within the first 12 months of handling, reduce the efficacy of the handling and are associated with higher rates of infusion-related adverse events. Accordingly, patients should be tested for NABs at 6 and 12 months of therapy and after for infusion-related agin events or treatment failure. NABs tin can occur transiently and positive findings should therefore exist confirmed within 3 months before deciding to switch therapy. Testing can be discontinued in patients who remain NAB negative during the first year of therapy.

Alemtuzumab

Alemtuzumab is a recombinant, humanized monoclonal antibiotic directed against CD52, a jail cell surface antigen present at high levels on especially T and B lymphocytes. Alemtuzumab acts through antibody-dependent cellular cytolysis and complement-mediated lysis following prison cell surface bounden. The mechanism by which alemtuzumab exerts its therapeutic effects in MS is suggested to be by a depletion and repopulation of lymphocytes that reduces the potential for relapses and thereby delays disease progression ⁴⁶. Alemtuzumab is administered by intravenous infusion for 2 handling courses. The initial handling course is 12 mg/solar day for v consecutive days (60 mg full dose), and the 2d handling course is 12 mg/day for three consecutive days (36 mg full dose) administered 12 months afterwards the initial treatment course. Boosted courses may exist given 12 months later the latest treatment course if necessary. Based on the European Medicines Bureau (EMA) licence alemtuzumab has indication every bit a first-line medication in agile RRMS. Because the treatment increases the chance of secondary autoimmunity, most European neurologists would utilize this drug as a second-line grooming, yet.

Two phase III trials of RRMS accept shown that alemtuzumab 12, compared to interferon beta-1a 44 μg administered subcutaneously iii times weekly, reduced the ARR by 49%–55%, the charge per unit of disability progression by 30%–42% and MRI gadolinium-enhancing lesions by 61%–63% ^{47 , 48}. Alemtuzumab has currently non been studied in patients with CIS or PPMS and has not been demonstrated to be effective in SPMS ^{49 , 50}.

Patients usually experience infusion-associated reactions including flushing, nausea, headache, tachycardia, urticaria, rash, pruritus, pyrexia and fatigue ^{47 – 50}. Oral antiviral prophylaxis with aciclovir 200 mg twice daily (or equivalent) should be administered and continued for a minimum of i month afterward the last dose. Alemtuzumab treatment is associated with increased risk of upper respiratory tract infection and urinary tract infection. Alemtuzumab treatment may also consequence in the formation of autoantibodies and increased adventure of autoimmune-mediated weather condition (occurring a median of 32 months after the first treatment), including thyroid disorders (41%), immune thrombocytopenic purpura (3.5%) or, rarely, nephropathies (due east.g. anti-glomerular basement membrane disease) (<ane%) ⁵¹. Based on the risk of autoimmune-mediated conditions, monthly blood and urine analyses are recommended for iv years subsequently the last dosing of alemtuzumab.

Mitoxantrone

Mitoxantrone is a synthetic anthracenedione derivative and is mostly used in treating various malignancies. It interacts with nuclear Deoxyribonucleic acid and is a potent immunosuppressive agent targeting proliferating allowed cells, inhibiting proliferation and inducing apoptosis of T lymphocytes, B lymphocytes, macrophages and other antigen-presenting cells.

Express efficacy information are bachelor, but controlled studies of highly active RRMS take shown significant efficacy of the handling, as shown by a 60%–70% reduction in the relapse rate (compared with placebo or intravenous methylprednisolone) every bit well as reduced inability progression and MRI disease action ^{52 , 53}. The largest phase 3 investigator-blinded written report randomized patients with worsening RRMS and SPMS for 5 or 12 mg of mitoxantrone per square metre of trunk surface or placebo every iii months for 2 years ⁵⁴. The treatment showed a 66% reduction in the ARR in the high-dose arm compared with placebo, and reduced disability progression and MRI disease activeness. Mitoxantrone has not been included in treatment trials of patients with CIS or PPMS.

Side effects such equally transient nausea, fatigue, mild hair loss (for days to a calendar week) and menstrual disturbances are frequent (lx%–70%) ⁵⁴. Additional side effects are urinary tract infection (about xxx%) as well as elevated liver enzymes and leucopenia (about 15%–20%). Mitoxantrone-induced amenorrhoea and acute promyelocytic leukaemia take likewise been reported. The treatment induces transient leucopenia, with a nadir later on almost 10 days, and thus follow-up blood command is needed. Although not in the phase Iii trial, lethal congestive heart failure and therapy-related leukaemia take been reported, even years later on treatment ends ^{55 , 56}. Due to the potential cardiotoxicity, the maximum cumulative dose is restricted to 120–140 mg/yard² of torso surface, and echocardiograms should be done earlier, during and after treatment. Mitoxantrone is teratogenic and is absolutely contraindicated in pregnancy. The apply of mitoxantrone has rapidly decreased due to the risk of astringent complications and the increasing number of alternative highly effective and less toxic treatment options.

Suggested handling strategies

Individualized therapy is advocated; the ideal treatment option would be the safest treatment that eliminates clinical and radiological evidence of disease action ³. Most patients would start on a first-line therapy only then be inverse quickly to a 2nd-line medication in the case of quantum disease activity (Fig. ​ one). Testify of clinical disease activity (relapses and/or accumulating inability) with or without new MRI lesions is in general accepted as an indication for switching to more potent 2nd-line therapies. In this context, models like the Rio or modified Rio score ⁵⁷ have been increasingly accepted every bit a tool to monitor the handling issue. The score is based on evaluation of treatment response by the combination of clinical (relapse and disability progression) and MRI disease activity (Rio score) or relapse and MRI affliction activeness only (modified Rio score) during the first twelvemonth of interferon treatment. Increasing evidence indicates that patients experiencing a new clinical relapse with significant influence on disability and/or new signs of radiological disease activity (≥3 active MRI lesions) during the concluding year, whilst on outset-line medications, should be considered for switching to more than potent medications ^{58 , 59}.

Treatment algorithm for handling-naïve patients with RRMS. *Patients with quickly evolving severe RRMS should first directly on a second-line therapy. Breakthrough illness action is defined as one new clinical relapse with meaning influence on disability and/or new signs of radiological disease activity (≥3 active MRI lesions) during the terminal year whilst on commencement-line medication.

Another possible treatment strategy is induction handling, which consists of early on apply of immunosuppressive medications followed by long-term maintenance therapy ^sixty. This treatment government has been used with success for patients with aggressive RRMS, using mitoxantrone ⁶¹. The use of mitoxantrone is declining because of its long-term safety profile. Alemtuzumab is approved as a first-line therapy, and could besides be considered an consecration treatment because of its long-term effects on the immune arrangement. This could be an attractive handling selection for patients with a highly active disease course, as 70.1% of the alemtuzumab-treated patients in the Intendance-MS written report remained costless of new lesions and MRI activity in year four, despite most receiving their last treatment course 3 years prior ⁶².

Choosing amongst the beginning-line medications

The main findings from the pivotal and phase 3 studies performed are given in Tables ​ i and ​ 2. Although the placebo-controlled trials indicate numerically college efficacy on ARR from dimethyl fumarate (about 44%–53%) compared to the other outset-line preparations (about xxx%–35%), information on direct comparisons of the agents are limited. Head-to-head comparison between dimethyl fumarate and glatiramer acetate indicated numerically (although not statistically significant) better event from dimethyl fumarate ³⁵. Head-to-head comparison between teriflunomide and high-frequency interferon beta-1a showed comparable effects on the ARR ²⁹. Head-to-caput comparisons between intramuscular depression-dose and low-frequency interferon beta-1a and subcutaneous high-dose and loftier-frequency interferon beta-1a and interferon beta-1b take shown that loftier-dose and high-frequency interferon beta regimens have short-term benefits on the relapse charge per unit and MRI activity ^{63 , 64}. Limitations in the blueprint of these studies have been widely discussed, however, and the long-term differences in efficacy may be reduced by a significantly lower frequency of NAB germination with low-dose and low-frequency interferon beta-1a. Caput-to-head comparisons of glatiramer acetate and subcutaneous loftier-dose and high-frequency interferon beta-1a and interferon beta-1b have shown similar clinical benefit from the treatments, with some MRI parameters in favour of the interferon beta preparations ^{65 , 66}.

Table 1

Randomized placebo-controlled stage III clinical trials of the canonical relapsing−remitting multiple sclerosis medications

Medication	N	Trial name (reference)	ARR		Disability progression
			Relative reduction	ARR	Relative reduction	EDSS progression
First-line
Interferon beta-1b	124 vs. 123	MSSG 6	34%	0.84 vs. 1.27	29% (Due north.S.)	0.20 vs. 0.28
Interferon beta-1a i.chiliad.	158 vs. 143	MSCRG seven	18%	0.67 vs. 0.82	37%	0.22a vs. 0.35a
Interferon beta-1a s.c.	184 vs. 187	PRISMS eight	32%	1.73 vs. 2.56	32%	0.26 vs. 0.38
Peginterferon-1a	500 vs. 512	Advance 10	36%	0.26 vs. 0.40	36%	0.07 vs. 0.11
Glatiramer acetate	125 vs. 126	CMSSG 24	29%	ane.19 vs. 1.68	12% (Due north.Southward.)	0.22 vs. 0.25
Teriflunomide	358 vs. 363	TEMSO 29	31%	0.37 vs. 0.54	26%	0.20 vs. 0.27
Teriflunomide	370 vs. 388	TOWER xxx	36%	0.32 vs. 0.50	24%	0.sixteen vs. 0.21
Dimethyl fumarate	410 vs. 408	Define 34	53%	0.17 vs. 0.36	41%	0.xvi vs. 0.27
Dimethyl fumarate	359 vs. 363	CONFIRM 35	44%	0.22 vs. 0.40	24% (North.S.)	0.13 vs. 0.17
Second-line
Fingolimod	425 vs. 418	FREEDOMS 38	55%	0.18 vs. 0.40	28%	0.18 vs. 0.25
Fingolimod	358 vs. 355	FREEDOMS-two 39	48%	0.21 vs. 0.40	xiv% (N.S.)	0.25 vs. 0.29
Natalizumab	627 vs. 315	Affirm 41	68%	0.23 vs. 0.73	42%	0.17 vs. 0.29
Mitoxantroneb	lx vs. 64	MIMS 54	66%	0.35 vs. ane.02	64%	0.08 vs. 0.22

Table 2

Randomized controlled phase Three clinical trials of the canonical relapsing−remitting multiple sclerosis medications, where the medications have been compared head-to-caput with another active multiple sclerosis medication

Medication	Compared to	Northward	Trial proper noun (reference)	ARR		Disability progression
				Relative reduction	ARR	Relative reduction	EDSS progression
Get-go-line
Interferon beta-1b	Interferon beta-1a i.m.	92 vs. 96	INCOMIN 63	24%	0.v vs. 0.7	44%	0.xiii vs. 0.30
Interferon-beta-1a s.c.	Interferon-beta-1a i.m.	339 vs. 338	EVIDENCE 64	xvi%a	0.54 vs. 0.64	xiii% (N.S.)	0.xiii vs. 0.15
Interferon beta-1a s.c.	Glatiramer acetate	386 vs. 378	REGARD 65	3% (Due north.S)	0.30 vs. 0.29	25% (N.S.)	0.12 vs. 0.09
Interferon-beta-1b	Glatiramer acetate	899 vs. 448	BEYOND 66	3% (N.S)	0.33 vs. 0.34	5% (Due north.Southward.)	0.22 vs. 0.xx
Teriflunomide	Interferon-beta 1a southward.c.	111 vs. 104	TENERE 31	four% (N.S)	0.26 vs. 0.22	-	-
Dimethyl fumarate	Glatiramer acetate	359 vs. 350	CONFIRM 35	24% (N.S)	0.22 vs. 0.29	17% (N.Southward.)	0.13 vs. 0.16
Second-line
Fingolimod	Interferon beta-1a i.m.	431 vs. 435	TRANSFORMS 40	52%a	0.16 vs. 0.33	25% (N.Due south.)	0.06 vs. 0.08
Alemtuzumab	Interferon beta-1a south.c.	376 vs. 202	CARE MS-one 47	55%	0.18 vs. 0.39	thirty% (N.S.)	0.08b vs. 0.11b
Alemtuzumab	Interferon beta-1a s.c.	426 vs. 202	Intendance MS-2 48	49%	0.26 vs. 0.52	42%	0.13b vs. 0.21b

Disease-modifying handling for MS is a long-lasting therapy for most patients. Adherence to treatment is thus crucial, and many patients may therefore adopt oral treatment. Consequently starting with an oral first-line drug is suggested. In the example of intolerability or unacceptable side effects, switching between the oral preparations or with 1 of the injectable preparations should exist considered. The injectable medications take been used for a longer period than the oral medications, and more long-term safety data are therefore available ^{20 , 21}. Similarly, there are more long-term prophylactic data on pregnancies occurring during treatments with both glatiramer acetate and interferons, pointing to a relative safety of utilize ⁶⁷. These could be good reasons for still choosing an injectable medication as beginning-line treatment. Information technology is of import to continuously evaluate the treatment regimen, aiming for optimal adherence, because both the administration form and side-effect profiles.

Choosing amidst the 2nd-line medications

In the case of breakthrough disease activity despite a full and adequate grade of a first-line training, switching to natalizumab, fingolimod or alemtuzumab should be considered. Although alemtuzumab is licensed as a first-line medication in active RRMS, many European neurologists would use this drug as a second-line preparation, due to potential side furnishings. Second-line therapy should also be considered in the case of patients with rapidly evolving severe RRMS defined by two or more disabling relapses in 1 year, and with gadolinium-enhancing lesions on brain MRI or a meaning increase in T2 lesion load compared to a previous recent MRI. Careful risk stratification for potential adverse effects is important, and most neurologists would prefer fingolimod or alemtuzumab for patients who are JCV positive. Similarly, in the instance of contraindications for fingolimod or alemtuzumab, ane of the other second-line treatment options should be considered. The use of mitoxantrone has become less frequent due to the relatively high adventure of serious side effects, and may only exist used in some cases of SPMS. Stratification for differences in clinical issue is hard due to the lack of treatment studies with head-to-head comparisons of second-line therapies. Some neurologists would prefer natalizumab for JCV-negative patients due to the numerically college reduction of ARR in pivotal trials, although treatment effect cannot be direct compared between different study populations.

For a small grouping of patients who do not reply to the approved 2nd-line treatments, off-label treatments like rituximab ⁶⁸ or ofatumumab ⁶⁹ or experimental therapy with autologous haematopoietic stalk cell transplantation ⁷⁰ may be considered. These treatment options have currently non been tested in large phase 3 trials, but phase II trials or instance series reports have shown promising results. These treatment options besides seem to exist effective against RRMS and non the progressive forms of the illness ⁷¹.

Conclusions and future challenges

Although the last decade has shown a revolution in treatment options for patients with MS, this has mainly benefited newly diagnosed patients with an RRMS disease class. None of the approved medications or experimental therapies has shown convincing evidence of slowing down or preventing disease progression in patients with SPMS or PPMS. Thus there is an urgent demand to also amend the handling options for patients who take entered a progressive phase.

Disclosure of conflicts of involvement

Ø. Torkildsen has participated on a scientific advisory board for Biogen Idec, Merck-Serono and Genzyme and received speaker honoraria and travel grants from Genzyme, Merck-Serono, Novartis and Biogen Idec. G.-Chiliad. Myhr has participated on scientific informational boards for Novartis Norway, Biogen Idec and Genzyme; received funding for travel from Bayer, Novartis, Merck-Serono and Biogen Idec; received speaker honoraria from Bayer, Genzyme, Sanofi-Aventis, Novartis, Merck-Serono and Biogen Idec; and received unrestricted research back up from Bayer, Sanofi-Aventis, Novartis, Merck-Serono, Biogen Idec, Pronova Biocare and the Norwegian MS Social club. 50. Bø has participated on scientific advisory boards for Novartis Norway; received funding for travel from Sanofi-Aventis, Novartis, Merck-Serono and Biogen Idec; received speaker honoraria from Bayer, Genzyme, Sanofi-Aventis, Novartis, Merck-Serono and Biogen Idec; and received unrestricted research support from Bayer, Sanofi-Aventis, Novartis, Merck-Serono and Biogen Idec.

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Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4670697/