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Current immunotherapies for multiple sclerosis and neuromyelitis optica spectrum disorders: the similarities and differences

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Neurosciences 2019;6:8.
10.20517/2347-8659.2019.06 |  © The Author(s) 2019.
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Abstract

Multiple sclerosis (MS) and neuromyelitis optica spectrum disorders (NMOSD) are autoimmune demyelinating diseases of the central nervous system. Neuromyelitis optica was considered a variant of MS until the discovery of NMO-IgG in 2004, which changed our understanding of the pathophysiology of NMOSD. This review focuses on the similarities and differences in the immune treatments of MS and NMOSD.

Keywords

Multiple sclerosis, neuromyelitis optica spectrum disorders, pathophysiology, treatment, disease-modifying drugs

Introduction

Multiple sclerosis (MS) and neuromyelitis optica spectrum disorders (NMOSD) are chronic immune-mediated demyelinating diseases of the central nervous system (CNS) with distinct immunological and pathological features[1-3]. MS is common in Western countries (incidence, > 100 per 100,000 in the European and North American populations), where it is the most common non-traumatic disabling disease among young people. However, MS is not common in Asia (incidence, 0-20 per 100,000 in Asian populations)[4]. Interestingly, the farther away one goes from the equator, the higher is the prevalence of MS[5]. MS generally progresses from a period of relapses and remissions to progressive disability. The pathogenetic mechanism underlying MS is an autoimmune reaction to myelin or oligodendrocytes, but no MS-specific autoantigen has been identified.

NMO/NMOSD typically manifest as optic neuritis and longitudinally extensive transverse myelitis, and can lead to severe disability. The prevalence of NMOSD rarely exceeds 5/100,000, and is comparatively similar globally[4]. In 2004, Lennon et al.[6] discovered NMO autoantibodies, which clearly differentiated NMO from MS. Up to 80% of NMO patients test positive for antibodies against aquaporin4 (AQP4), which is a water channel protein found in many organs of the body[7]. In the CNS, AQP4 is expressed in a perivascular distribution on astrocytic foot processes[6]. The distinctive immunopathology of NMO lesions supports a central role for AQP4-IgG in the pathogenesis of this disease. AQP4-IgG damages the blood-brain barrier (BBB) through complement-dependent astrocytic damage. AQP4-IgG-positive NMOSD is not a classic demyelinating disease as MS, marked by secondary demyelination due to astrocyte loss[8,9]. In addition to the optic nerve and spinal cord, areas of high AQP4 expression around the ventricles are often involved, such as the area postrema of the medulla oblongata, thalamus, peripheral area of the third and fourth ventricles, corpus callosum, and white matter of the cerebral hemisphere. The high specificity of AQP4-IgG extends the study of NMO and its related diseases. Previously, the diagnostic criteria for NMO required optic nerve and spinal cord involvement. In 2007, Wingerchuk proposed the concept of NMOSD[10]. In 2015, the International Panel for NMO Diagnosis removed the separate definition of NMO and integrated NMO into the broader term of NMOSD[11]. NMOSD are a class of antigen-antibody-mediated CNS inflammatory demyelinating diseases that are primarily mediated by humoral immunity, with or without AQP4 positivity[12].

Pathogenesis of MS and NMOSD

MS is considered a classic autoimmune disease mediated by autoreactive T-lymphocytes, specifically CD4+ T-helper (Th)1 cells and Th17 cells. Th1 cells produce interferon (IFN)-γ, while Th17 cells are a T-cell subgroup producing IFN-γ and interleukin (IL)-17[13,14]. Activated T-cells can express a variety of adhesion molecules that combine with receptors on the vessel wall. Furthermore, vascular endothelial cells express selectins that bind to T-cells, and chemokines can induce T-cells to enter the CNS. Additionally, T-cells secrete matrix metalloproteinases that degrade the collagen component of blood-vessel walls, destroying the BBB and facilitating the entry of T- and B-lymphocytes and monocytes into the brain. In the CNS, T-cells secrete inflammatory cytokines and chemokines, which cause the activation of other inflammatory cells, resulting in a series of complex cascades of immune responses that finally lead to damage to the myelin sheath and even axons[13-16]. IL-4 stimulates the differentiation of CD4+ T-cells into anti-inflammatory Th2 cells and inhibits Th1 and Th17 cells. IL-2 and transforming growth factor (TGF)-β stimulate the production of regulatory T cells, which can inhibit Th17, Th1, and CD8+ T-cells in the CNS[17]. Th1 cells can recognize major histocompatibility complex (MHC) class II molecules, cross the BBB, and induce CNS autoimmunity. And Th17 lymphocytes are capable of crossing the BBB, and their secretion damages the BBB and promotes the entry of other inflammatory cells into the CNS[18]. In recent years, it has been found that B-cells also play an important role in the pathogenesis of MS. In most MS patients, oligoclonal bands and B-cell clonal proliferation occur in the CSF, and B-cell proliferation and germinal-center formation may occur in the meningeal follicles[19].

NMOSD are humoral immune-mediated autoimmune diseases. B-lymphocytes secrete specific antibodies that bind to complement, then deposit and destroy AQP4, which is expressed on the surface of astrocytes. However, the role of B-cells in the pathogenesis of NMOSD may not be limited to the production of AQP4-IgG, and an imbalance between pro-inflammatory and anti-inflammatory B-cell functions may also be involved[20]. Other inflammatory cells such as macrophages, eosinophils, and neutrophils are then attracted towards the injured tissue and secrete inflammatory factors that cause myelin loss and axonal damage[21]. A study has shown that peripheral blood neutrophils show a primed phenotype in NMOSD[22]. In some NMOSD patients, antibodies against myelin-oligodendrocyte-glycoprotein (MOG) rather than AQP4 antibodies are detectable. The clinical features of MOG-IgG-positive NMOSD are different from those of the classic AQP4-IgG-positive NMOSD, and the underlying pathogenesis of the two conditions may also be different. MOG is a glycoprotein localized on the myelin surface as well as in the cell bodies and processes of oligodendrocytes. The MOG antibody is a subtype of IgG1, which is effective in regulating complement-dependent cytotoxicity. MOG antibodies target myelin-forming oligodendrocytes, whereas AQP4 antibodies damage astrocytes leading to secondary demyelination[23,24]. In terms of clinical features, MOG-IgG-positive NMOSD tends to be monophasic, more common among men, and have a younger onset age and a better prognosis[25]. At present, it is unclear whether CNS demyelinating diseases mediated by MOG antibodies should be independent of MS and NMOSD[26,27]. However, according to the revised NMOSD diagnostic criteria in 2015, AQP4-IgG positive or negative diseases and MOG-IgG positive diseases can be classified as NMOSD[11]. AQP4 antibodies and MOG antibodies are mainly produced extrathecally and are therefore less frequently found in the CSF than in the serum. AQP4 antibodies can be detected in the CSF in only 70% of patients who are seropositive for AQP4 antibodies and in none of the patients who are seronegative for AQP4 antibodies[28,29]. Furthermore, the levels of AQP4 and MOG antibodies may vary during the course of the disease. However, AQP4 antibody titers do not seem to predict long-term disease duration, and the serum AQP4 antibody status does not predict immunotherapy response[30,31].

Treatment of acute attacks

At present, there is no cure for MS and NMOSD. The primary goal of therapy in the acute phase is to alleviate symptoms, shorten the disease course, and prevent complications. Currently available treatments only act on the inflammatory components of the disease process, and no therapy that can directly reverse myelin loss or neuronal damage exists. As in other autoimmune diseases, the recommended management strategy for patients with MS or NMOSD during the acute phase includes intravenous methylprednisolone (IVMP) pulse therapy, plasma exchange (PE), and intravenous immunoglobulin (IVIG)[32,33]. The treatment of acute attacks shortens the duration of relapses and reduces symptoms, but does not have long-term neuroprotective effects[34,35]. IVMP is considered the standard treatment for acute attacks[36,37]. Mainly in patients with contraindications to IVMP or disease that is refractory to IVMP, PE and IVIG are alternative therapies. NMOSD lesions are associated with IgG, IgM, and complement deposition; all of these are targeted by PE, which has a good therapeutic effect in NMOSD[38]. Immunoadsorption (IA) can remove immunoglobulins from the circulation, and is an alternative treatment for acute attacks[39,40]. For severe attacks, PE and IA can be used as initial therapies[41]. IVIG is a safe and well-tolerated immunotherapy that could also be used as a treatment alternative for MS and NMOSD[42,43]. However, this recommendation is based mostly on clinical experience, because of a lack of trials on IVIG monotherapy in the treatment of acute attacks. Furthermore, IVIG probably confers no advantage over IVMP and PE[44]. For MS, IVIG is usually only used for patients with contraindications to IVMP and PE, as the efficacy of IVIG is uncertain. NMOSD are humoral-mediated diseases, and therefore, therapeutic agents that inhibit B-cells or antibody production may be effective[45]. IVIG can reduce anti-AQP4 levels[46]; however, the efficacy of IVIG for acute attacks still needs to be proven.

Corticosteroids are an important therapy in the acute phase of relapse. High-dose methylprednisolone (0.5-1.0 g intravenously for 3-5 days) is recommended in the acute phase. The mechanisms of action of IVMP include dampening the inflammatory cytokine cascade, inhibiting the activation of T-cells, decreasing the expression of MHC-II molecules on antigen-presenting cells and the entry of immune cells into the CNS, and facilitating the apoptosis of activated immune cells[47]. Some studies have shown that oral methylprednisolone is no worse than IVMP in terms of the clinical and radiological outcomes of MS relapses[48-51]. The European Federation of Neurological Societies guidelines recommend an oral methylprednisolone dose of at least 0.5 g/day for 5 days (cumulative dose, 2.5 g)[52]. Several studies have shown the safety of stopping a short course of high-dose corticosteroids without a tapering regimen[53,54]. In addition, one study showed that in MS, IVMP combined with low-dose oral hormones did not improve disability progression compared with IVMP alone[55]. However, low-dose oral corticosteroids may help prevent relapses in NMOSD[56]. In some patients with NMOSD, a rebound effect may occur if corticosteroids are stopped quickly. A study of 59 patients with relapsing MOG antibody-associated demyelination showed that most cases of relapse occurred within 2 months of prednisolone cessation and in patients who had been administered daily doses of < 10 mg[57]. Therefore, an oral weaning course of prednisolone over 2-6 months and long-term maintenance with low-dose oral prednisolone is recommended[58,59]. Compared with MS, NMOSD relapse is often more severe and less responsive to IVMP[60,61]. A retrospective study showed that IVMP has a significant effect on acute relapses in both MS and NMOSD patients, but the effects in MS were slightly better than those in NMOSD based on the changes in the Expanded Disability Status Scale score before and after IVMP[62].

PE can remove circulating autoantibodies, macromolecular immune complexes, inflammatory cytokines, and other mediators. It can also affect lymphocyte proliferation and activation[63]. Common side effects of PE include hypocalcemia, bleeding, and infections. When remission is absent or insufficient, PE every other day is recommended, with removal of 1-1.5 plasma volumes each time (30-40 mL/kg). A total of 5-7 treatments are recommended. Studies have found that the exchanged molecules will drop to less than 20% of their initial level after 5 exchanges[64,65]. In addition, IA is a more selective method that eliminates certain proteins, such as antibodies, while retaining other plasma proteins. The effects of IA and PE are comparable in the treatment of MS- or NMOSD-relapses[66]. Patients with a suboptimal response to methylprednisolone and those who present with severe symptoms should be treated with PE/IA. Some results support the use of PE in severe relapses of MS unresponsive to corticosteroids[67]. PE and IA can clear AQP4-IgG and are effective therapies for NMOSD. The results of a retrospective cohort study suggest early use of PE/IA in NMOSD attacks[68]. And no superiority was shown for one of the 2 apheresis techniques[68]. PE/IA combined with IVMP is more effective than IVMP alone in NMOSD[69,70]. In addition to steroids, it is recommended that PE/IA be started as soon as possible[71,72]. A study showed that the early initiation of PE (≤ 5 days) is more beneficial than delayed PE for cases that are refractory to IVMP[71].

IVIG is another important therapy that can affect a variety of immunomodulatory and antigenic-recognition pathways, including humoral and cellular immunity. It interacts with various subsets of B- and T-cells, modulates cytokines, scavenges complement, and blocks idiotypic antibodies[73]. Patients should be given IVIG at a dose of 0.4 g/kg/day for 5 days[74]. In MS, studies have shown that IVIG combined with IVMP is not superior to IVMP alone[75,76]. Few studies have assessed the efficacy of IVIG monotherapy for MS relapses. IVIG has a good effect in other humoral immune-mediated neuroimmunological diseases. IVIG may affect certain steps of pathological processes in NMOSD. Clinical experience suggests that this therapy may be of benefit in NMOSD patients[44]. A retrospective study with a small sample size has shown the efficacy of IVIG treatment for NMOSD relapses[43]. Furthermore, it has been shown that regular IVIG could prevent relapses in both MS and NMOSD[77-80].

Treatments in the remission period

In most instances, the initial course of MS consists of relapses and remissions, known as relapsing-remitting MS (RRMS), with disability progression over the course of the disease. Most patients eventually enter a secondary phase of progressive disease, i.e., secondary progressive MS (SPMS). In a few patients, the initial course is progressive with no relapsing-remitting phase; that is known as primary progressive MS (PPMS)[81]. The relationship between disability progression and relapses in MS is not yet clear. Unlike MS, in NMOSD, disability is the result of cumulative inflammatory damage caused by acute attacks[58]. The purpose of treatment during the remission period is reducing the risk of relapse and disability progression. In both MS and NMOSD, treatment during remission should be started as soon as possible[58,59,82,83]. Therapeutic drugs in the remission period include conventional immunosuppressants and some new immunomodulators as well as biological agents. The latest guidelines in the United States and Europe recommend disease-modifying drugs (DMDs) to regulate MS[82,83]. Most recommendations for NMOSD are still based on expert advice because of the lack of clinical evidence, as until recently, most studies reporting treatment outcomes were conducted in a non-random and often retrospective environment[84-86]. There exist differences in the mechanisms of action, routes of administration, and approved indications of different drugs. The various medications are presented in Table 1. Table 2 lists the results of some important trials.

Table 1

Disease-modifying drugs for multiple sclerosis and neuromyelitis optica spectrum disorders

DMDTrade name, available sinceDosageMechanism of actionClinical trials
IFN-β1bBetaseron, 1993
Extavia, 2009
250 μg, every other day, scReduces Th1 and Th17 production; promotes Th2 proliferation; regulates T-, B-, natural killer, and dendritic cells; blocks leukocyte migration to the central nervous system[99-101]RRMS[87-93], SPMS[94-96], PPMS[97,98]
IFN-β1aAvonex, 199630 μg, once a week, im
Rebif, 200222 or 44 μg, three times a week, sc
Pegylated IFN-β1aPlegridy, 2014125 μg, once 2 weeks, sc
GACopaxone, 199620 mg, once a day, sc
40 mg, 3 times a week, sc
Binds MHC class II; interferes with development of self-reactive proinflammatory T-cells; promotes Th2 proliferation; regulates various immune cells[102-104]RRMS[105-109],
PPMS[110]
MitoxantroneNovantrone, 200012 mg/m2, once every 3 months, ivInhibits type-II topoisomerase; disrupts DNA synthesisRRMS[111,112],
SPMS[113-115],
PPMS[114]
FingolimodGilenya, 20100.5 mg, once a day, poSphingosin-1 phosphate receptor agonist; induces lymphocytes to enter secondary lymphoid organs[116-118]RRMS[119-124], PPMS[125]
TeriflunomideAubagio, 20127 or 14 mg, once a day, poPrevents dihydroorotate dehydrogenase activation; suppresses activated T-lymphocyte proliferation[126,127]RRMS[128-131]
Dimethyl fumarateTecfidera, 2013240 mg, twice a day, poTh1-Th2 shift, lymphocyte apoptosis[132,133]RRMS[134-136]
NatalizumabTysabri, 2006300 mg, once every 4 weeks, ivInhibits α4-integrin; prevents activated CD4+ T-cells from crossing the blood-brain barrier[137-139]RRMS[140-145],
SPMS[146]
AlemtuzumabLemtrada, 201312 mg, once a day for 5 days, then for 3 days one year later, ivAnti-CD52; depletes CD52-positive lymphocytes[147]RRMS[148-150]
OcrelizumabOcrevus, 2017600 mg, every 6 months, ivAnti-CD20, depletes a large part of the B-cell lineagePPMS[151], RRMS[152,153]
CladribineMavenclad, 2017Cumulative doses: 3.5 mg/kg or 5.25 mg/kg, poSynthetic purine nucleoside analogue, disrupts DNA repair and synthesis, achieves therapeutic depletion of lymphocytesRRMS[154,155]
SiponimodMayzent, 20192 mg, once a day, poA new sphingosine 1-phosphate receptor modulator, depletes circulating lymphocytes, promotes CNS repair by modulating
S1P1 on astrocytes and S1P5 on oligodentrocytes[157]
SPMS[156]
RRMS[157,158]
RituximabMabthera 1997Two sessions of slow iv infusion of 1 g rituximab 14 days apart or 375 mg/m2 each week for 4 weeksAnti-CD20, attacks B-cells and plasmoblastsNMOSD[159],
RRMS[160,161],
PPMS[162]
Azathioprine2-3 mg/(kg·day), poInhibits purine nucleotide synthesis; activates mitochondrial apoptotic pathway; activated T-cell apoptosis[163,164]NMOSD[159,165,166], RRMS[167]
Mycophenolate mofetilCellCept1000-3000 mg/day, poBlocks guanine nucleotide production; inhibits lymphocyte proliferation[168,169]NMOSD[170-172]
Table 2

Clinical trials of multiple sclerosis and neuromyelitis optica spectrum disorders

DrugComparator  TrialDiseaseDurationSample sizeFindings
IFN-β1b[87]PlaceboRandomized, double-blindRRMS2 yearsn = 372,
1:1:1 ratio of placebo,
1.6 million IU, and 8 million IU
Annual exacerbation rate:
Placebo, 1.27; 1.6 million IU, 1.17; 8 million IU, 0.84
IFN-β1a[89]PlaceboRandomized,
phase III, double-blind
RRMS104 weeksn = 301,
1:1 ratio of placebo and
30 μg IFN-β1a
Annual exacerbation rate:
Placebo, 0.9; interferon β-1a 0.61;
Patients with disability progression:
Placebo, 34.9%; IFN-β1a, 21.9%
PegIFN-β1a, ADVANCE trial[93]PlaceboRandomized,
phase III, double-blind
RRMS2 yearsPlacebo (n = 500),
PegIFN every 2 weeks (n = 512),
PegIFN every 4 weeks (n = 500)
Annual relapse rate:
Placebo, 0.397 (95%CI: 0.328-0.481);
PegIFN every 2 weeks, 0.256 (95%CI: 0.206-0.318);
PegIFN every 4 weeks, 0.288 (95%CI: 0.234-0.355)
GA[105]PlaceboRandomized,
phase III, double-blind
RRMS2 yearsGA (n = 125),
placebo (n = 126)
Annual relapse rate:
Placebo, 0.84; GA, 0.59
GA[109]PlaceboRandomized, double-blindRRMS1 yearGA (n = 943),
placebo (n = 461)
Annual relapse rate:
Placebo, 0.505; GA, 0.331
Teriflunomide, TOWER trial[128]PlaceboRandomized,
phase III, double-blind
RRMS48 weeksPlacebo (n = 388),
7 mg (n = 407),
14 mg (n = 370)
Annual relapse rate:
Placebo, 0.50 (95%CI: 0.43-0.58);
7 mg, 0.39 (95%CI: 0.33-0.46);
14 mg, 0.32
(95%CI: 0.27-0.38)
No effect on sustained accumulation of disability (7 mg)
(HR: 0.95, 95%CI: 0.68-1.35)
Teriflunomide, TEMSO[129]PlaceboRandomized trialRRMS108 weeksn = 1088
1:1:1 ratio of placebo, 7 mg, and 14 mg
Annual relapse rate:
Placebo, 0.54; 7 mg, 0.37;
14 mg, 0.37
Patients with confirmed disability progression:
Placebo, 27.3%; 7 mg, 21.7%; 14 mg, 20.2%
DMF[135]Placebo,
GA
Randomized,
phase III, double-blind
RRMS96 weeksPlacebo (n = 363)
Twice-daily DMF (n = 359), Thrice-daily DMF (n = 345),
GA (n = 350)
Annual relapse rate:
Placebo, 0.40; Twice-daily DMF, 0.22;
Thrice-daily DMF, 0.20; GA, 0.29
Fewer new or enlarging hyperintense lesions on T2-weighted images (P < 0.001)
DMF[134]PlaceboRandomized,
phase III, double-blind
RRMS2 yearsPlacebo
(n = 408),
Twice-daily DMF (n = 410), Thrice-daily DMF (n = 416)
Annual relapse rate:
Placebo, 0.36; Twice-daily DMF, 0.17;
Thrice-daily DMF, 0.19
Confirmed disability progression:
Placebo, 27%; Twice-daily DMF, 16%;
Thrice-daily DMF, 18%
Fingolimod, FREEDOMS II trial[120]PlaceboRandomized,
phase III, double-blind
RRMS24 monthsPlacebo (n = 355),
0.5 mg (n = 358),
Annual relapse rate:
Placebo, 0.40 (95%CI: 0.34-0.48); 0.5 mg, 0.21 (95%CI: 0.17-0.25);
Percentage brain volume change:
Placebo, -1.28 (SD, 1.50);
0.5 mg, -0.86 (SD, 1.22)
Fingolimod[119]PlaceboRandomized,
phase III, double-blind
RRMS24 monthsPlacebo (n = 355),
0.5 mg (n = 358),
1.25 mg (n = 370)
Annual relapse rate:
Placebo, 0.40; 0.5 mg, 0.18; 1.25 mg 0.16
Cumulative probability of disability progression (confirmed after 3 months):
Placebo, 24.1%; 0.5 mg, 17.7%; 1.25 mg, 16.6%
Cladribine,
CLARITY study[154]
PlaceboRandomized, phase III, double-blindRRMS96 weeksPlacebo (n = 437),
3.5 mg/kg (n = 433),
5.25 mg/kg (n = 456)
Annual relapse rate:
Placebo, 0.33; 3.5 mg/kg, 0.14; 5.25 mg/kg, 0.13
Natalizumab,
AFFIRM trial[140]
PlaceboRandomized,
phase III, double-blind
RRMS2 yearsPlacebo (n = 627),
Natalizumab (n = 315)
Cumulative probability of progression:
Placebo, 29%; Natalizumab, 17%
Rate of relapse at 1 year reduced by 68%
Alemtuzumab[148]IFN-β1aRandomized,
phase III, double-blind
RRMS2 yearsIFN-β1a (n = 231)
Alemtuzumab (12mg) (n = 436)
Patients with relapse:
IFN-β1a, 51%; Alemtuzumab, 35%
Cumulative disability:
IFN-β1a, 20%; Alemtuzumab, 13%
Ocrelizumab[151]PlaceboRandomized,
phase III, double-blind
PPMS120 weeksPlacebo (n = 244),
Ocrelizumab (n = 488)
Worse performance on timed 25-foot walk:
Placebo, 55.1%; Ocrelizumab, 38.9%
Siponimod[156]PlaceboRandomized,
phase III, double-blind
SPMS3 yearsPlacebo (n = 546),
Siponimod (n = 1099)
Patients with 3-month confirmed disability progression:
Placebo, 32%; Siponimod,
26%
Rituximab[161]SelfPhase IIRRMS52 weeksn = 30Median GdE lesions reduced from 1.0 to 0;
MSFC improved (P = 0.02)
Rituximab[162]PlaceboRandomized, double-blindPPMS96 weeksPlacebo (n = 147),
Rituximab (n = 292)
Patients with CDP:
Placebo, 38.5%; Rituximab, 30.2% (P = 0.14)
Mean (SD) T2 volume change:
Placebo, 2,205 (4306); Rituximab, 1,507 (3739)
Rituximab[159]AZARandomized clinical trialNMOSD12 monthsRituximab (n = 33),
AZA (n = 35)
Decreased annual relapse rate:
Rituximab, 1.09; AZA, 0.49
Relapse-free disease:
Rituximab, 78.8%; AZA, 54.3%
AZA[167]IFN-βRandomized,
phase III, single-blind
RRMS2 yearsAZA (n = 77),
IFN-β (n = 73)
Annual relapse rate:
AZA, 0.26; IFN-β, 0.39
Annualized new T2 lesion rate:
AZA, 0.76; IFN-β, 0.69

Attack prevention in MS

The pathogenesis of MS includes focal inflammatory demyelination and axonal loss. The available DMDs are mainly beneficial for controlling inflammation and have a poor effect on the degenerative component of the disease[173]. Since the first DMD, IFN-β1b became available in 1993, the US Food and Drug Administration has approved more than a dozen DMDs for MS: IFN-β1b, IFN-β1a, glatiramer acetate (GA), mitoxantrone, natalizumab, fingolimod, teriflunomide, dimethyl fumarate (DMF), alemtuzumab, pegylated IFN-β1a, daclizumab, ocrelizumab, cladribine and siponimod. The mechanisms of action of these DMDs have been depicted in [Figure 1].

Current immunotherapies for multiple sclerosis and neuromyelitis optica spectrum disorders: the similarities and differences

Figure 1. Pathogenesis of multiple sclerosis and targets of drug action. ➀ Reduced production of Th1 and Th17 cells and Th1-Th2 shift (interferon-β, teriflunomide, dimethyl fumarate); ➁ Competitive binding of MHC class II molecules (glatiramer acetate); ➂ Depletion of CD20-positive lymphocytes (ocrelizumab, rituximab); ➃ Regulation of T-cells, B-cells, NK cells, and dendritic cells (interferon-b, glatiramer acetate); ➄ Depletion of CD52-positive lymphocytes (alemtuzumab); ➅ Alteration of lymphocyte distribution (fingolimod); ➆ Preventing activated CD4+ T-cells from crossing the blood-brain barrier (natalizumab, interferon-β); ➇ Promoting leukocyte migration to the central nervous system (glatiramer acetate). VLA-4: very late antigen-4; MMP: matrix metalloproteinase; MHC: major histocompatibility complex; IFN: interferon; IL: interleukin; NK: natural killer; TCR: T-cell receptor; Th: T helper

Currently, three types of IFNs have been approved for RRMS: IFN-β1b, IFN-β1a, and pegylated IFN-β1a. The biological activity of IFN-β1a is 10 times higher than that of IFN-β1b. However, pegylated IFN-β1a, which consists of covalently linked IFN and polyethylene glycol, has a long half-life, which decreases the required frequency of administration[99,100]. IFN-β and GA, which were approved more than 20 years ago, are safe and effective. Both drugs are often considered as standard therapies in clinical trials of new DMDs. Among the DMDs for MS, mitoxantrone is not recommended firstly because of its cardiac toxicity. The cardiotoxicity of anthracyclines is thought to be dose dependent and irreversible, leading to a reduction in left ventricular ejection fraction and congestive heart failure. Regular and frequent cardiac monitoring is required during mitoxantrone therapy[174]. Daclizumab was delisted because of its high risk of serious inflammatory brain disorders, including encephalitis and meningoencephalitis[175,176]. Ocrelizumab, which has an anti-CD20 action, is the only drug approved for PPMS. Last month, siponimod has been approved by FDA. It may reduce the activity of the disease and has a modest effect on the gradual disability accrual in SPMS[156].

Monoclonal antibodies are more effective than other immunomodulators and can reduce the annual relapse rate by almost 50%[82]. Alemtuzumab (anti-CD52), fingolimod, or natalizumab (α4-integrin inhibitor) are recommended for patients with highly active MS[83]. Patients who use fingolimod, DMF, natalizumab, ocrelizumab, or rituximab should be evaluated for their risk of progressive multifocal leukoencephalopathy (PML). Cases of PML due to the use of fingolimod or DMF are fortunately rare[177,178]. However, the overall risk of PML with natalizumab use is high (4 per 1000)[179-181]. Patients with MS taking natalizumab should be switched to another DMD with a lower PML risk, if the anti-JC virus antibody index exceeds 0.9 during treatment. High-dose steroid and maraviroc (1000-3000 mg/day, po) may be beneficial for natalizumab-associated PML, and are lacking in experience[182,183]. The advent of oral DMDs has greatly facilitated the daily management of MS patients and improved compliance to treatment. Rituximab, which is usually used to treat NMOSD, has also been used for MS since the discovery of the role of B-cells in the pathogenesis of MS[160-162].

Attack prevention in NMOSD

Since the cumulative inflammatory damage caused by acute attacks leads to disability in NMOSD, attack prevention is crucial for long-term efficacy. It is accepted that first-line immunotherapies for the prevention of relapses in NMOSD include azathioprine, mycophenolate mofetil, and rituximab[41,84-86]. It should be noted that most studies on this topic were not well-controlled or randomized, and may have some bias in their results. Azathioprine antagonizes purine metabolism, and was the first immunosuppressant drug that was found to be effective in preventing NMOSD relapses[165]. Mycophenolate mofetil blocks lymphocyte proliferation by inhibiting the synthesis of guanine. It causes fewer adverse reactions, so it is a safe and generally well tolerated drug for NMOSD[169]. The efficacy of rituximab is better than that of azathioprine and mycophenolate mofetil, and is probably the best choice at present[184-187]. Rituximab is a human-mouse chimeric monoclonal antibody against CD20, which is a regulatory factor for the early activation and differentiation of B-cells. It acts on B-cells and plasmablasts. After a single dose of rituximab, the number of B-cells typically decreases to their minimum value by 2 weeks, and this effect is generally maintained for 6 months. Studies have found that long-term rituximab treatment often leads to significant reduction in immunoglobulins[188]. There have been reports of infections with long-term rituximab treatment. It is important to monitor CD19+ B-cell counts, the total and specific Ig levels before and during treatment with rituximab to prevent complications[188,189]. Other immunosuppressants that have been used to treat NMOSD include tacrolimus, cyclophosphamide, methotrexate, and cyclosporin A. Tacrolimus and cyclosporin A produce good selective inhibition of Th cells, and methotrexate inhibits folate metabolism. However, these drugs have not been used frequently because of their uncertain effects[84-86]. Some studies have found that some new DMDs for MS, such as fingolimod, DMF, alemtuzumab, and natalizumab, may cause the disease to worsen, mainly in patients with AQP4-IgG-positive NMOSD[190-194]. There are insufficient data to support or discourage the use of GA and IFN-β in NMOSD[195,196]. Currently, experience in the treatment of MOG-IgG-positive NMOSD is still lacking, and long-term immunosuppression may be effective[197,198].

Conclusion

Currently, MS and NMOSD are incurable diseases. There is no consensus on the best treatment strategy or treatment target. Early, conventional immunosuppressive agents, such as azathioprine and cyclophosphamide, have been used for the treatment of MS and NMOSD. Various immunosuppressive agents have different degrees of efficacy in MS or NMOSD. Among them, only azathioprine and mycophenolate mofetil are currently recommended for the treatment of NMOSD, but no credible randomized controlled trial has yet proved their effects. Now, more than a dozen DMDs are available for MS, with varying levels of efficacy and safety. Immunomodulators against MS have been marketed since 1993, and conventional immunosuppressive agents have rarely been used in this condition. Compared with new immunomodulators, conventional immunosuppressants have more side effects and worse drug targeting. However, in some countries and regions, due to economic reasons or a lack of DMDs, cyclophosphamide, tacrolimus, and other drugs are still used to treat MS and have some therapeutic effect[199-201]. Despite the use of DMDs, some patients still have exacerbations and develop progressive disease. Few DMDs are available for NMOSD, and there is a lack of large-scale clinical trials.Several new drugs are currently undergoing clinical trials, including tocilizumab (IL-6 receptor blocker), eculizumab (C5 complement inhibitor), and inebilizumab (CD19 B-cell depletion)[202].

More efficacious therapies that alter the disease course are therefore required. Additional research on neuroprotection and repair is urgently needed. Many therapies are currently under study, including hematopoietic stem cell transplantation, neural stem cell-based regenerative approaches, and exosomes derived from bone marrow mesenchymal stem cells. The future of MS and NMOSD treatment is extremely promising as more effective treatments are being developed.

Declarations

Authors’ contributions

Summarized the references and wrote the manuscript: Zhang L

Discussed paper writing and revised the manuscript: Zhang L, Tian JY, Li B

Read and approved the final manuscript: Li B

Availability of data and materials

Not applicable.

Financial support and sponsorship

None.

Conflicts of interest

All authors declared that there are no conflicts of interest.

Ethical approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Copyright

© The Author(s) 2019.

REFERENCES

1. Compston A, Coles A. Multiple sclerosis. Lancet 2002;359:1221-31.

2. Lublin FD, Reingold SC, Cohen JA, Cutter GR, Sørensen PS, et al. Defining the clinical course of multiple sclerosis. Neurology 2014;83:278-86.

3. Jarius S, Wildemann B. [Neuromyelitis optica]. Nervenarzt 2007;78:1365-77.

4. Mori M, Kuwabara S, Paul F. Worldwide prevalence of neuromyelitis optica spectrum disorders. J Neurol Neurosurg Psychiatry 2018;89:555-6.

5. Ochi H, Fujihara K. Demyelinating diseases in Asia. Curr Opin Neurol 2016;29:222-8.

6. Lennon VA, Wingerchuk DM, Kryzer TJ, Pittock SJ, Lucchinetti CF, et al. A serum autoantibody marker of neuromyelitis optica: distinction from multiple sclerosis. Lancet 2004;364:2106-12.

7. Jarius S, Wildemann B, Paul F. Neuromyelitis optica: clinical features, immunopathogenesis and treatment. Clin Exp Immunol 2014;176:149-64.

8. Takeshita Y, Obermeier B, Cotleur AC, Spampinato SF, Shimizu F, et al. Effects of neuromyelitis optica-IgG at the blood-brain barrier in vitro. Neurol Neuroimmunol Neuroinflamm 2016;4:e311.

9. Zekeridou A, Lennon VA. Aquaporin-4 autoimmunity. Neurol Neuroimmunol Neuroinflamm 2015;2:e110.

10. Wingerchuk DM, Lennon VA, Lucchinetti CF, Pittock SJ, Weinshenker BG. The spectrum of neuromyeliis. Lancet Neurol 2007;6:805-15.

11. Wingerchuk DM, Banwell B, Bennett JL, Cabre P, Carroll W, et al. International consensus diagnostic criteria for neuromyelitis optica spectrum disorders. Neurology 2015;85:177-89.

12. Kawachi I, Lassmann H. Neurodegeneration in multiple sclerosis and neuromyelitis optica. J Neurol Neurosurg Psychiatry 2017;88:137-45.

13. Dargahi N, Katsara M, Tselios T, Androutsou ME, de Courten M, et al. Multiple sclerosis: immunopathology and treatment update. Brain Sci 2017;7:E78.

14. Lovett-Racke AE, Yang Y, Racke MK. Th1 versus Th17: are T cell cytokines relevant in multiple sclerosis? Biochim Biophys Acta 2011;1812:246-51.

15. Garg N, Smith TW. An update on immunopathogenesis, diagnosis, and treatment of multiple sclerosis. Brain Behav 2015;5:e00362.

16. Lehmann PV, Rottlaender A, Kuerten S. The autoimmune pathogenesis of multiple sclerosis. Pharmazie 2015;70:5-11.

17. Van Kaer L, Wu L, Parekh VV. Natural killer t cells in multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis. Immunology 2015;146:1-10.

18. Dendrou CA, Fugger L, Friese MA. Immunopathology of multiple sclerosis. Nat Rev Immunol 2015;15:545-58.

19. von Büdingen HC, Palanichamy A, Lehmann-Horn K, Michel BA, Zamvil SS, et al. Update on the autoimmune pathology of multiple sclerosis: B-cells as disease-drivers and therapeutic targets. Eur Neurol 2015;73:238-46.

20. Bennett JL, O’Connor KC, Bar-Or A, Zamvil SS, Hemmer B, et al. B lymphocytes in neuromyelitis optica. Neurol Neuroimmunol Neuroinflamm 2015;2:e104.

21. Graber DJ, Levy M, Kerr D, Wade WF. Neuromyelitis optica pathogenesis and aquaporin 4. J Neuroinflammation 2008;5:22.

22. Hertwig L, Pache F, Romero-Suarez S, Stürner KH, Borisow N, et al. Distinct functionality of neutrophils in multiple sclerosis and neuromyelitis optica. Mult Scler 2016;22:160-73.

23. Borisow N, Mori M, Kuwabara S, Scheel M, Paul F, et al. Diagnosis and treatment of NMO spectrum disorder and MOG-encephalomyelitis. Front Neurol 2018;9:888.

24. Narayan R, Simpson A, Fritsche K, Salama S, Pardo S, et al. MOG antibody disease: a review of MOG antibody seropositive neuromyelitis optica spectrum disorder. Mult Scler Relat Disord 2018;25:66-72.

25. Zamvil SS, Slavin AJ. Does MOG Ig-positive AQP4-seronegative opticospinal inflammatory disease justify a diagnosis of NMO spectrum disorder? Neurol Neuroimmunol Neuroinflamm 2015;2:e62.

26. Pelt ED, Wong YY, Ketelslegers IA, Hamann D, Hintzen RQ, et al. Neuromyelitis optica spectrum disorders: comparison of clinica land magnetic resonanceimaging characteristics of AQP4-IgG versus MOG- IgG seropositive cases in the Netherlands. EurJNeurol 2016;23:580-7.

27. Vourc’h P, Andres C. Oligodendrocyte myelin glycoprotein (OMgp): evolution, structure and function. Brain Res Brain Res Rev 2004;45:115-24.

28. Jarius S, Ruprecht K, Kleiter I, Borisow N, Asgari N, et al. MOG-IgG in NMO and related disorders: a multicenter study of 50 patients. Part 1: frequency, syndrome specificity, influence of disease activity, longterm course, association with AQP4-IgG, and origin. J Neuroinflamm 2016;13:279.

29. Jarius S, Paul F, Franciotta D, Ruprecht K, Ringelstein M, et al. Cerebrospinal fluid findings in aquaporin-4 antibody positive neuromyelitis optica: results from 211 lumbar punctures. J Neurol Sci 2011;306:82-90.

30. Mealy MA, Kim SH, Schmidt F, López R, Jimenez Arango JA, et al. Aquaporin-4 serostatus does not predict response to immunotherapy in neuromyelitis optica spectrum disorders. Mult Scler 2018;24:1737-42.

31. Jarius S, Ruprecht K, Stellmann JP, Huss A, Ayzenberg I, et al. MOG-IgG in primary and secondary chronic progressive multiple sclerosis: a multicenter study of 200 patients and review of the literature. J Neuroinflamm 2018;15:88.

32. Diebold M, Derfuss T. Immunological treatment of multiple sclerosis. Semin Hematol 2016;53:S54-7.

33. Kleiter I, Gold R. Present and future therapies in neuromyelitis optica spectrum disorders. Neurotherapeutics 2016;13:70-83.

34. Inglese M, Petracca M. Therapeutic strategies in multiple sclerosis: a focus on neuroprotection and repair and relevance to schizophrenia. Schizophr Res 2015;161:94-101.

35. Morrow SA, Metz LM, Kremenchutzky M. High dose oral steroids commonly used to treat relapses in canadian ms clinics. Can J Neurol Sci 2009;36:213-5.

36. Compston DA, Milligan NM, Hughes PJ, Gibbs J, McBroom V, et al. A double-blind controlled trial of high dose methylprednisolone in patients with multiple sclerosis: 2. Laboratory results. J Neurol Neurosurg Psychiatry 1987;50:517-22.

37. Barkhof F, Hommes OR, Scheltens P, Valk J. Quantitative MRI changes in gadolinium-DTPA enhancement after high-dose intravenous methylprednisolone in multiple sclerosis. Neurology 1991;41:1219-22.

38. Bonnan M, Cabre P. Plasma exchange in severe attacks of neuromyelitis optica. Mult Scler Int 2012;2012:787630.

39. Trebst C, Bronzlik P, Kielstein JT, Schmidt BM, Stangel M, et al. Immunoadsorption therapy for steroid-unresponsive relapses in patients with multiple sclerosis. Blood Purif 2012;33:1-6.

40. Koziolek MJ, Tampe D, Bahr M, Dihazi H, Jung K, et al. Immunoadsorption therapy in patients with multiple sclerosis with steroid-refractory optical neuritis. J Neuroinflammation 2012;9:80.

41. Trebst C, Jarius S, Berthele A, Paul F, Schippling S, et al. Update on the diagnosis and treatment of neuromyelitis optica: recommendations of the Neuromyelitis Optica Study Group (NEMOS). J Neurol 2014;261:1-16.

42. Elovaara I, Kuusisto H, Wu X, Rinta S, Dastidar P, et al. Intravenous immunoglobulins are a therapeutic option in the treatment of multiple sclerosis relapse. Clin Neuropharmacol 2011;34:84-9.

43. Elsone L, Panicker J, Mutch K, Boggild M, Appleton R, et al. Role of intravenous immunoglobulin in the treatment of acute relapses of neuromyelitis optica: experience in 10 patients. Mult Scler 2014;20:501-4.

44. William M, Carroll, Fujihara Kazuo. Neuromyelitis optica. Neurology 2010;12:244-55.

45. Wingerchuk DM. Neuromyelitis optica: potential roles for intravenous immunoglobulin. J Clin Immunol 2013;33:S33-7.

46. Yu Z, Lennon VA. Mechanism of intravenous immune globulin therapy in antibody-mediated autoimmune diseases. N Engl J Med 1999;340:227-8.

47. Sloka JS, Stefanelli M. The mechanism of action of methylprednisolone in the treatment of multiple sclerosis. Mult Scler 2005;11:425-32.

48. Martinelli V, Roca MA, Annovazzi P, Pulizzi A, Rodegher M, et al. A short-term randomized MRI study of high dose oral vs intravenous methylprednisolone in MS. Neurology 2009;73:1842-8.

49. Burton JM, O’Connor PW, Hohol M, Beyene J. Oral versus intravenous steroids for treatment of relapses in multiple sclerosis. Cochrane Database Syst Rev 2009;8:CD006921.

50. Ramo-Tello C, Grau-López L, Tintoré M, Rovira A, Ramió i Torrenta L, et al. A randomized clinical trial of oral versus intravenous methylprednisolone for relapse of MS. Mult Scler 2014;20:717-25.

51. Le Page E, Veillard D, Laplaud DA, Hamonic S, Wardi R, et al. Oral versus intravenous high-dose methylprenisolone for treatment of relapses in patients with multiple sclerosis (COPOUSEP): a randomized, controlled, double-blind, non-inferiority trial. Lancet 2015;386:974-81.

52. Sellebjerg F, Barnes D, Filippini G, Midgard R, Montalban X, et al. EFNS guideline on treatment of multiple sclerosis relapses: report of an EFNS task force on treatment of multiple sclerosis relapses. Eur J of Neurol 2005;12:939-46.

53. Perumal JS, Caon C, Hreha S, Zabad R, Tselis A, et al. Oral prednisone taper following intravenous steroids fails to improve disability or recovery from relapses in multiple sclerosis. Eur J Neurol 2008;15:677-80.

54. Levic Z, Micic D, Nikolic J, Stojisavljević N, Sokić D, et al. Short-term high dose steroid therapy does not affect the hypothalamic-pituitary-adrenal axis in relapsing multiple sclerosis patients. J Endocrinol Invest 1996;19:30-4.

55. Wenning GK, Wietholter H, Schnauder G, Muller PH, Kanduth S, et al. Recovery of the hypothalamic-pituitary-adrenal axis from suppression by short-term, high-dose intravenous prednisolone therapy in patients with MS. Acta Neurol Scand 1994;89:270-3.

56. Watanabe S, Misu T, Miyazawa I, Nakashima I, Shiga Y, et al. Low-dose corticosteroids reduce relapses in neuromyelitis optica: a retrospective analysis. Mult Scler 2007;13:968-74.

57. Ramanathan S, Mohammad S, Tantsis E, Nguyen TK, Merheb V, et al. Clinical course, therapeutic responses and outcomes in relapsing MOG antibody-associated demyelination. J Neurol Neurosurg Psychiatry 2018;89:127-37.

58. Sato D, Callegaro D, Lana-Peixoto MA, Fujihara K; Brazilian Committee for Treatment and Research in Multiple Sclerosis. Treatment of neuromyelitis optica: an evidence based review. Arq Neuropsiquiatr 2012;70:59-66.

59. Palace J, Leite MI, Jacob A. A practical guide to the treatment of neuromyelitis optica. Pract Neurol 2012;12:209-14.

60. Wingerchuk DM, Hogancamp WF, O’Brien PC, Weinshenker BG. The clinical course of neuromyelitis optica (Devic’s syndrome). Neurology 1999;53:1107-14.

61. Bichuetti DB, Oliveira EM, Souza NA, Tintoré M, Gabbai AA. Patients with neuromyelitis optica have a more severe disease than patients with relapsing remitting multiple sclerosis, including higher risk of dying of a demyelinating disease. Arq Neuropsiquiatr 2013;71:275-9.

62. Yamasaki R, Matsushita T, Fukazawa T, Yokoyama K, Fujihara K, et al. Efficacy of intravenous methylprednisolone pulse therapy in patients with multiple sclerosis and neuromyelitis optica. Mult Scler 2016;22:1337-48.

63. Carroll WM, Fujihara K. Neuromyelitis optica. Curr Treat Options Neurol 2010;12:244-55.

64. Brecher ME. Plasma exchange: why we do what we do. J Clin Apher 2002;17:207-11.

65. McDaneld LM, Fields JD, Bourdette DN, Bhardwaj A. Immunomodulatory therapies in neurologic critical care. Neurocrit Care 2010;12:132-43.

66. Lipphardt M, Mühlhausen J, Kitze B, Heigl F, Mauch E, et al. Immunoadsorption or plasma exchange in steroid-refractory multiple sclerosis and neuromyelitis optica. Available from: https://onlinelibrary.wiley.com/doi/abs/10.1002/jca.21686. [Last accessed on 23 Apr 2019].

67. Correia I, Ribeiro JJ, Isidoro L, Batista S, Nunes C, et al. Plasma exchange in severe acute relapses of multiple sclerosis - results from a portuguese cohort. Mult Scler Relat Disord 2018;19:148-52.

68. Kleiter I, Gahlen A, Borisow N, Fischer K, Wernecke KD, et al. Apheresis therapies for NMOSD attacks: a retrospective study of 207 therapeutic interventions. Neurol Neuroimmunol Neuroinflamm 2018;5:e504.

69. Watanabe S, Nakashima I, Misu T, Miyazawa I, Shiga Y, et al. Therapeutic efficacy of plasma exchange in NMO-IgG-positive patients with neuromyelitis optica. Mult Scler 2007;13:128-32.

70. Merle H, Olindo S, Jeannin S, Valentino R, Mehdaoui H, et al. Treatment of optic neuritis by plasma exchange (add-on) in neuromyelitis optica. Arch Ophthalmol 2012;130:858-62.

71. Bonnan M, Valentino R, Debeugny S, Merle H, Fergé JL, et al. Short delay to initiate plasma exchange is the strongest predictor of outcome in severe attacks of NMO spectrum disorders. J Neurol Neurosurg Psychiatry 2018;89:346-51.

72. Kleiter I, Gahlen A, Borisow N, Fischer K, Wernecke KD, et al. Neuromyelitis optica: Evaluation of 871 attacks and 1,153 treatment courses. Ann Neurol 2016;79:206-16.

73. Schwab, Nimmerjahn F. Intravenous immunoglobulin therapy: how does IgG modulate the immune system? Nat Rev Immunol 2013;13:176-89.

74. Elsone L, Panicker J, Mutch K, Boggild M, Appleton R, et al. Role of intravenous immunoglobulin in the treatment of acute relapses of neuromyelitis optica: experience in 10 patients. Mult Scler 2014;20:501-4.

75. Sorensen PS, Haas J, Sellebjerg F, Olsson T, Ravnborg M, et al. IV immunoglobulins as add-on treatment to methylprednisolone for acute relapses in MS. Neurology 2004;63:2028-33.

76. Visser LH, Beekman R, Tijssen CC, Uitdehaag BM, Lee ML, et al. A randomized, double-blind, place-controlled pilot study of IV immune globulins in combination with IV methylprednisolone in the treatment of relapses in patients with MS. Mult Scler 2004;10:89-91.

77. Olyaeemanesh A, Rahmani M, Goudarzi R, Rahimdel A. Safety and effectiveness assessment of intravenous immunoglobulin in the treatment of relapsing-remitting multiple sclerosis: a meta-analysis. Med J Islam Repub Iran 2016;30:336.

78. Magraner MJ, Coret F, Casanova B. The effect of intravenous immunoglobulin on neuromyelitis optica. Neurologia 2013;28:65-72.

79. Viswanathan S, Wong AH, Quek AM, Yuki N. Intravenous immunoglobulin may reduce relapse frequency in neuromyelitis optica. J Neuroimmunol 2015;282:92-6.

80. Okada K, Tsuji S, Tanaka K. Intermittent intravenous immunoglobulin successfully prevents relapses of neuromyelitis optica. Intern Med 2007;46:1671-2.

81. Dendrou CA, Fugger L, Friese MA. Immunopathology of multiple sclerosis. Nat Rev Immunol 2015;15:545-58.

82. Montalban X, Gold R, Thompson AJ, Otero-Romero S, Amato MP, et al. ECTRIMS/EAN guideline on the pharmacological treatment of people with multiple sclerosis. Mult Scler 2018;24:96-120.

83. Rae-Grant A. Practice guideline recommendations summary: disease-modifying therapies for adults with multiple sclerosis: report of the guideline development, dissemination, and implementation subcommittee of the American Academy of Neurology. Neurology 2019;92:110-1.

84. Sahraian MA, Moghadasi AN, Azimi AR, Asgari N, et al. Diagnosis and management of Neuromyelitis Optica Spectrum Disorder (NMOSD) in Iran: a consensus guideline and recommendations. Mult Scler Relat Disord 2017;18:144-51.

85. Sellner J, Boggild M, Clanet M, Hintzen RQ, Illes Z, et al. EFNS guidelines on diagnosis and management of neuromyelitis optica. Eur J Neurol 2010;17:1019-32.

86. Trebst C, Berthele A, Jarius S, Kümpfel T, Schippling S, et al. Diagnosis and treatment of neuromyelitis optical consensus recommendations of the Neuromyelitis Optica Study Group. Nervenarzt 2011;82:768-77.

87. The IFNB Multiple Sclerosis Study Group. Interferon beta-1b is effective in relapsing-remitting multiple sclerosis. I. Clinical results of a multicenter, randomized, double-blind, placebo-controlled trial. Neurology 1993;43:655-61.

88. Paty DW, Li DK; UBC MS/MRI Study Group and the IFNB Multiple Sclerosis Study Group. Interferon beta-1b is effective in relapsing-remitting multiple sclerosis. II. MRI analysis results of a multicenter, randomized, double-blind, placebo-controlled trial. Neurology 1993;43:662-7.

89. Jacobs LD, Cookfair DL, Rudick RA, Herndon RM, Richert JR, et al. Intramuscular interferon beta-1a for disease progression in relapsing multiple sclerosis. The Multiple Sclerosis Collaborative Research Group (MSCRG). Ann Neurol 1996;39:285-94.

90. Pozzilli C, Bastianello S, Koudriavtseva T, Gasperini C, Bozzao A, et al. Magnetic resonance imaging changes with recombinant human interferon-beta-1a: a short term study in relapsing-remitting multiple sclerosis. J Neurol Neurosurg Psychiatry 1996;61:251-8.

91. Rudick RA, Goodkin DE, Jacobs LD, Cookfair DL, Herndon RM, et al. Impact of interferon beta-1a on neurologic disability in relapsing multiple sclerosis. The Multiple Sclerosis Collaborative Research Group (MSCRG). Neurology 1997;49:358-63.

92. Simon JH, Jacobs LD, Campion M, Wende K, Simonian N, et al. Magnetic resonance studies of intramuscular interferon beta-1a for relapsing multiple sclerosis. The Multiple Sclerosis Collaborative Research Group. Ann Neurol 1998;43:79-87.

93. Calabresi PA, Kieseier BC, Arnold DL, Balcer LJ, Boyko A, et al. Pegylated interferon beta-1a for relapsing remitting multiple sclerosis (ADVANCE): a randomised, phase 3, double- blind study. Lancet Neurol 2014;13:657-65.

94. Polman CH, Dahlke F, Thompson AJ, Ghazi M, Kappos L, et al. Interferon beta-1b in secondary progressive multiple sclerosis-outline of the clinical trial. Mult Scler 1995;1:S51-4.

95. Kuhle J, Hardmeier M, Disanto G, Gugleta K2, Ecsedi M, et al. A 10-year follow-up of the European multicenter trial of interferonβ-1b in secondary-progressive multiple sclerosis. Mult Scler 2016;22:533-43.

96. Andersen O, Elovaara I, Färkkilä M, Hansen HJ, Mellgren SI, et al. Multicentre, randomised, double blind, placebo controlled, phase III study of weekly, low dose, subcutaneous interferon beta-1a in secondary progressive multiple sclerosis. J Neurol Neurosurg Psychiatry 2004;75:706-10.

97. ITur C, Montalban X, Tintoré M, Nos C, Río J, et al. Interferonβ-1b for the treatment of primary progressive multiple sclerosis: five-year clinical trial follow-up. Arch Neurol 2011;68:1421-7.

98. Montalban X, Sastre-Garriga J, Tintoré M, Brieva L, Aymerich FX, et al. A single-center, randomized, double-blind, placebo-controlled study of interferon beta-1b on primary progressive and transitional multiple sclerosis. Mult Scler 2009;15:1195-205.

99. Hegen H, Auer M, Deisenhammer F. Pharmacokinetic considerations in the treatment of multiple sclerosis with interferon-β. Expert Opin Drug Metab Toxicol 2015;11:1803-19.

100. Bailon P, Won CY. PEG-modified biopharmaceuticals. Expert Opin Drug Deliv 2009;6:1-16.

101. Furber KL, Van Agten M, Evans C, Haddadi A, Doucette JR, et al. Advances in the treatment of relapsing-remitting multiple sclerosis: the role of pegylated interferonβ-1a. Degener Neurol Neuromuscul Dis 2017;7:47-60.

102. Lalive PH, Neuhaus O, Benkhoucha M, Burger D, Hohlfeld R. Glatiramer acetate in the treatment of multiple sclerosis: emerging concepts regarding its mechanism of action. CNS Drugs 2011;25:401-14.

103. Aharoni R. The mechanism of action of glatiramer acetate in multiple sclerosis and beyond. Autoimmun Rev 2013;12:543-53.

104. Racke MK, Lovett-Racke AE, Karandikar NJ. The mechanism of action of glatiramer acetate treatment in multiple sclerosis. Neurology 2010;74:S25-30.

105. Johnson KP, Brooks BR, Cohen JA, Ford CC, Goldstein J, et al. Copolymer 1 reduces relapse rate and improves disability in relapsing remitting multiple sclerosis: results of a phase III multicenter, double-blind, placebo-controlled trial.1995. Neurology 2001;57:S16-24.

106. Johnson KP, Brooks BR, Cohen JA, Ford CC, Goldstein J, et al. Extended use of glatiramer acetate (Copaxone) is well tolerated and maintains its clinical effect on multiple sclerosis relapse rate and degree of disability. Copolymer 1 Multiple Sclerosis Study Group. Neurology 1998;50:701-8.

107. Johnson KP, Brooks BR, Ford CC, Goodman A, Guarnaccia J, et al. Sustained clinical benefits of glatiramer acetate in relapsing multiple sclerosis patients observed for 6 years. Copolymer 1 Multiple Sclerosis Study Group. Mult Scler 2000;6:255-66.

108. Liu C, Blumhardt LD. Benefits of glatiramer acetate on disability in relapsing-remitting multiple sclerosis. An analysis by area under disability/time curves. The Copolymer 1 Multiple Sclerosis Study Group. J Neurol Sci 2000;181:33-7.

109. Khan O, Rieckmann P, Boyko A, Selmaj K, Zivadinov R, et al. Three times weekly glatiramer acetate in relapsing remitting multiple sclerosis. Ann Neurol 2013;73:705-13.

110. Wolinsky JS, Narayana PA, O’ Connor P, Coyle PK, Ford C, et al. Glatiramer acetate in primary progressive multiple sclerosis: results of a multinational, multicenter, double-blind, placebo-controlled trial. Ann Neurol 2007;61:14-24.

111. Millefiorini E, Gasperini C, Pozzilli C, D’Andrea F, Bastianello S, et al. Randomized placebo-controlled trial of mitoxantrone in relapsing-remitting multiple sclerosis: 24-month clinical and MRI outcome. J Neurol 1997;244:153-9.

112. Le Page E, Leray E, Taurin G, Coustans M, Chaperon J, et al. Mitoxantrone as induction treatment in aggressive relapsing remitting multiple sclerosis: treatment response factors in a 5 year follow-up observational study of 100 consecutive patients. J Neurol Neurosurg Psychiatry 2008;79:52-6.

113. Rivera VM, Jeffery DR, Weinstock-Guttman B, Bock D, Dangond F. Results from the 5-year, phase IV RENEW (Registry to Evaluate Novantrone Effects in Worsening Multiple Sclerosis) study. BMC Neurol 2013;13:80.

114. Hartung HP, Gonsette R, König N, Kwiecinski H, Guseo A, et al. Mitoxantrone in progressive multiple sclerosis: a placebo-controlled, double-blind, randomised, multicentre trial. Lancet 2002;360:2018-25.

115. van de Wyngaert FA, Beguin C, D’Hooghe MB, Dooms G, Lissoir F, et al. A double-blind clinical trial of mitoxantrone versus methylprednisolone in relapsing, secondary progressive multiple sclerosis. Acta Neurol Belg 2001;101:210-6.

116. Mehling M, Brinkmann V, Antel J, Bar-Or A, Goebels N, et al. FTY720 therapy exerts differential effects on T cell subsets in multiple sclerosis. Neurology 2008;71:1261-7.

117. Miron VE, Ludwin SK, Darlington PJ, Jarjour AA, Soliven B, et al. Fingolimod (FTY720) enhances remyelination following demyelination of organotypic cerebellar slices. Am J Pathol 2010;176:2682-94.

118. Miron VE, Schubart A, Antel JP. Central nervous system-directed effects of FTY720 (fingolimod). J Neurol Sci 2008;274:13-7.

119. Kappos L, Radue EW, O’ Connor P, Polman C, Hohlfeld R, et al. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med 2010;362:387-401.

120. Calabresi PA, Radue EW, Goodin D, Jeffery D, Rammohan KW, et al. Safety and efficacy of fingolimod in patients with relapsing-remitting multiple sclerosis (FREEDOMS II): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Neurol 2014;13:545-56.

121. Khatri B, Barkhof F, Comi G, Hartung HP, Kappos L, et al. Comparison of fingolimod with interferon beta-1a in relapsing-remitting multiple sclerosis: a randomised extension of the TRANSFORMS study. Lancet Neurol 2011;10:520-9.

122. Saida T, Kikuchi S, Itoyama Y, Hao Q, Kurosawa T, et al. A randomized, controlled trial of fingolimod (FTY720) in Japanese patients with multiple sclerosis. Mult Scler 2012;18:1269-77.

123. Ordoñez-Boschetti L, Rey R, Cruz A, Sinha A, Reynolds T, et al. Safety and tolerability of fingolimod in Latin American patients with relapsing-remitting multiple sclerosis: the open-label FIRST LATAM study. Adv Ther 2015;32:626-35.

124. Cohen JA, Khatri B, Barkhof F, Comi G, Hartung HP, et al. Long-term (up to 4.5 years) treatment with fingolimod in multiple sclerosis: results from the extension of the randomized TRANSFORMS study. J Neurol Neurosurg Psychiatry 2016;87:468-75.

125. Lublin F, Miller DH, Freedman MS, Cree BAC, Wolinsky JS, et al. Oral fingolimod in primary progressive multiple sclerosis (INFORMS): a phase 3, randomised, double-blind, placebo-controlled trial. Lancet 2016;387:1075-84.

126. Papadopoulou A, Kappos L, Sprenger T. Teriflunomide for oral therapy in multiple sclerosis. Expert Rev Clin Pharmacol 2012;5:617-28.

127. Martin R, Sospedra M, Rosito M, Engelhardt B. Current multiple sclerosis treatments have improved our understanding of MS autoimmune pathogenesis. Eur J Immunol 2016;46:2078-90.

128. Confavreux C, O’ Connor P, Comi G, Freedman MS, Miller AE, et al. Oral teriflunomide for patients with relapsing multiple scle-rosis (TOWER): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Neurol 2014;13:247-56.

129. O’ Connor P, Wolinsky JS, Confavreux C, Comi G, Kappos L, et al. Randomized trial of oral teriflunomide for relapsing multiple sclerosis. N Engl J Med 2011;365:1293-303.

130. O’ Connor P, Comi G, Freedman MS, Miller AE, Kappos L, et al. Long-term safety and efficacy of teriflunomide: nine-year follow-up of the randomized TEMSO study. Neurology 2016;86:920-30.

131. Vermersch P, Czlonkowska A, Grimaldi LM, Confavreux C, Comi G, et al. Teriflunomide versus subcutaneous interferon beta-1a in patients with relapsing multiple sclerosis: a randomised, controlled phase 3 trial. Mult Scler 2014;20:705-16.

132. Salmen A, Gold R. Mode of action and clinical studies with fumarates in multiple sclerosis. Exp Neurol 2014;262:52-6.

133. Dubey D, Kieseier BC, Hartung HP, Hemmer B, Warnke C, et al. Dimethyl fumarate in relapsing-remitting multiple sclerosis: rationale, mechanisms of action, pharmacokinetics, efficacy and safety. Expert Rev Neurother 2015;15:339-46.

134. Gold R, Kappos L, Arnold DL, Bar-Or A, Giovannoni G, et al. Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. N Engl J Med 2012;367:1098-107.

135. Fox RJ, Miller DH, Phillips JT, Hutchinson M, Havrdova E, et al. Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis. N Engl J Med 2012;367:1087-97.

136. Gold R, Arnold DL, Bar-Or A, Hutchinson M, Kappos L, et al. Long-term effects of delayed-release dimethyl fumarate in multiple sclerosis: interim analysis of ENDORSE, a randomized extension study. Mult Scler 2017;23:253-65.

137. Yednock TA, Cannon C, Fritz LC, Sanchez-Madrid F, Steinman L, et al. Prevention of experimental autoimmune encephalomyelitis by antibodies against alpha 4 beta 1 integrin. Nature 1992;356:63-6.

138. Derfuss T, Kuhle J, Lindberg R, Kappos L. Natalizumab therapy for multiple sclerosis. Semin Neurol 2013;33:26-36.

139. Rudick RA, Stuart WH, Calabresi PA, Confavreux C, Galetta SL, et al. Natalizumab plus interferon beta-1a for relapsing multiple sclerosis. N Engl J Med 2006;354:911-23.

140. Polman CH, O’ Connor PW, Havrdova E, Hutchinson M, Kappos L, et al. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 2006;354:899-910.

141. Putzki N, Yaldizli O, Mäurer M, Cursiefen S, Kuckert S, et al. Efficacy of natalizumab in second line therapy of relapsing-remitting multiple sclerosis: resultsfrom a multi-center study in German speaking countries. Eur J Neurol 2010;17:31-7.

142. Outteryck O, Ongagna JC, Zéphir H, Fleury MC, Lacour A, et al. Demographic and clinic characteristics of French patients treated with natalizumab in clinical practice. J Neurol 2010;257:207-11.

143. Putzki N, Yaldizli O, Mäurer M, Cursiefen S, Kuckert S, et al. Efficacy of natalizumab in second line therapy of relapsing-remitting multiple sclerosis: results from a multicenter study in German speaking countries. Eur J Neurol 2010;17:31-7.

144. Butzkueven H, Kappos L, Pellegrini F, Trojano M, Wiendl H, et al. Efficacy and safety of natalizumab in multiple sclerosis: interim observational programme results. J Neurol Neurosurg Psychiatry 2014;85:1190-7.

145. Saida T, Kira JI, Kishida S, Yamamura T, Sudo Y, et al. Efficacy, safety, and pharmacokinetics of natalizumab in Japanese multiple sclerosis patients: a double-blind, randomized controlled trial and open-label pharmacokinetic study. Mult Scler Relat Disord 2017;11:25-31.

146. Cadavid D, Jurgensen S, Lee S. Impact of natalizumab on ambulatory improvement in secondary progressive and disabled relapsing-remitting multiple sclerosis. PLoS One 2013;8:e53297.

147. Ruck T, Bittner S, Wiendl H, Meuth SG. Alemtuzumab in multiple sclerosis: mechanism of action and beyond. Int J Mol Sci 2015;16:16414-39.

148. Coles AJ, Twyman CL, Arnold DL, Cohen JA, Confavreux C, et al. Alemtuzumab for patients with relapsing multiple sclerosis after disease-modifying therapy: a randomised controlled phase 3 trial. Lancet 2012;380:1829-39.

149. Cohen JA, Coles AJ, Arnold DL, Confavreux C, Fox EJ, et al. Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing-remitting multiple sclerosis: a randomised controlled phase 3 trial. Lancet 2012;380:1819-28.

150. Tuohy O, Costelloe L, Hill-Cawthorne G, Bjornson I, Harding K, et al. Alemtuzumab treatment of multiple sclerosis: long-term safety and efficacy. J Neurol Neurosurg Psychiatry 2015;86:208-15.

151. Montalban X, Hauser SL, Kappos L, Arnold DL, Bar-Or A, et al. Ocrelizumab versus placebo in primary progressive multiple sclerosis. N Engl J Med 2017;376:209-20.

152. Kappos L, Li D, Calabresi PA, O’Connor P, Bar-Or A, et al. Ocrelizumab in relapsing-remitting multiple sclerosis: a phase 2, randomised, placebo-controlled, multicentre trial. Lancet 2011;378:1779-87.

153. Hauser SL, Bar-Or A, Comi G, Giovannoni G, Hartung HP, et al. Ocrelizumab versus interferon Beta-1a in relapsing multiple sclerosis. N Engl J Med 2017;376:221-34.

154. Giovannoni G, Comi G, Cook S, Rammohan K, Rieckmann P, et al. A placebo-controlled trial of oral cladribine for relapsing multiple sclerosis. N Engl J Med 2010;362:416-26.

155. Stelmasiak Z, Solski J, Nowicki J, Jakubowska B, Ryba M, et al. Effect of parenteral cladribine on relapse rates in patients with relapsing forms of multiple sclerosis: results of a 2-year, double-blind, placebo-controlled, crossover study. Mult Scler 2009;15:767-70.

156. Kappos L, Bar-Or A, Cree BAC, Fox RJ, Giovannoni G, et al. Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND): a double-blind, randomised, phase 3 study. Lancet 2018;391:1263-73.

157. Kappos L, Li DK, Stüve O, Hartung HP, Freedman MS, et al. Safety and efficacy of Siponimod (BAF312) in patients with relapsing-remitting multiple sclerosis: dose-blinded, randomized extension of the phase 2 BOLD study. JAMA Neurol 2016;73:1089-98.

158. Selmaj K, Li DK, Hartung HP, Hemmer B, Kappos L, et al. Siponimod for patients with relapsing-remitting multiple sclerosis (BOLD): an adaptive, dose-ranging, randomised, phase 2 study. Lancet Neurol 2013;12:756-67.

159. Nikoo Z, Badihian S, Shaygannejad V, Asgari N, Ashtari F, et al. Comparison of the efficacy of azathioprine and rituximab in neuromyelitis optica spectrum disorder: a randomized clinical trial. J Neurol 2017;264:2003-9.

160. Bar-Or A, Calabresi PA, Arnold D, Markowitz C, Shafer S, et al. Rituximab in relapsing-remitting multiple sclerosis: a 72-week, open-label, phase I trial. Ann Neurol 2008;63:395-400.

161. Naismith RT, Piccio L, Lyons JA, Lauber J, Tutlam NT, et al. Rituximab add-on therapy for breakthrough relapsing multiple sclerosis: a 52-week phase II trial. Neurology 2010;74:1860-7.

162. Hawker K, O’ Connor P, Freedman MS, Calabresi PA, Antel J, et al. Rituximab in patients with primary progressive multiple sclerosis: results of a randomized double-blind placebo-controlled multicenter trial. Ann Neurol 2009;66:460-71.

163. Huang TL, Lin KH, Wang JK, Tsai RK. Treatment strategies for neuromyelitis optica. Ci Ji Yi Xue Za Zhi 2018;30:204-8.

164. Mandler RN, Ahmed W, Dencoff JE. Devic’s neuromyelitis optica: a prospective study of seven patients treated with prednisone and azathioprine. Neurology 1998;51:1219-20.

165. Bichuetti DB, Perin MMM, Souza NA, Oliveira EML. Treating neuromyelitis optica with azathioprine: 20-year clinical practice. Mult Scler 2018; doi: 10.1177/1352458518776584.

166. Qiu W, Kermode AG, Li R, Dai Y, Wang Y, et al. Azathioprine plus corticosteroid treatment in Chinese patients with neuromyelitis optica. J Clin Neurosci 2015;22:1178-82.

167. Massacesi L, Tramacere I, Amoroso S, Battaglia MA, Benedetti MD, et al. Azathioprine versus beta interferons for relapsing-remitting multiple sclerosis: a multicentre randomized non-inferiority trial. PLoS One 2014;9:e113371.

168. Goldsmith D, Carrey EA, Edbury S, Smolenski RT, Jagodzinski P, et al. Mycophenolate mofetil, an inhibitor of inosine monophosphate dehydrogenase, causes a paradoxical elevation of GTP in erythrocytes of renal transplant patients. Clin Sci (Lond) 2004;107:63-8.

169. Torres J, Pruitt A, Balcer L, Galetta S, Markowitz C, et al. Analysis of the treatment of neuromyelitis optica. J Neurol Sci 2015;351:31-5.

170. Huh SY, Kim SH, Hyun JW, Joung AR, Park MS, et al. Mycophenolate mofetil in the treatment of neuromyelitis optica spectrum disorder. JAMA Neurol 2014;71:1372-8.

171. Jacob A, Matiello M, Weinshenker BG, Wingerchuk DM, Lucchinetti C, et al. Treatment of neuromyelitis optica with mycophenolate mofetil: retrospective analysis of 24 patients. Arch Neurol 2009;66:1128-33.

172. Huang Q, Wang J, Zhou Y, Yang H, Wang Z, et al. Low-dose mycophenolate mofetil for treatment of neuromyelitis optica spectrum disorders: a prospective multicenter study in South China. Front Immunol 2018;9:2066.

173. Bruck W, Stadelmann C. Inflammation and degeneration in multiple sclerosis. J Neurol Sci 2003;24:S265-7.

174. Paul F, Dörr J, Würfel J, Vogel HP, Zipp F. Early mitoxantrone-induced cardiotoxicity in secondary progressive multiple sclerosis. J Neurol Neurosurg Psychiatry 2007;78:198-200.

175. Stettner M, Gross CC, Mausberg AK, Pul R, Junker A, et al. A fatal case of daclizumab-induced liver failure in a patient with MS. Neurol Neuroimmunol Neuroinflamm 2019;6:e539.

176. Luessi F, Engel S, Spreer A, Bittner S, Zipp F. GFAPα IgG-associated encephalitis upon daclizumab treatment of MS. Neurol Neuroimmunol Neuroinflamm 2018;5:e481.

177. Baharnoori M, Lyons J, Dastagir A, Koralnik I, Stankiewicz JM. Nonfatal PML in a patient with multiple sclerosis treated with dimethyl fumarate. Neurol Neuroimmunol Neuroinflamm 2016;3:e274.

178. Berger JR, Cree BA, Greenberg B, Hemmer B, Ward BJ, et al. Progressive multifocal leukoencephalopathy after fingolimod treatment. Neurology 2019;92:151.

179. Maillart E, Vidal JS, Brassat D, Stankoff B, Fromont A, et al. Natalizumab-PML survivors with subsequent MS treatment: clinico-radiologic outcome. Neurol Neuroimmunol Neuroinflamm 2017;4:e346.

180. Meira M, Sievers C, Hoffmann F, Haghikia A, Rasenack M, et al. Natalizumab-induced POU2AF1/Spi-B upregulation: a possible route for PML development. Neurol Neuroimmunol Neuroinflamm 2016;3:e223.

181. Major EO, Nath A. A link between long-term natalizumab dosing in MS and PML: putting the puzzle together. Neurol Neuroimmunol Neuroinflamm 2016;3:e235.

182. Bsteh G, Auer M, Iglseder S, Walchhofer LM, Langenscheidt D, et al. Severe early natalizumab-associated PML in MS: Effective control of PML-IRIS with maraviroc. Neurol Neuroimmunol Neuroinflamm 2017;4:e323.

183. Hodecker SC, Stürner KH, Becker V, Elias-Hamp B, Holst B, et al. Maraviroc as possible treatment for PML-IRIS in natalizumab-treated patients with MS. Neurol Neuroimmunol Neuroinflamm 2017;4:e325.

184. Yang Y, Wang CJ, Wang BJ, Zeng ZL, Guo SG. Comparison of efficacy and tolerability of azathioprine, mycophenolate mofetil, and lower dosages of rituximab among patients with neuromyelitis optica spectrum disorder. J Neurol Sci 2018;385:192-7.

185. Etemadifar M, Salari M, Mirmosayyeb O, Serati M, Nikkhah R, et al. Efficacy and safety of rituximab in neuromyelitis optica: review of evidence. J Res Med Sci 2017;22:18.

186. Rommer PS, Dörner T, Freivogel K, Haas J, Kieseier BC, et al. Safety and clinical outcomes of rituximab treatment in patients with multiple sclerosis and neuromyelitis optica: experience from a national online registry (GRAID). J Neuroimmune Pharmacol 2016;11:1-8.

187. Damato V, Evoli A, Iorio R. Efficacy and safety of rituximab therapy in neuromyelitis optica spectrum disorders: a systematic review and meta-analysis. JAMA Neurol 2016;73:1342-8.

188. Marcinnò A, Marnetto F, Valentino P, Martire S, Balbo A, et al. Rituximab-induced hypogammaglobulinemia in patients with neuromyelitis optica spectrum disorders. Neurol Neuroimmunol Neuroinflamm 2018;5:e498.

189. Ellwardt E, Ellwardt L, Bittner S, Zipp F. Monitoring B-cell repopulation after depletion therapy in neurologic patients. Neurol Neuroimmunol Neuroinflamm 2018;5:e463.

190. Kowarik MC, Hoshi M, Hemmer B, Berthele A. Failure of alemtuzumab as a rescue in a NMOSD patient treated with rituximab. Neurol Neuroimmunol Neuroinflamm 2016;3:e208.

191. Gahlen A, Trampe AK, Haupeltshofer S, et al. Aquaporin-4 antibodies in patients treated with natalizumab for suspected MS. Neurol Neuroimmunol Neuroinflamm 2017;4:e363.

192. Azzopardi L, Cox AL, McCarthy CL, Jones JL, Coles AJ. Alemtuzumab use in neuromyelitis optica spectrum disorders: a brief case series. J Neurol 2016;263:25-9.

193. Trebst C, Jarius S, Berthele A, Paul F, Schippling S. Update on the diagnosis and treatment of neuromyelitis optica: recommendations of the neuromyelitis optica study group (NEMOS). J Neurol 2014;261:1-16.

194. Popiel M, Psujek M, Bartosik-Psujek H. Severe disease exacerbation in a patient with neuromyelitis optica spectrum disorder during treatment with dimethyl fumarate. Mult Scler Relat Disord 2018;26:204-6.

195. Stellmann JP, Krumbholz M, Friede T, Gahlen A, Borisow N, et al. Immunotherapies in neuromyelitis optica spectrum disorder: efficacy and predictors of response. J Neurol Neurosurg Psychiatry 2017;88:639-47.

196. Ayzenberg I, Schöllhammer J, Hoepner R, Hellwig K, Ringelstein M, et al. Efficacy of glatiramer acetate in neuromyelitis optica spectrum disorder: a multicenter retrospective study. J Neurol 2016;263:575-82.

197. Jarius S, Ruprecht K, Kleiter, Borisow N, Asgari N, et al. MOG-IgG in NMO and related disorders: a multicenter study of 50 patients. Part 2: Epidemiology, clinical presentation, radiological and laboratory features, treatment responses, and long-term outcome. J Neuroinflammation 2016;13:280.

198. Jurynczyk M, Messina S, Woodhall MR, Raza N, Everett R, et al. Clinical presentation and prognosis in MOG-antibody disease: a UK study. Brain 2017;140:3128-38.

199. Zipoli V, Portaccio E, Hakiki B, Siracusa G, Sorbi S, et al. Intravenous mitoxantrone and cyclophosphamide as second-line therapy in multiple sclerosis: an open-label comparative study of efficacy and safety. J Neurol Sci 2008;266:25-30.

200. Brochet B, Deloire MS, Perez P, Loock T, Baschet L, et al. Double-blind controlled randomized trial of cyclophosphamide versus methylprednisolone in secondary progressive multiple sclerosis. PLoS One 2017;12:e0168834.

201. Jacques F, Gaboury I, Christie S, Grand’maison F. Combination therapy of interferon Beta-1b and tacrolimus: a pilot safety study. Mult Scler Int 2012;2012:935921.

202. Paul F, Murphy O, Pardo S, Levy M. Investigational drugs in development to prevent neuromyelitis optica relapses. Expert Opin Investig Drugs 2018;27:265-71.

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Zhang L, Tian JY, Li B. Current immunotherapies for multiple sclerosis and neuromyelitis optica spectrum disorders: the similarities and differences. Neurosciences 2019;6:8. http://dx.doi.org/10.20517/2347-8659.2019.06

AMA Style

Zhang L, Tian JY, Li B. Current immunotherapies for multiple sclerosis and neuromyelitis optica spectrum disorders: the similarities and differences. Neuroimmunology and Neuroinflammation. 2019; 6: 8. http://dx.doi.org/10.20517/2347-8659.2019.06

Chicago/Turabian Style

Zhang, Lu, Jing-Yuan Tian, Bin Li. 2019. "Current immunotherapies for multiple sclerosis and neuromyelitis optica spectrum disorders: the similarities and differences" Neuroimmunology and Neuroinflammation. 6: 8. http://dx.doi.org/10.20517/2347-8659.2019.06

ACS Style

Zhang, L.; Tian J.Y.; Li B. Current immunotherapies for multiple sclerosis and neuromyelitis optica spectrum disorders: the similarities and differences. Neurosciences. 2019, 6, 8. http://dx.doi.org/10.20517/2347-8659.2019.06

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