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Zhang et al. Neuroimmunol Neuroinflammation 2019;6:8 I http://dx.doi.org/10.20517/2347-8659.2019.06 Page 5 of 16

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.

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].

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
[82]
rate by almost 50% . Alemtuzumab (anti-CD52), fingolimod, or natalizumab (α4-integrin inhibitor) are
[83]
recommended for patients with highly active MS . 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