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Int J Clin Exp Med 2019;12(10):11999-12012 www.ijcem.com /ISSN:1940-5901/IJCEM0098522

Review Article A critical review and bibliometric analysis of immunosuppressive therapy for neuroimmunological disorders, post-1965

Yuheng Shan1, Yanchen Lin1, Shijiang Zhong1, Xiaohui Xiang2

Departments of 1Neurology, 2Hepatopancreatobiliary and Splenic Medicine, Characteristic Medical Center of People’s Armed Police Force, Tianjin 300162, China Received June 16, 2019; Accepted September 5, 2019; Epub October 15, 2019; Published October 30, 2019

Abstract: The aim of this bibliometric analysis was to identify the characteristics and hotspots of scientific on immunosuppressive therapy for neuroimmunological disorders. Publications were retrieved from the Science Index-Expanded (SCI-E) of the (WOS) from 1965 to 2018. Bibliometric parameters, namely, citation numbers, journals, article types, country proportions, increase pattern and research hotspots, were ex- tracted and analyzed by Excel and VOSviewer software. In total, 10,181 papers were included, which were cited 285,022 times, with an average of approximately 28.00 per paper. English was the predominant language used, and the US published the largest number of articles (n = 2659). A total of 10,220 author keywords appeared 34,333 times in the retrieval, and “multiple sclerosis” was the most frequent term (n = 2626). In addition, novel immunosuppressive therapy was the pivotal research direction. Large, multicenter, randomized, placebo-controlled trials were needed to assess the efficacy of these agents in different neuroimmunological disorders.

Keywords: Bibliometric, immunosuppressive therapy, neuroimmunological disorders, hotspots

Introduction Immunosuppressive therapy is the cornerstone of the management of these neuroimmunologi- Neurological disorders encompass a broad cal disorders [6]. In general, immunosuppres- spectrum of diseases, including disorders of sive agents can be classified into five groups: the brain, spinal cord, cranial nerves, peripher- glucocorticoids, cytostatics, , drugs al nerves, autonomic nervous system, neuro- acting on immunophilins and others [7]. During muscular junction, and muscles [1]. Among the past decade, an enormous amount of scien- these disorders, several require immunosup- tific about neuroimmunology advance- pressive therapy, including neuroimmunologi- ments has improved our understanding of cal disorders [2]. This term refers to an etiologi- these immunosuppressive agents [8]. Many cal category of neurological disorders that are novel agents, such as mycophenolate mofetil characterized by the dysregulation of the (MMF) [9], [10] and [11], immune system, such as multiple sclerosis, have shown better efficacy in many neuroimmu- myasthenia gravis, immune-mediated polyneu- nological disorders. ropathy disorders and idiopathic inflammatory myopathies (IIM) [3]. These disorders are not is a quantitative and statistical rare and share common characteristics that method used to analyze the citation frequen- are progressive and disabling, which result in a cies, growth trends and research hotspots of a significant social burden [4]. Consequently, specific subject [12]. Since the first bibliometric treatment paradigms have evolved from the article was published in the Journal of the amelioration of symptoms only, into both etio- American Medical Association (JAMA) in 1987, logical treatment and symptom treatment, aim- the bibliometric method has evolved [13]. To ing at remission and cure [5]. date, many neurological disorders, such as Review in immunosuppressive therapy for neuroimmunological disorders stroke [14], migraine [15], epilepsy [16], multi- such as letters and editorial materials, repre- ple sclerosis [17], and Parkinson’s disease [18], sented less than 1.67%. Only scientific articles have been summarized and analyzed using the were included for further analysis. The majority bibliometric method; however, to the best of of the articles retrieved were in English (9,363, our knowledge, there has been no bibliometric 92.0%), followed by German (319, 3.13%), study on immunosuppressive therapies for French (198, 1.94%) and Spanish (158, 1.55%), neuroimmunological disorders. This study which corresponded to other bibliometric aimed to analyze the citation numbers, jour- analyses. nals, article types, country proportions, in- crease pattern and research hotspots of arti- Increased pattern of the articles cles related to immunosuppressive therapies of neuroimmunological disorders, searched The first article, named “Treatment of severe from SCI-Expanded post-1965. myasthenia gravis with immunosuppressive agents”, was published by Mertens et al. in Methods European Neurology in 1969 [19]. From 1969 to 1990, the number of global publications per A comprehensive, bibliographic retrieval was year remained low, representing only 0.88% of performed from the SCI-E database, accessed all articles. The annual number of articles has through the Web of Science (WOS) platform on grown rapidly since 1990. The growing trend Mar. 1, 2016. The time span was between from 1990 to 2017 fitted the curves as follows: 1965 and 2018. To obtain articles on immuno- F(x) = 0.4145×2-1633.8×+2E+06, R² = 0.9875 suppressive therapies of neuroimmunological (Figure 1). disorders as much as possible, the following search terms were used: (Immunosuppres* OR Country proportions and journals OR Cyclosporin* OR OR Natalizumab OR “” OR The 10,181 articles originated from 52 coun- OR Rituximab OR OR tries and territories (Figure 2). We extracted the OR OR top 10 countries, which contributed 7,163 pub- OR Cyclophosphamide OR Mycophenolate OR lications, accounting for 73.50% of all relevant “Glatiramer Acetate”) AND (neuropath* OR publications. Six of these countries were in encephalopath* OR “nervous system vasculi- Europe, two were in Asia, and two were in tis” OR “multiple sclerosis” OR demyelina* OR America. The US published the highest number “nervous system disease” OR dermatomyositis of publications (2,659, 27.29%), followed by OR polymyositis OR myopath* OR neuritis OR Germany (1,003, 10.29%), Italy (840, 8.62%), encephalitis OR leukoencephalopathy OR neu- France (530, 5.44%) and Japan (500, 5.13%). romyelitis OR myelitis OR “myasthenia gravis” In addition, the top 10 most productive journals OR polyneuropath*) AND treatment. The origi- are summarized in Table 1. Neurology ranked nal data were extracted for further analysis. first and contributed the most articles (373), Two researchers conducted and verified the followed by the Journal of Neuroimmunology bibliographic retrieval independently. (372) and Multiple Sclerosis Journal (278).

Results Characteristics of the top 10 most frequently cited articles The distribution of publication type and lan- guage The top ten articles accounted for 13,396 cita- tions, which represented 4.70% of the total The literature search yielded a total of 15,011 (Table 2). A study by Jacobs et al., published in publications on immunosuppressive therapies 1996 [20], was the most cited article (1,885 of neurological disorders from January 1965 to times), while a study by Polman et al., published March 2018. Among them, 10,181 were scien- in 2006 [21], received the most annual cita- tific articles, comprising 67.8% of the total pub- tions (140.33 times). Among these ten articles, lications. Other popular document types were eight were related to immunosuppressive ther- reviews (2,676, 17.8%), meeting abstracts apies of multiple sclerosis, investigating the (1,038, 6.91%) and proceedings papers (504, treatment efficacy of interferon, natalizumab 3.36%). The remaining types of publications, and fingolimod.

12000 Int J Clin Exp Med 2019;12(10):11999-12012 Review in immunosuppressive therapy for neuroimmunological disorders

Figure 1. Model fitting curves of growth trends of the accumulated number of publications on immunosuppressive therapy for neuroimmunological disorders from 1969 to 2017 worldwide. The fitting equation from 1990 to 2017 is: Y = 0.4145×2-1633.8×+2E+06, R² = 0.9875. Y is the number of articles, and X is the year.

12001 Int J Clin Exp Med 2019;12(10):11999-12012 Review in immunosuppressive therapy for neuroimmunological disorders

Figure 2. Map of countries and territories that published articles. The size of the symbols represents the number of articles, and the thickness of the line represents country co-authorships.

Table 1. Leading 10 journals for immunosuppressive therapy publications SCR Journal name Number of documents (%) IFa 1st Neurology 373 (3.66) 7.592 2nd Journal of Neuroimmunology 372 (3.65) 2.72 3rd Multiple Sclerosis Journal 278 (2.73) 4.84 4th Journal of Neurology 209 (2.05) 3.389 5th Journal of the Neurological Sciences 206 (2.02) 2.295 6th Plos One 205 (2.01) 2.806 7th Multiple Sclerosis 190 (1.87) NA 8th Journal of Immunology 134 (1.32) 4.856 9th European Journal of Neurology 116 (1.14) 3.988 10th Journal of Neurology, Neurosurgery and Psychiatry 113 (1.11) 7.349 SCR, standard competition ranking; IF, . aThe impact factor was reported according to Journal Citation Reports (JCR) 2017.

Main research hotspots limod (85.4%), rituximab (53.2%), progressive multifocal leukoencephalopathy (PML) (61.6%), To identify the main research hotspots in immu- neuromyelitis optica (NMO) (71.6%), relapsing nosuppressive therapies for neuroimmunologi- remitting multiple sclerosis (RRMS) (61.5) and cal disorders, author keywords were retrieved disease modifying therapy (65.5%), which may from these articles. Then, we integrated some represent the hotspots in this field. author keywords that represent identical disor- ders or medicine, such as “natalizumab” and Author keywords appearing more than 70 times “Tysabri”, “fingolimod” and “FTY720”, “dimethyl were entered into the VOSviewer software to fumarate” and “BG12”, etc. A total of 10,220 construct their concurrence network. Overall, author keywords appeared 34,333 times, 47 terms were set out in the figure and mainly including 7,561 author keywords that appeared stratified into four clusters Figure ( 3A). The only once. Articles before 1988 lacked key- green cluster included terms mainly represent- words, so the research hotspots were based on ing central nervous system inflammatory demy- keywords from 1988 to 2017. To determine the elinating diseases (CIDD) and relevant treat- research trends in this field, we divided the ments, such as multiple sclerosis, NMO and studies into 5 periods, namely, 1988 to 1993, interferon beta. The red cluster included terms 1994 to 1999, 2000 to 2005, 2006 to 2011 mainly related to other autoimmune diseases and 2012 to 2017. Among these keywords, and neurological disorders, such as myasthe- multiple sclerosis was the most frequent term nia gravis, dermatomyositis and polymyositis. (2,626 times), followed by five mainly used The blue cluster included terms about mecha- drugs, interferon beta (611 times), natalizumab nisms of autoimmune disease, such as cyto- (396 times), fingolimod (335 times), glatiramer kine, inflammation and neuroprotection. Finally, acetate (GA) (330 times) and rituximab (278 the yellow cluster included terms about side times). The top 30 most frequently used author effects of immunosuppressive treatment, such keywords and their rankings in different peri- as PML and John Cunningham (JC) virus. ods were listed in Table 3, of which 11 key- words were immunosuppressive drugs, and 7 According to the average of each author key- keywords were neuroimmunological disorders. word appearing each year, VOSviewer coded The ranking and percentage of the frequency of these terms in different colors (Figure 3B). author keywords in different periods was sym- Terms in blue represented earlier appearances bolized as “R (%)” in Table 3. Author keywords than those in yellow and red. Most neurological that appeared more than half of the time from disorders were in blue and yellow, such as mul- 2012 to 2017 were natalizumab (66.2%), fingo- tiple sclerosis, myasthenia gravis and dermato-

12002 Int J Clin Exp Med 2019;12(10):11999-12012 Review in immunosuppressive therapy for neuroimmunological disorders

Table 2. The top 10 papers with the most citation frequency for immunosuppressive therapy publication Citation frequency Title First author Journal Year Citations Main conclusion per year Intramuscular interferon beta-1 alpha for Jacobs [20] Annals of Neurology 1996 1885 85.68 They confirmed that intramuscular interferon beta-1 alpha disease progression in relapsing multiple had a significant beneficial impact in relapsing MS patients sclerosis and provided a foundation for standard treatment of relapsing multiple sclerosis. A reversible posterior leukoencephalopathy Hinchey [22] New England Journal of Medicine 1996 1767 80.32 They reported a reversible syndrome named reversible syndrome posterior leukoencephalopathy syndrome that may develop in patients who have renal insufficiency or who are immunosup- pressed. A randomized, placebo-controlled trial of Polman [21] New England Journal of Medicine 2006 1684 140.33 Treatment with alpha-4 antagonist natalizumab led natalizumab for relapsing multiple sclerosis to fewer inflammatory brain lesions and fewer relapses over a six-month period in patients with relapsing MS. Interferon beta-1b is effective in relapsing- Duquette [23] Neurology 1993 1571 62.84 Subcutaneous injection interferon beta-1b at a dose of either remitting multiple sclerosis. I. Clinical results 1.6 or 8 MIU every other day was confirmed to be efficacious of a multicenter, randomized, double-blind, in the reduction of exacerbation rates for relapsing-remitting placebo-controlled trial MS. Randomized double-blind placebo-controlled Ebers [24] Lancet 1998 1487 74.35 Subcutaneous interferon beta-1a was an effective treatment study of interferon beta-1a in relapsing/ for relapsing-remitting MS in terms of relapse rate and de- remitting multiple sclerosis fined disability in a dose-related manner. Oral fingolimod or intramuscular interferon Cohen [25] New England Journal of Medicine 2010 1083 135.38 They showed superior efficacy of oral fingolimod at a daily for relapsing multiple sclerosis dose of either 1.25 or 0.5 mg for relapsing-remitting MS compared with intramuscular interferon beta-1a at a weekly dose of 30 µg. Interferon beta-1b is effective in relapsing- Paty [26] Neurology 1993 1080 43.2 Through yearly MRI analyses on relapsing-remitting MS pa- remitting multiple sclerosis. II. MRI analysis tients, interferon beta-1b was confirmed to have a significant results of a multicenter, randomized, impact on the natural history of MS. double-blind, placebo-controlled trial Intramuscular interferon beta-1a therapy Jacobs [27] New England Journal of Medicine 2000 1032 57.33 Initiating treatment with interferon beta-1a at the time of a initiated during a first demyelinating event in first demyelinating event is beneficial for patients with brain multiple sclerosis lesions on MRI that indicate a high risk of clinically definite multiple sclerosis. IL-17 plays an important role in the Komiyama [28] Journal of Immunology 2006 973 81.08 They demonstrated that IL-17, rather than IFN-gamma, plays a development of experimental autoimmune crucial role in the development of EAE. encephalomyelitis Interferon beta-1b in the treatment of Duquette [29] Neurology 1995 834 36.26 Interferon beta-1b had a persistent beneficial effect on the ex- multiple-sclerosis final outcome of the acerbation rate and MRI burden of disease and was relatively randomized controlled trial free of long-term side effects. MS, multiple sclerosis; MIU, million international units; EAE, experimental autoimmune encephalomyelitis.

12003 Int J Clin Exp Med 2019;12(10):11999-12012 Review in immunosuppressive therapy for neuroimmunological disorders

Table 3. Top 30 author keywords from 1988-2017 for immunosuppressive therapy publications 1988-2017 1988-1993 1994-1999 2000-2005 2006-2011 2012-2017 Author keywords TP TP R (%) TP R (%) TP R (%) TP R (%) TP R (%) Multiple sclerosis 2626 16 1 (0.6) 161 1 (6.1) 451 1 (17.2) 761 1 (29.0) 1216 1 (46.3) Interferon beta 611 NA NA 46 2 (7.5) 158 2 (25.9) 211 2 (34.5) 192 4 (31.4) Natalizumab 396 NA NA NA NA 8 97 (2.0) 123 3 (31.1) 262 3 (66.2) Fingolimod 335 NA NA NA NA 2 476 (0.1) 41 22 (12.2) 286 2 (85.4) Glatiramer acetate 330 NA NA 3 152 (1.0) 77 3 (23.3) 120 4 (36.4) 127 7 (38.5) Treatment 295 NA NA 31 4 (10.5) 45 8 (15.3) 80 8 (27.1) 135 6 (45.8) Rituximab 278 NA NA NA NA 15 48 (5.4) 109 5 (39.2) 148 5 (53.2) MRI 276 5 10 (1.8) 21 9 (7.6) 50 5 (18.1) 80 9 (29.0) 117 8 (42.4) Myasthenia gravis 257 10 4 (3.9) 28 6 (10.9) 46 7 (17.5) 87 6 (33.9) 84 14 (32.7) Interferon 253 8 6 (3.2) 20 10 (7.9) 48 6 (19.0) 85 7 (33.6) 92 11 (36.4) Cytokine 246 4 14 (1.6) 41 3 (16.7) 62 4 (25.2) 69 10 (28.0) 67 17 (27.2) PML 185 NA NA 6 57 (3.2) 10 67 (5.4) 54 12 (29.2) 114 9 (61.6) EAE 178 7 9 (3.9) 6 57 (3.4) 25 20 (13.4) 49 15 (27.5) 88 13 (49.4) Dermatomyositis 176 7 8 (4.0) 9 38 (5.1) 12 34 (6.8) 50 14 (28.4) 75 16 (42.6) 176 7 7 (4.0) 30 5 (17.0) 28 16 (15.9) 57 11 (32.4) 53 24 (30.1) Neuromyelitis optica 155 NA NA NA NA 3 269 (1.9) 41 20 (26.5) 111 10 (71.6) Cyclophosphamide 146 11 3 (7.5) 20 11 (13.7) 27 18 (18.5) 41 21 (28.1) 46 30 (31.5) Interferon beta 1a 145 NA NA 11 30 (7.6) 45 9 (31.0) 43 17 (29.6) 46 29 (31.7) RRMS 143 NA NA 4 91 (2.8) 20 27 (14.0) 30 34 (21.0) 88 12 (61.5) Autoimmunity 141 4 16 (2.8) 22 8 (15.6) 35 11 (24.8) 40 24 (28.4) 39 39 (27.7) Interferon gamma 136 5 9 (3.7) 26 7 (19.1) 41 10 (30.1) 27 43 (19.9) 32 51 (23.5) Polymyositis 131 4 15 (3.1) 14 17 (10.7) 32 14 (24.4) 32 31 (24.4) 48 27 (36.6) Inflammation 129 1 272 (0.8) 6 67 (4.65) 22 24 (17.1) 34 28 (26.4) 64 18 (49.6) Disease modifying therapy 128 NA NA NA NA 3 286 (2.3) 44 16 (34.4) 84 15 (65.6) Autoimmune disease 123 2 33 (1.6) 8 45 (6.5) 24 22 (19.5) 33 30 (26.8) 55 23 (44.7) Therapy 118 3 26 (2.5) 9 36 (7.6) 32 13 (27.1) 42 18 (35.6) 31 54 (26.3) Interferon beta 1b 115 NA NA 13 21 (11.3) 30 15 (26.1) 29 37 (25.2) 42 35 (36.5) Neutralizing antibodies 110 NA NA 4 96 (3.6) 19 33 (17.3) 50 13 (45.5) 37 42 (33.6) IVIg 105 3 29 (2.9) 13 20 (12.4) 18 39 (17.1) 41 21 (39.0) 30 58 (28.6) Hepatitis C 105 NA NA 12 25 (11.4) 19 26 (18.1) 34 29 (32.4) 32 52 (30.5) NA, not available; TP, total articles; R (%), ranking and percentage of author keywords; PML, progressive multifocal leukoencephalopathy; EAE, experimental autoimmune encephalomyelitis; RRMS, relapsing remitting multiple sclerosis; IVIg, intravenous immunoglobulin. myositis, with the exception of NMO and RRMS. Author keyword used in bibliometrics can be On the other hand, red items were mainly used to trace the research trend information immunosuppressive drugs, such as fingolimod and identify hotspots [31]. In this study, a total and natalizumab. of 10,220 author keywords appeared 34,333 times. In general, these keywords could be Discussion divided into two groups: neuroimmunological disorders and immunosuppressive drugs. Over the last two decades, marked progress has been made in the area of immunosuppres- Neuroimmunological disorders sive therapy for neuroimmunological disorders [30]. To our knowledge, this is the first study Neuroimmunological disorders were previously that presents a comprehensive bibliometric identified as several countable disorders, review on immunosuppressive therapies of including multiple sclerosis, myasthenia gravis, neuroimmunological disorders. In this study, polymyositis, dermatomyositis and Guillain- we have assessed bibliometric parameters, Barré syndrome (GBS) [32]. Since then, a broad including citation numbers, journals, article spectrum of neuroimmunological disorders has types, country proportions and increased pat- steadily grown based on numerous develop- tern. To detect the most researched topics, ments in molecular genetics, pathogenesis and research hotspots were highlighted in our diagnosis. Among these disorders, multiple study. sclerosis remains the predominant entity in

12004 Int J Clin Exp Med 2019;12(10):11999-12012 Review in immunosuppressive therapy for neuroimmunological disorders

12005 Int J Clin Exp Med 2019;12(10):11999-12012 Review in immunosuppressive therapy for neuroimmunological disorders

Figure 3. Map of keywords appearing more than 70 times on immunosuppressive therapy for neuroimmunological disorders. A. The size of the circle represents the frequency of the keyword, and the colors represent groups of terms that are strongly linked to each other. These keywords were divided into four clusters: cluster 1, “CIDD and relevant treatments”; cluster 2, “other neuroimmunological disorders except CIDD”; cluster 3, “mechanism of autoimmune disease”; and cluster 4, “side effects of immunosuppressant treatment”. B. Colors represent the earlier (blue color) or later (red color) years based on the average time of the appearance of each keyword. terms of social burden and prevalence [33]. In tively sparse and retrospective. Even so, aza- our study, multiple sclerosis, the most frequent- thioprine (AZA) and rituximab are still recom- ly observed author keyword, appeared 2,626 mended as first-line therapies for NMO [42]. In times. Moreover, RRMS, one of the main sub- 2017, an observational study compared the types of multiple sclerosis according to clinical efficacy and tolerability of MMF and AZA and courses, appeared 143 times. Another type of reported no significant differences in maintain- CIDD, NMO, once regarded as a rare form of ing a relapse-free state, but fewer and milder multiple sclerosis before aquaporin-4 (AQP4) adverse events were attributed to MMF than antibodies were found, appeared 155 times. To AZA [43]. This study indicates that MMF may be discriminate NMO from multiple sclerosis a better choice than AZA for NMO patients. beginning with optic neuritis and myelitis, diag- Other novel agents, namely, and nostic criteria of NMO was first published in , have reported promising results 1999 [34] and then revised in 2006 [35] and showing an improvement of annualized relapse 2015 [36]. These advances have made NMO rates and moderate adverse effects for NMO one of the research highlights of CIDD, and a [44]; however, these treatment recommenda- series of new concepts have been raised, such tions are mainly based on retrospective case- as NMO spectrum disorder (NMOSD) [37] and series, and prospective controlled trials are clinically isolated syndrome (CIS) [36]. The clini- needed to assess their effectiveness in treat- cal courses of these two conditions are similar ing this incurable disease. and include relapse and remission. For acute events, high-dose, intravenous methylprednis- Other than CIDD, myasthenia gravis, another olone, intravenous immunoglobulin (IVIg) and conventional type of autoimmune disease that plasma exchange may improve relapse symp- is characterized by fluctuating muscle weak- toms and restore neurological functions [38]. ness and fatigue, appeared 257 times. Due to For long-term therapy, immunosuppressive the detection of autoimmune antibodies ag- treatment is indispensable in preventing fur- ainst the acetylcholine receptor (AChR) [45], ther attacks. According to a network meta-anal- muscle-specific kinase (MuSK) [46] and lipo- ysis published in 2015, moderate- to high- protein-related protein 4 (LRP4) [47], myasthe- quality evidence (Grading of Recommendations nia gravis is now identified as a B-cell-mediated Assessment, Development and Evaluation, disease. Immunosuppressive treatment is nec- GRADE) suggests that alemtuzumab, natali- essary for patients who do not adequately zumab, fingolimod and dimethyl fumarate can respond to pyridostigmine [48]. Corticosteroids reduce relapsing in RRMS, and natalizumab is and cyclosporine were the preferred immuno- even associated with a lower risk of condition suppressant, and MMF and AZA were used as worsening [39]. These immunosuppressive second-choice agents [49]. In addition, small drugs have changed the treatment protocols of case series indicate satisfactory efficacy of RRMS over the last 20 years. However, many rituximab, particularly in AChR -nega- people living with RRMS cannot access these because of their high costs [40]. tive, MuSK antibody-positive patients [50]. On the grounds of a cost-utility analysis pub- Another two relatively uncommon neuroimmu- lished in 2018, natalizumab and nological disorders are dermatomyositis and dominated the other immunosuppressive drugs polymyositis, which appeared 176 times and with more quality-adjusted life-years for lower 131 times, respectively. These two diseases costs, which may make them a preferred choice are subtypes of IIM and can result in persisting for RRMS patients [41]. muscle weakness with significant disability [51]. Corticosteroids are the principal treat- On the other hand, evidence on the long-term ment to IIM, while other immunosuppressive immunosuppressive treatment of NMO is rela- agents, such as infliximab and AZA, have not

12006 Int J Clin Exp Med 2019;12(10):11999-12012 Review in immunosuppressive therapy for neuroimmunological disorders shown certain efficacy due to a lack of high- , another frequently used author quality RCTs [52]. keyword that appeared 1,260 times, represent a family of cytokines that were originally named Nevertheless, not all neuroimmunological dis- for their ability to “interfere” with viral replica- orders require immunosuppressant treatment. tion and can be classed into three subfamilies, GBS is known as a neuroimmunological disor- namely, type I, type II, and type III [60]. der with an autoantibody response against the Interferon beta was initially used as a first-line outer surface of the Schwann cell since four therapeutic for the treatment of RRMS 20 years ganglioside antibodies were found, namely, ago. To date, subcutaneous interferon beta is GM1, GD1a, GT1a, and GQ1b [53]. Both B and still the most commonly used drug for RRMS, T lymphocytes are likely to play a role in the dif- reducing relapse rates by approximately 35% ferent stages of GBS. In this respect, immuno- and extending remission periods [61]. The suppressant treatment in GBS seems reason- mechanism of how interferon beta works is still able. In contrast, either oral corticosteroids or unclear. Potential mechanisms include the inhi- intravenous methylprednisolone has been bition of immune cell trafficking across the shown to be invalid in the treatment of patients blood-brain barrier, the regulation of immune with GBS [54]. In addition to glucocorticoids, cell activation and proliferation, triggering T-cell MMF, a relatively new immune suppressive apoptosis and possibly also neuroprotective agent and suppressor of B and T lymphocy- effects [62]; however, the usage of interferon tes, displayed no additional value either [55]. beta in neuroimmunological disorders is Compared to immunosuppressant treatment, restricted to multiple sclerosis. Previously, plasma exchange [56] and IVIg [57] have shown interferon beta was tried as a therapeutic for significant benefit and availability, and IVIg is NMO, but it turned out to be ineffective and the preferred treatment. The reason for the even harmful in some cases [63]. Another wide- ineffectiveness of immunosuppressant treat- ly used first-line therapeutic for RRMS is GA. ment may be due to the acute, one-way course The mechanism of action for GA probably of GBS and pattern of ganglioside antibodies, includes the inhibition of the immune response which are mainly of the Immunoglobulin G (IgG) to myelin basic protein and other myelin anti- subclass. gens [64]. A meta-analysis published in 2016 Other rare neuroimmunological disorders, such compared the effects of interferon beta and GA as multifocal motor neuropathy (MMN) and IgM in the treatment of people with RRMS and anti-myelin-associated peripheral neuropathy, found no significant difference in disease have responded to some novel agents, such as relapse and progression [65]. The efficacy of rituximab, cladribine and fludarabine, in several GA in other neuroimmunological disorders is uncontrolled studies [58]. Nevertheless, these unclear and not recommended. flawed and variable conclusions are insufficient Unlike those conventional drugs, monoclonal to support the use of immunosuppressant ther- antibodies are a new generation of drugs for apies in clinical settings. Thus, large and well- immunosuppressive therapy, represented by designed, randomized trials are needed to natalizumab and rituximab. Natalizumab is a assess the efficacy of novel immunosuppres- kind of humanized against sant treatment for disorders with uncertain alpha-4 integrin on the surface of lymphocytes, efficacy. inhibiting the entry of CD4+ and CD8+ T lym- Immunosuppressive drugs phocytes into the brain through the blood-brain barrier [66]. Natalizumab is the first and, to According to the different mechanisms and date, the only monoclonal antibody that is structures, immunosuppressive drugs can be approved by the US Food and Drug divided into five groups, namely, glucocorti- Administration (FDA) for the treatment of coids, cytostatics, antibodies, drugs acting on RRMS, which could reduce the annual relapse immunophilins and others [59]. Other than glu- rate by approximately 60% [67]; however, natal- cocorticoids, commonly used immunosuppres- izumab fails to control disease activity in sive drugs in clinical settings are interferons, patients with NMO and other neuroimmunologi- GA, natalizumab, rituximab, cyclophosphamide cal disorders [68]. Rituximab is a type of anti- (CTX), MMF and AZA. CD20 B-cell depleting agent, similar to ocreli-

12007 Int J Clin Exp Med 2019;12(10):11999-12012 Review in immunosuppressive therapy for neuroimmunological disorders zumab and ofatumumab [69]. In a retrospective ment was 3.1% at 5 years and 5.9% at 8 years, study published in 2018, rituximab was com- which revealed no statistically significant differ- pared to all other treatments in a cohort of ence compared with the general population RRMS, showing better efficacy and drug dis- [78]. This negative result, apparently contradic- continuation than other commonly used immu- tory to traditional concepts, may be explained nosuppressive drugs in patients with newly by the low cumulative doses that patients diagnosed RRMS [70]. Rituximab is also used received. As for the newest immunosuppres- as first-line therapy for NMO. In a retrospective sive drugs, such as dimethyl fumarate, ritux- analysis, NMO patients receiving rituximab pre- imab and ocrelizumab, no risk of cancer has sented a 97% decrease of annualized relapse been reported. Nevertheless, a strict, long- rate and was well tolerated [71]. This result is term follow-up must be planned in patients tak- inspiring but also dubious because of the small ing immunosuppressive drugs to avoid a poten- scale of the study. Other than CIDD, rituximab tial risk of cancer. also shows good efficacy in other neuroimmu- nological disorders, such as myasthenia gravis Limitations [50] and IIM [72]. There are several limitations to this study. First, Considering the side effects, however, immuno- we only recruited papers in English and may suppressant treatment is a double-edged have missed some important research pub- sword. Therefore, physicians have historically lished in other languages. Secondly, we may been reluctant in regard to the usage of immu- have missed a considerable amount of papers nosuppressive drugs. In addition to the many published in non-SCI journals, since the data in side effects, which include conditions such as this study were only collected from SCI-E in hypertension, hyperglycemia, peptic ulcers, WOS. Third, the search strategy was not perfect and liver and kidney injury, immunodeficiency, for either “neuroimmunological disorders” or resulting in increased susceptibility to infec- “immunosuppressive drugs” due to difficulty to tions and higher risk of cancer, is a major con- summarize. To compensate for this pitfall, cern [73]. Natalizumab was initially approved another study representing the whole global by the FDA in 2004 but was withdrawn in 2005 research output in this field is needed to make because three participants in the drug’s clinical a thorough review on immunosuppressive ther- trials developed PML [74]. PML is an opportu- apies of neuroimmunological disorders. nistic demyelinating brain disease caused by JC virus infection after immune deficiency. Conclusions Although natalizumab was subsequently ap- proved again by FDA in 2006, positive JC virus Over the last two decades, marked progress serology results remain the primary cause for has been made in the area of immunosuppres- therapy discontinuation. Prior to 2015, there sive therapy in neuroimmunological disorders. were 563 confirmed cases of PML during natal- Treatment options have grown from the use of izumab therapy for multiple sclerosis [75]. The steroids only to the use of recombinant cyto- overall incidence was almost four per 1,000 kines, monoclonal antibodies and other com- patients treated. pounds specifically targeting committed steps of an evolving autoimmune reaction. However, For classical, cytotoxic, immunosuppressive most neuroimmunological disorders are still drugs such as CTX and AZA, the major side incurable. Novel immunosuppressive therapy is effect is the increase in risk of cancer due to one of the pivotal research directions, but for impaired immune surveillance, facilitation of many indications, the efficacy is only docu- oncogenic viruses and alterations to DNA [76]. mented by small studies. Thus, large, multi- Many publications have reported that chronic center, randomized, placebo-controlled trials immunosuppression with AZA increases the should be performed to assess the efficacy of risk of malignancy in humans, especially for these agents in different neuroimmunological long-term (>10 years) treatment, and high disorders. cumulative CTX doses are associated with an increased risk of bladder cancer and lympho- Acknowledgements mas [77]. In a prospective study on a cohort of CTX treated multiple sclerosis patients, the This study was funded by the Key Technologies cumulative incidence of cancer after CTX treat- R&D Program of Tianjin (No. 16KG136) and

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National Foundation of China Camdessanche JP, Labauge P, Moreau T, Bras- (No. 31200838). sat D, Stankoff B, de Seze J, Vukusic S, Mari- gnier R; NOMADMUS study group and the Ob- Disclosure of conflict of interest servatoire Français de la Sclérose en Plaques (OFSEP). Effectiveness of mycophenolate None. mofetil as first-line therapy in AQP4-IgG, MOG- IgG, and seronegative neuromyelitis optica Address correspondence to: Dr. Shijiang Zhong, spectrum disorders. Mult Scler 2017; 23: Department of Neurology, Characteristic Medical 1377-1384. Center of People’s Armed Police Force, 220 Chenglin [10] Setayeshgar S, Kingwell E, Zhu F, Zhang X, Road, Hedong District, Tianjin 300162, China. Tel: Zhang T, Marrie RA, Carruthers R and Tremlett H. Use of the new oral disease-modifying ther- +86-13102296029; E-mail: zhongshijiang1@163. apies for multiple sclerosis in British Columbia, com; Dr. Xiaohui Xiang, Department of Hepatopan- Canada: the first five-years. Mult Scler Relat creatobiliary and Splenic Medicine, Characteristic Disord 2018; 25: 57-60. Medical Center of People’s Armed Police Force, 220 [11] Ziemssen T and Thomas K. Alemtuzumab in Chenglin Road, Hedong District, Tianjin 300162, the long-term treatment of relapsing-remitting China. Tel: +86-2260-578929; E-mail: xiaohuixi- multiple sclerosis: an update on the clinical [email protected] trial evidence and data from the real world. Ther Adv Neurol Disord 2017; 10: 343-359. References [12] Han JS and Ho YS. Global trends and perfor- mances of research. Neurosci [1] Liewluck T and Miravalle A. Immune-mediated Biobehav Rev 2011; 35: 680-687. neurological disorders. Curr Neurol Neurosci [13] Garfield E. 100 citation classics from the jour- Rep 2015; 15: 61. nal of the American medical association. JAMA [2] Bhattacharya A, Derecki NC, Lovenberg TW 1987; 257: 52-59. and Drevets WC. Role of neuro-immunological [14] Malhotra K, Saeed O, Goyal N, Katsanos AH factors in the pathophysiology of mood disor- and Tsivgoulis G. Top-100 highest-cited origi- ders. Psychopharmacology (Berl) 2016; 233: nal articles in ischemic stroke: a bibliometric 1623-1636. analysis. World Neurosurg 2018; 111: e649- [3] Johnson C, Rosen P, Lloyd T, Horton M, Christo- e660. pher-Stine L, Oddis CV, Mammen AL and Dan- [15] Park KM, Park BS, Park S, Yoon DY and Bae JS. off SK. Exploration of the MUC5B promoter Top-100 cited articles on headache disorders: variant and ILD risk in patients with autoim- a bibliometric analysis. Clin Neurol Neurosurg mune myositis. Respir Med 2017; 130: 52-54. 2017; 157: 40-45. [4] Falkenberg KJ and Johnstone RW. Histone [16] Park KM, Kim SE, Lee BI, Kim HC, Yoon DY, deacetylases and their inhibitors in cancer, Song HK and Bae JS. Top 100 cited articles on neurological diseases and immune disorders. epilepsy and status epilepticus: a bibliometric Nat Rev Drug Discov 2014; 13: 673-691. analysis. J Clin Neurosci 2017; 42: 12-18. [5] Florez-Grau G, Zubizarreta I, Cabezon R, Villo- [17] Rikos D, Dardiotis E, Tsivgoulis G, Zintzaras E slada P and Benitez-Ribas D. Tolerogenic den- and Hadjigeorgiou GM. Reporting quality of dritic cells as a promising antigen-specific randomized-controlled trials in multiple sclero- therapy in the treatment of multiple sclerosis sis from 2000 to 2015, based on CONSORT and neuromyelitis optica from preclinical to statement. Mult Scler Relat Disord 2016; 9: clinical trials. Front Immunol 2018; 9: 1169. 135-139. [6] Schnider C, Seebach JD, Ribi C and Spertini F. [18] Araujo R, Sorensen AA, Konkiel S and Bloem Systemic and neurological uses of immuno- BR. Top altmetric scores in the parkinson’s dis- suppressive agents. Rev Med Suisse 2013; 9: ease literature. J Parkinsons Dis 2017; 7: 81- 915-921. 87. [7] Diekmann F. Immunosuppressive minimiza- [19] Wang L, Huan X, Xi JY, Wu H, Zhou L, Lu JH, tion with mTOR inhibitors and belatacept. Zhang TS and Zhao CB. Immunosuppressive Transpl Int 2015; 28: 921-927. and monoclonal antibody treatment for myas- [8] Patti F, Chisari CG, D’Amico E and Zappia M. thenia gravis: a network meta-analysis. CNS Pharmacokinetic drug evaluation of daclizum- Neurosci Ther 2019; 25: 647-658. ab for the treatment of relapsing-remitting [20] Jacobs LD, Cookfair DL, Rudick RA, Herndon multiple sclerosis. Expert Opin Drug Metab RM, Richert JR, Salazar AM, Fischer JS, Good- Toxicol 2018; 14: 341-352. kin DE, Granger CV, Simon JH, Alam JJ, Barto- [9] Montcuquet A, Collongues N, Papeix C, Zephir szak DM, Bourdette DN, Braiman J, Brown- H, Audoin B, Laplaud D, Bourre B, Brochet B, scheidle CM, Coats ME, Cohan SL, Dougherty

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