Long-term efficacy of mycophenolate mofetil in myelin ...diagnosis, we used IIFT with a MOG antibody in this real-world clinical study. The imbalance follow-up times is a bias that

ARTICLE OPEN ACCESS CLASS OF EVIDENCE

Long-term efficacy of mycophenolate mofetilin myelin oligodendrocyte glycoproteinantibody-associated disordersA prospective study

Shengde Li MD Haitao Ren BS Yan Xu MD PhD Tao Xu MD Yao Zhang MD Hexiang Yin MD

Weihua Zhang MD Jiuwei Li MD Xiaotun Ren MD Fang Fang MD Wenhan Li MD Yicheng Zhu MD

Bin Peng MD Jing Wang MD Yong Zhong MD and Liying Cui MD

Neurol Neuroimmunol Neuroinflamm 20207e705 doi101212NXI0000000000000705

Correspondence

Dr Xu

xuyanpumchhotmailcom

AbstractObjectiveTo investigate whether the use of mycophenolate mofetil (MMF) could reduce the relapse risk inpatients with myelin oligodendrocyte glycoprotein (MOG)-immunoglobulin G (IgG)-associateddisorders (MOGADs)

MethodsThis prospective observational cohort study included patients with MOGAD at Peking UnionMedical College Hospital between January 1 2017 and April 30 2019 The patients weredivided into 2 groups those with (MMF+) or without (MMFminus) MMF therapy The primaryoutcome was relapse at follow-up We used Cox proportional hazards models to calculatehazard ratios (HRs) for relapse

ResultsSeventy-nine patients were included in ourMOG cohort Fifty (633) were adults at index dateand 47 (595) were women Fifty-four (684) were in theMMF+ group and 25 (316) werein the MMFminus group Clinical and demographic factors MOG-IgG titer and follow-up time(median 4725 days for MMF+ 2610 days for MMFminus) were comparable between the groupsRelapse rates were 74 (454) in theMMF+ group and 440 (1125) in theMMFminus group Ofall potential confounders only the use of MMF was associated with reduced risk of relapse TheHR for relapse among patients in the MMF+ group was 014 (95 CI 005ndash045) and was 008(95 CI 002ndash028) in a model adjusted for age sex disease course and MOG-IgG titer MMFtherapy also remained associated with a reduced relapse risk in sensitivity analyses Only onepatient (19) discontinued MMF therapy because of adverse effect

ConclusionsThese findings provide a clinical evidence that MMF immunosuppression therapy may preventrelapse in patients with MOGAD

Classification of evidenceThis study provides class IV evidence that for patients with MOGAD MMF reduces relapserisk

MORE ONLINE

Class of EvidenceCriteria for ratingtherapeutic and diagnosticstudies

NPuborgcoe

From the Department of Neurology (SL HR YX Y Zhang HY Y Zhu BP LC) Peking Union Medical College Hospital Peking Union Medical College and Chinese Academy ofMedical Sciences Department of Epidemiology and Biostatistics Institute of Basic Medical Sciences (TX) Chinese Academy of Medical Sciences amp School of Basic Medicine PekingUnion Medical College Department of Neurology (WZ JL XR FF) Beijing Childrenrsquos Hospital Capital Medical University National Center for Childrenrsquos Health Oumeng VMedicalLaboratory (WL) Hangzhou CAS Key Laboratory of Mental Health (JW) Institute of Psychology Beijing China Department of Psychology University of Chinese Academy of SciencesDepartment of Ophthalmology (Y Zhong) Peking UnionMedical College Hospital Peking UnionMedical College and Chinese Academy ofMedical Sciences andNeurosciences Center(LC) Chinese Academy of Medical Sciences Beijing China

Go to NeurologyorgNN for full disclosures Funding information is provided at the end of the article

The Article Processing Charge was funded by the authors

This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 40 (CC BY-NC-ND) which permits downloadingand sharing the work provided it is properly cited The work cannot be changed in any way or used commercially without permission from the journal

Copyright copy 2020 The Author(s) Published by Wolters Kluwer Health Inc on behalf of the American Academy of Neurology 1

Myelin oligodendrocyte glycoprotein (MOG) which isexpressed on the surface of myelin sheaths in the CNS istargeted by antibodies (MOG-immunoglobulin G [IgG]) ininflammatory demyelinating disorders12 including MS acutedisseminated encephalomyelitis (ADEM) neuromyelitisoptica spectrum disorder (NMOSD) and optic neuritis al-though positive rate is very low in MS134 However clinicalradiologic CSF and prognostic features in patients with se-ropositive MOG-IgG are distinct from those in patients withseropositive AQP4-IgG NMOSD seronegative NMOSD orMS5ndash7 With the aid of serum MOG-IgG detected by trans-fected cell-based assay seropositive MOG-IgG demyelinatingdisorders are now classified as a separate disease entity withdistinct diagnostic criteria28

Patients with MOG-IgG-associated disorders (MOGADs)exhibit a predominantly relapsing and often severe diseasecourse from 36 relapse rate in a median 16-month to 80 ina mean 75-month follow-up period910 Many patients do notcompletely recover from the onset attack with 47 ofpatients having permanent disability10 Although the long-term immunosuppression therapy seemed to reduce relapserisk there is a lack of prospective data and large samplestudies910 In view of the heterogeneity of the treatmentsgiven there is still a need to define an optimal strategy es-pecially considering that the relapse rate of treated patients isstill too high9 Therefore prophylactic long-term treatmentsremain insufficiently effective with little evidence for theability of long-term therapy to reduce relapse risk amongpatients with MOGAD Here we conducted a prospectiveobservational cohort study of patients with MOGAD to de-termine the association of relapse risk and the use of myco-phenolate mofetil (MMF) because the efficiency and safety ofMMF has been confirmed in patients with NMOSD1112

MethodsStudy design and patientsPatients enrolled in the Peking Union Medical College hospitalMSNMOBase database12 were followed up prospectively in theperiod of 2017ndash2019 after undergoing a MOG-IgG laboratorytest (figure 1) Participating patients were included into theMOG cohort when they met all the following criteria (1)clinical presentation of ADEM optic neuritis (including chronicrelapsing inflammatory optic neuropathy) transverse myelitisandor brain or brainstem syndrome compatible with de-myelination (2) serum positive for MOG-IgG by a fixed cell-based indirect immunofluorescence test (IIFT) (3) exclusion

of alternative diagnoses based on clinical features serum andCSF results and imaging findings and (4) diagnosis of MOG-IgG-associated disorder confirmed by a neurologist

The Institutional Review Board of Peking Union MedicalCollege Hospital approved this study and confirmed that itdid not meet the definition of human subjects research underthe common law because deidentified data were analyzedwhich waived the need for informed consent

ProceduresPatient data including sociodemographic information clinicalevents medical history Expanded Disability Status Scale(EDSS) score prescriptions imaging and results of serumand CSF tests were prospectively collected at the time ofMSNMOBase enrollment If a patient was suspected of hav-ing a MOGAD by a neurologist serum MOG-IgG wasdetected by IIFT (FA 1156-1010-50 Euroimmun AGLuebeck Germany) using full-length human MOG trans-fected into EUROIMMUN 90 cells13 Owing to the recom-mended semiquantitative evaluation for the IIFTmethodology MOG-IgG titers were determined according totheir fluorescence of the different sample dilutions

On January 1 2017 the board of neurologists (leader)ophthalmologists and pediatricians on MOGAD wasestablished Participating patients in the MOG cohort re-ceived either MMF or non-MMF on to the decisions of thepatient or their guardians after a complete and thoroughdiscussion with the board According to the purpose of thisstudy patients who rejected MMF but chose azathioprine(AZA) as an alternative were excluded Thus the partici-pating patients in the MOG cohort were divided into 2therapeutic groups those with and without MMF therapyie MMF + and MMFminus respectively (figure 1) Besides allpatients in the MOG cohort were given standard of care(see below) The index date (ie start of the follow-up) wasdefined as the date when the patient was diagnosed with anMOGAD We regarded the onset prior and closest to theindex date as the ldquoindex onsetrdquo

We did clinic follow-up every 6 months after index date In-formation was collected at each time on relapse EDSS andresults of serum tests Images of the brain and spinal cord werescanned annually Adverse effects were also monitored regu-larly All available information gathered from assessments wasreviewed by the neurologist The endpoint of a follow-up inour analysis was on April 30 2019

GlossaryADEM = acute disseminated encephalomyelitis ARR = annualized relapse rate AZA = azathioprine EDSS = expandeddisability status scale HR = hazard ratio IgG = immunoglobulin G IIFT = indirect immunofluorescence test IQR =interquartile range MMF = mycophenolate mofetil MOG = myelin oligodendrocyte glycoprotein MOGAD = MOG-IgG-associated disorders NMOSD = neuromyelitis optica spectrum disorder

2 Neurology Neuroimmunology amp Neuroinflammation | Volume 7 Number 3 | May 2020 NeurologyorgNN

Assessment of relapseThe primary outcome was relapse which was defined asa neurologic disturbance for at least 24 hours in the absence ofother identifiable causes such as fever or infection occurringmore than 1 month after index onset and confirmed by a neu-rologist The definition of relapse was based on the diagnosticcriteria for MS and NMOSD and clinical judgment1415

Standard of careStandard of care was defined as relatively fixed therapy in theacute or remission stage of the index onset Standard of careincluded IV high-dose methylprednisolone IV immuno-globulin or a combination thereof in the acute phase fol-lowed by tapering of oral prednisone in the remission stage(table e-1 linkslwwcomNXIA223) Patients in the MMF+andMMFminus groups received the same tapering strategy of oralprednisone in the remission stage

MMF therapyMMF therapy was defined as the administration of MMF afterthe index date and lasting more than 14 days continuously Foradults standard MMF therapy was 075 g twice per day (15 gper day) For children (lt14 years) standardMMF therapy wascalculated and adjusted by body surface area (600 mg per m2)twice per day (fixed to 15 g per day if the maximum dosecalculated by body surface area exceeded 15 g per day)

Potential confoundersChildren were considered lt14 years of age and adults wereconsidered ge14 years of age MOG-IgG titers of ge1100 and

lt1100 were defined as high and low respectively Pro-dromes were divided into 3 groups none precedinginfectionvaccination or other (eg fatigue and pregnancy)According to the symptoms and neurologic examinationonset attacks were classed as pure optic neuritis pure cere-brum involvement pure spinal involvement or other (egbrainstem syndrome table e-1 linkslwwcomNXIA223)Disease course at index onset was divided into 2 subgroupsfirst (only one attack before index date) or nonfirst onset(ge2 attacks before index date) The annualized relapse rate(ARR) before the index date was calculated by dividing thenumber of relapses by time in years ARR was classified into3 levels 0 lt30 or ge30 (table e-1 linkslwwcomNXIA223)

Sample sizeThe primary analysis was performed using the Cox pro-portional hazards model to assess the efficacy of MMF ther-apy on relapse as the outcome measure Hence powercalculation described by Rosner et al and Freedman et al wasused1617

Based on the studies by Huh et al and Jarius et al911 therelapse rates assumed in the MMF+ group and MMFminus groupwere 24 and 60 respectively By considering the size ratio ofthe MMF+ to MMFminus groups as 2 to 1 this study assumeda sample size of 42 and 21 in the MMF+ group and MMFminusgroup respectively Then we further assumed a postulatedhazard ratio (HR) of 03 and a type I error rate of 005 thisstudy had more than 90 power to detect a HR of 03 or lower

Figure 1 Selection of patients

AZA = azathioprine MMF = mycophenolate mofetil MOG-IgG = myelin oligodendrocyte glycoprotein immunoglobulin G

NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 7 Number 3 | May 2020 3

Statistical analysisContinuous variables with non-normal distributions werepresented as median and interquartile range (IQR) and cat-egorical variables were presented as frequencies and percen-tages Independent categorical and continuous variables withnon-normal distributions were compared between theMMF+and MMFminus groups with χ2 and Mann-Whitney U tests re-spectively Continuous variables with normal distributionswere compared with t tests

The Cox proportional hazards model was performed to assessthe association between the prescriptions of MMF therapyand relapse rate Confounders were evaluated by the changein estimate approach18

We also assessed whether the association between MMFtherapy and relapse differed between the following subgroupschildren vs adults at index date men vs women high vs lowMOG-IgG titer prodrome type onset type time from firstonset to index date and first vs nonfirst onset disease courseStratified Cox proportional hazards regressions were con-ducted for subgroup analysis All statistical tests were two-sided with a significance level of p lt 005 Statistical analyseswere conducted using SPSS version 260 (IBM)

Data availabilityThe data that support the findings of this study are availablefrom the corresponding author on reasonable request

ResultsPatient characteristicsSeventy-nine patients from MSNMOBase were enrolled(figure 1) The baseline characteristics of the overall cohortMMF+ group and MMFminus group are presented in table 1Median age on index date was 190 years (IQR 100ndash300years) and 47 patients (595) were women Patients in theMMF+ group were slightly older than those in the MMFminusgroup whereas other demographic characteristics clinical fea-tures MOG-IgG titer and follow-up times were comparablebetween groups (table 1) Most patients with nonfirst onsetdisease course received heterogenous and irregular prednisonetherapy before index date (1000 in the MMFminus group and976 in the MMF+ group p = 1000) but only 3 patients hadcyclophosphamideAZA therapy (1 in the MMFminus group and 2in the MMF+ group p = 1000) The previous therapies beforeindex date were also comparable between the MMF+ andMMFminus groups among all patients (data not shown)

After index date 25 patients (1000) in the MMFminus groupand 47 (870) in the MMF+ group received formularystandard tapering prednisone therapy (table 1) While in theMMF+ group 1 patient (19) modified prednisone forsuspected new lesion on brain MRI 2 (37) stopped takingprednisone and the other 4 patients (74) did not receiveprednisone therapy The prednisone therapy and its tapering

time were comparable between 2 groups (table 1) Theantibodyrsquos rates of negative transformation persistent sero-positivity and undetermined status were 240 200 and560 in the MMFminus group and 167 537 and 296 inthe MMF+ group (p = 0017) The mean intervals of negativetransformation were 2308 days in the MMFminus group and1968 days in the MMF+ group (p = 0733)

Overall outcomesThe relapse rates in the MMFminus and MMF+ groups were440 (1125) and 74 (454) respectively Median follow-up times for the MMFminus and MMF+ groups were 2610 and4725 days respectively The time from index date to relapsein the MMFminus group (mean 1185 days) was similar to that inthe MMF+ group (mean 1143 days) (table 1) Most relapseevents in the MMFminus group (818) and the MMF+ group(750) occurred within the first 200 days after the indexdate For the MMF+ group the median delay from the indexdate to receiving therapy was 21 days and delay times werecomparable between relapse (median 155 days) and non-relapse (median 225 days) groups (p = 0427) One (19)patient in the MMF+ group discontinued MMF because ofadverse effects (decreased neutrophilia count 089109L)The numbers needed to treat were 27

Predictors of relapseThe Kaplan-Meier curves of survival free of relapse are shownin figure 2 The unadjusted Cox model indicates that MMFtherapymarkedly reduced the likelihood of relapse (HR = 01495 CI 005 to 045 p = 0001 table 2) This associationremained significant after adjusting for age type (ie children vsadults) at index date sex disease course and initial level ofMOG-IgG titer (HR = 008 95 CI 002ndash028 p lt 0001)

Age type at first onset age type at index date sex prodrome tofirst onset first onset type disease course ARR and time fromfirst onset to the index date were not associated with relapseas determined by the log-rank tests (tables e-2 linkslwwcomNXIA223)

Of 79 patients including 2 with missing data 29 (377) hada low MOG-IgG titer and 48 (623) had a high MOG-IgGtiter Compared with a low titer a high titer was not associatedwith relapse as determined by a log-rank test Demographiccharacteristics clinical factors and testing time were compa-rable between patients with low vs high titers as was treat-ment types in the acute phase (table e-3 linkslwwcomNXIA223) In the multivariable Cox regression model shown intable 2 the HR for relapse in patients with a high titer com-pared with those with a low titer was 205 (95 CI 054ndash779p = 0291)

Subgroup analysesThe results of subgroup analyses are presented in figure 3The reduction in relapse rate with MMF was consistentacross all major subgroups There were no significantinteractions for any of the subgroups although the power to


Table 1 Clinical and serologic characteristics of the patients with MOG-IgG-associated disorders

Characteristic

Median (IQR)

p ValueTotal MMF2 MMF+

Patients n () 79 25 (316) 54 (684) NA

Age at first onset y 150 (70ndash270) 100 (60ndash240) 185 (78ndash320) 0023

Adults at first onset n () 44 (557) 11 (440) 33 (611) 0154

Age at index date y 190 (100ndash300) 110 (65ndash255) 230 (100ndash330) 0004

Adults at index date n () 50 (633) 12 (480) 38 (704) 0055

Female n () 47 (595) 16 (640) 31 (574) 0579

Prodrome to first onset n () 0371

None 21 (266) 5 (200) 16 (296)

Preceding infectionvaccination 48 (608) 18 (720) 30 (556)

Othera 10 (127) 2 (80) 8 (148)

First onset type n () 0951

Pure optic neuritis 28 (354) 9 (360) 19 (352)

Pure cerebral involvement 24 (304) 8 (320) 16 (296)

Pure spinal involvement 5 (63) 1 (40) 4 (74)

Otherb 22 (278) 7 (280) 15 (278)

First onset disease course n ()c 22 (278) 9 (360) 13 (241) 0271

ARR before index date 10 (0ndash35) 10 (0ndash48) 11 (01ndash24) 0721

Level of ARR before index date n()d 0139

0 22 (278) 9 (360) 13 (241)

lt30 35 (443) 7 (280) 28 (519)

ge30 22 (278) 9 (360) 13 (241)

Initial MOG-IgG titer n()e 0636

110 6 (78) 3 (125) 3 (57)

132 23 (299) 6 (250) 17 (321)

1100 32 (416) 11 (458) 21 (396)

1320 16 (208) 4 (167) 12 (226)

Long-term standardprednisone n ()f

72 (911) 25 (1000) 47 (870) 0091

Time of standard taperingprednisone n ()g

0143

lt3 mo 14 (194) 6 (240) 8 (170)

3ndash6 mo 4 (56) 3 (120) 1 (21)

ge6 mo 54 (750) 16 (640) 38 (809)

Time from first onset toindex date d

2780 (870ndash13060) 1530 (850ndash7930) 4565 (915ndash14908) 0155

Time from index onset toindex date d


Time from index date to relapsed mean (SD)h

1173 (1134) 1185 (1239) 1143 (940) 0952

EDSS score at last follow-up 0 (0ndash1) 0 (0ndash1) 0 (0ndash1) 0872

Continued


detect significant interactions might have been limited bythe number of patients Although not statistically significantMMF tended to be more effective in adults at index date andin patients who had a first onset with preceding infectionvaccination pure optic neuritis at first onset or a highMOG-IgG titer The association between MMF therapy andrelapse did not vary by sex or time from the first onset toindex date

Sensitivity analysesTwo patients had the index onset under the monthsrsquo therapyof AZA and continued AZA after index onset which mightaffect the efficacy of MMF because both were in the MMF+group Thus we performed a log-rank test and Cox regressionanalysis excluding both patients Sensitivity analysis including

77 patients showed that MMF markedly reduced the relapserisk (HR = 011 95CI 003ndash039 p = 0001) In addition toexclude the bias of nonstandard prednisone therapy Coxregression analysis were conducted in 72 patients with stan-dard tapering prednisone therapy (25 in the MMFminus and 47 inthe MMF+ group) Sensitivity analysis showed that MMF stillpredicted a lower relapse risk (HR = 017 95 CI 005ndash052p = 0002) The HR was still lower in the MMF+ group(HR = 010 95 CI 003ndash033 p lt 0001) adjusted for agetype at index date sex disease course and level of initialMOG-IgG titer

DiscussionIn this prospective observational cohort study includingpatients with MOGAD we found that long-term MMFtherapy reduced the risk of relapse by 860 with a medianfollow-up time of 4000 days compared with treatmentwithout MMF Adverse effects were rare and detectablevia regular monitoring Unlike the relatively standardtherapeutic regimen in patients with NMOSD19 studies oflong-term treatments for MOGAD have evaluated AZAcyclophosphamide methotrexate interferon-beta ritux-imab mitoxantrone ciclosporin and tacrolimus and havereported varied or controversial outcomes for small num-bers of patients thus providing little evidence of therapyefficacy791020 For example Ramanathan et al21 reportedthat patients with MOGAD were highly responsive to ste-roids and also steroid-dependent MMF tended to reducerelapse risk but only with concurrent use of steroids Inaddition a study by Zhou et al22 showed that immuno-suppression therapy was effective in reducing relapse butwas limited to heterogenous therapeutic regimens and bya small sample size (23 patients) In addition previousstudies on reducing the relapse risk were all limited toretrospective analysis As the optimal long-term therapyremains inconclusive2223 our prospective study suggestsa new approach to effectively prevent relapse

Table 1 Clinical and serologic characteristics of the patients with MOG-IgG-associated disorders (continued)

Characteristic

Median (IQR)


EDSS score gt1 n ()i 7 (89) 1 (40) 6 (111) 0422

Duration of follow-up d 4000 (2160ndash7060) 2610 (970ndash6600) 4725 (2713ndash7090) 0159

Abbreviations ARR = annualized relapse rate EDSS = Expanded Disability Status Scale IQR = interquartile range MMF = mycophenolate mofetil MOG =myelin oligodendrocyte glycoprotein NA = not applicablea Other includes 3 patients who were pregnantlactating and 7 with fatiguepoor sleeptensionb Other includes 9 with cerebellumbrain stem involvement 4 with optic neuritis and cerebrum involvement 3 with myelitis and cerebrum involvement 2with optic neuritis and myelitis 2 with cerebellumbrain stem and cerebrum involvement and 2 with meningitisc Patients with only one attack before index dated 0 patients with 1 attack before the index date lt 30 patients with ge2 attacks before the index date and ARR lt30 ge30 patients with ge2 attacks before theindex date and ARR ge30e Two missing datapointsf Patients without prednisone (4) or without standard prednisone (3) were regarded as ldquowithout long-term standard prednisonerdquo p value for the Fisher testg Seventy-two patients with standard tapering prednisone were analyzed Details of tapering regimen were shown in table e-1 linkslwwcomNXIA223h t testi Fisher test

Figure 2 Kaplan-Meier curves showing the probability ofsurvival free of relapse in patients with an MOG-IgG-associated disorder

Log-rank test p lt 0001 Tick marks indicate censored patients MMF =mycophenolate mofetil MOG = myelin oligodendrocyte glycoprotein


In our study nearly half of the patients not receiving MMFsuffered relapse similar to previous reports (36ndash60)910

However patients who were under MMF therapy showeda much lower relapse rate than those reported by otherstudies such as 22ndash26 in the UK10 20 in France24

421 in China22 and 535 in the United States20 withmedian follow-up times of 16 months 2 23 and 5 yearsrespectively probably because of the differences between thestudies in treatment regimens and the concomitant use of oralprednisone20 However prednisone alone was unable tolower the relapse risk in our study The time from index onsetto relapse was similar to that in the previous studies (5ndash9months)29 Although a UK study reports that patientsyounger than 20 years or with pure optic neuritis showa tendency to relapse10 relapse risk in our study was notinfluenced by age type or first onset type

Jurynczyk et al10 found that prednisone tapering more than 6months was able to reduce the relapse rate In our study theduration and dosage of prednisone before index date wereheterogenous and unregular which was a possible bias to ourresults However there were no differences in the dosage anddurations of prednisone between 2 groups after index date aswere its usage rate before index date

The serum titer of MOG-IgG is associated with age onsettype therapy in the acute phase and disease activity and alsopredicts prognosis32526 The negative transformation of an-tibody predicts good prognosis2 whereas high titers predicta recurrent disease course27 All possible confounders in ourstudy were comparable between high and lowMOG-IgG titergroups We speculate that the titer is reflective of diseaseactivity Different from previous reports227 the titer level wasnot associated with the relapse risk However the effect ofMMF seemed more pronounced in patients with a high initialtiter although this requires further studies for confirmationIn addition we noticed that the transient seropositivity ofMOG-IgG rarely experienced relapse2 the negative trans-formation rate in theMMFminus group was higher than that in theMMF+ group (240 vs 167) which probably un-derestimate the effect of MMF in our study

Hacohen et al20 found that children with relapsingMOGAD were refractory to interferon-beta and glatiramerbut responsive to MMF AZA rituximab and oral prednis-olone with a significant reduction in ARR Our study

confirmed that a relapsing course at the index date was notassociated with subsequent relapse risk and MMF showeda consistent effect across the subgroups with different ARRsIn addition patients with both long and short diseasedurations responded well to MMF which has not beenpreviously reported920

Our study confirms the efficacy of MMF reported by previousretrospective studies with small numbers of patients2024 andshows that MMF therapy was the only predictor of relapseStandard treatment with prednisolone not only reduces re-lapse risk1020 but also limits the risk of MMF failure24 Fur-thermore we found that patients with pure optic neuritisprodromal infection or a higherMOG-IgG titer seemedmoreresponsive to MMF which have not been reported Howeverour study could not demonstrate that MMF is superior toother immunosuppressants For instance AZA and rituximabare still reasonable choices91020 Although more than 3months of immunosuppression therapy is associated witha lower relapse risk10 the underlying mechanism and theproper timing of immunosuppressant cessation remaininconclusive232829 Further studies on the role of B cells andits pathology during MMF therapy possibly provided newclues to optimize the MMF regimen30

The EDSS of both groups were lower than that in otherstudies910 We speculate 2 reasons (1) Chinese might re-spond well to immunosuppressants as another study in Chinashowed lower EDSS than that in the non-Chinesecohort91022 and (2) our study had shorter follow-up timesthan other studies910 which might have less relapses

In analysis all our patients were examined using the di-agnostic criteria for MOGAD proposed by Pittock et al2 andJarius et al8 and all met the above 2 diagnostic criteriaTherefore the results of our study are not restricted to ourcohort but may be generalizable to a larger population ofpatients with MOGAD

Recently Waters et al31 reported that clinical specificity forIIFT and live assays is 981 and 996ndash100 respectivelybut both methods are internationally recommended8 Thepositive predictive values of the commercial IIFT were lowerthan that of live assays indicating a higher number of falsepositive results but was within an acceptable range Becauselive assays are not economical or practical for routine

Table 2 Cox regression models for MMF therapy and relapse in patients with MOG-IgG-associated disorders

Therapy Events n ()

Unadjusted Adjusteda

HR (95 CI) p Value HR (95 CI) p Value

MMF2 11 (440) 1 (Reference) NA 1 (Reference) NA

MMF+ 4 (74) 014 (005ndash045) 0001 008 (002ndash028) lt0001

Abbreviations HR = hazard ratio MMF mycophenolate mofetil MOG = myelin oligodendrocyte glycoprotein NA not applicablea Adjusted for age type at index date sex disease course and initial level of MOG-IgG titer


diagnosis we used IIFT with a MOG antibody in this real-world clinical study

The imbalance follow-up times is a bias that usually leads tospurious difference in relapse between the MMF + andMMFminus groups Theoretically more relapse events wereexpected to observe in the MMF+ group which had a longermedian duration of follow-up However the observed data

showed the opposite (11 relapse events for MMFminus and 4relapse events for MMF+) which indicated that the follow-uptime of the MMF+ group had negative association with re-lapse events in patients with MOGAD

Our study had several limitations First it was an observa-tional study and its results could be biased by baseline patientcharacteristics such as age We were also unable to exclude

Figure 3 HRs for relapse in subgroup analyses

(A) Other includes 3 patients who were pregnantlactating and 7 with fatiguepoor sleeptension (B) Other includes 9 with cerebellumbrain stem in-volvement 4 with optic neuritis and cerebrum involvement 3 with myelitis and cerebrum involvement 2 with optic neuritis andmyelitis 2 with cerebellumbrain stemand cerebrum involvement and 2withmeningitis (C) 0 patientswith 1 attack before the index date lt30 patientswith ge2 attacks before the indexdate and ARR lt30 ge30 patients with ge2 attacks before the index date and ARR ge30 (D) Twomissing datapoints ARR = annualized relapse rate HR = hazardratio MMF = mycophenolate mofetil MOG = myelin oligodendrocyte glycoprotein


a placebo effect Second the detection of associations betweenother confounders and relapse might have been limited by therelatively small number of patients Thus the results of sub-group analyses should be interpreted cautiously and furtherstudies with larger patient populations and longer follow-upsare needed Third we noticed that almost 90 of patients inthe MMF+ group were using prednisone concomitantly andwe could not completely exclude the synergetic effect ofprednisone on MMF although standard therapy was given onboth groups Finally considering the adverse effects of pred-nisone among children and teratogenicity of MMF in pregnantwomen3233 neurologists must balance its benefits and risks inclinical practice because the follow-up time in our study mightnot have been sufficient to detect all adverse effects

Despite some limitations this prospective observational studysuggests that the use of MMF therapy may reduce the risk ofrelapse in patients with MOGAD A future large randomizedcontrolled trial with long-term follow-up is needed to evaluatethe safety and efficacy of MMF in patients with MOGAD It isalso important to elucidate the mechanisms underlying theassociation between MMF and reduced relapse risk to opti-mize MMF therapy

Study fundingThis study was funded by the National Key Researchand Development Program of China (Grant No2016YFC0901500) Peking Union Medical College HospitalScience Fund for Junior Faculty (pumch-2016-214) andPeking Union Medical College Education Reform Fund(2017zlgc0121)

DisclosureS Li H Ren Y Xu T Xu Y Zhang H Yin W Zhang J LiX Ren F Fang W Li Y Zhu B Peng J Wang Y Zhongand L Cui report no disclosures Go to NeurologyorgNNfor full disclosures

Publication historyReceived by Neurology Neuroimmunology amp NeuroinflammationOctober 19 2019 Accepted in final form February 5 2020

References1 Berg CT Khorooshi R Asgari N Owens T Influence of type I IFN signaling on anti-

MOG antibody-mediated demyelination J Neuroinflammation 2017141272 Lopez-Chiriboga AS MajedM Fryer J et al Association ofMOG-IgG serostatus with

relapse after acute disseminated encephalomyelitis and proposed diagnostic criteriafor MOG-IgG-associated disorders JAMA Neurol 2018751355ndash1363

3 Reindl M Di Pauli F Rostasy K Berger T The spectrum of MOG autoantibody-associated demyelinating diseases Nat Rev Neurol 20139455ndash461

4 Waters P Woodhall M OrsquoConnor KC et al MOG cell-based assay detects non-MSpatients with inflammatory neurologic disease Neurol Neuroimmunol Neuro-inflamm 20152e89 doi 101212NXI0000000000000089

5 Sato DK Callegaro D Lana-Peixoto MA et al Distinction between MOG antibody-positive and AQP4 antibody-positive NMO spectrum disorders Neurology 201482474ndash481

6 Dubey D Pittock SJ Krecke KN et al Clinical radiologic and prognostic features ofmyelitis associated with myelin oligodendrocyte glycoprotein autoantibody JAMANeurol 201976301ndash309

7 Zhou L Huang Y Li H et al MOG-antibody associated demyelinating disease of theCNS a clinical and pathological study in Chinese Han patients J Neuroimmunol201730519ndash28

8 Jarius S Paul F Aktas O et al MOG encephalomyelitis international recom-mendations on diagnosis and antibody testing J Neuroinflammation 201815134

9 Jarius S Ruprecht K Kleiter I et al MOG-IgG in NMO and related disordersa multicenter study of 50 patients Part 2 epidemiology clinical presentation ra-diological and laboratory features treatment responses and long-term outcomeJ Neuroinflammation 201613280

Appendix Authors

Name Location Contribution

ShengdeLi MD

Peking Union MedicalCollege Hospital BeijingChina

Designed and conceptualizedthe study interpreted andanalyzed the data drafted themanuscript for intellectualcontent

HaitaoRen BS


Major role in the acquisition ofdata

Yan XuMD PhD


Designed and conceptualizedthe study interpreted andanalyzed the data revised themanuscript for intellectualcontent

Appendix (continued)


Tao XuMD

Peking Union MedicalCollege Beijing China

Analyzed the data

YaoZhangMD



HexiangYin MD



WeihuaZhangMD

Beijing ChildrenrsquosHospital Beijing China


Jiuwei LiMD



XiaotunRen MD



FangFangMD



WenhanLi MD

Oumeng V MedicalLaboratory HangzhouChina


YichengZhu MD


Revised the manuscript forintellectual content

BinPengMD



JingWangMD

University of ChineseAcademy of SciencesBeijing China


YongZhongMD



LiyingCui MD




10 Jurynczyk M Messina S Woodhall MR et al Clinical presentation and prognosis inMOG-antibody disease a UK study Brain 20171403128ndash3138

11 Huh SY Kim SH Hyun JW et al Mycophenolate mofetil in the treatment of neu-romyelitis optica spectrum disorder JAMA Neurol 2014711372ndash1378

12 Xu Y Wang Q Ren HT et al Comparison of efficacy and tolerability of azathio-prine mycophenolate mofetil and cyclophosphamide among patients with neu-romyelitis optica spectrum disorder a prospective cohort study J Neurol Sci 2016370224ndash228

13 Fan S Xu Y Ren H et al Comparison of myelin oligodendrocyte glycoprotein(MOG)-antibody disease and AQP4-IgG-positive neuromyelitis optica spectrumdisorder (NMOSD) when they co-exist with anti-NMDA (N-methyl-D-aspartate)receptor encephalitis Mult Scler Relat Disord 201820144ndash152

14 Polman CH Reingold SC Banwell B et al Diagnostic criteria for multiple sclerosis2010 revisions to the McDonald criteria Ann Neurol 201169292ndash302

15 Wingerchuk DM Banwell B Bennett JL et al International consensus diagnosticcriteria for neuromyelitis optica spectrum disorders Neurology 201585177ndash189

16 Freedman LS Tables of the number of patients required in clinical trials using the log-rank test Stat Med 19821121ndash129

17 Rosner B Fundamentals of Biostatistics 6th ed Boston MA Duxbury Press 200618 Robins JM Greenland S The role of model selection in causal inference from non-

experimental data Am J Epidemiol 1986123392ndash40219 Trebst C Jarius S Berthele A et al Neuromyelitis Optica Study Group

(NEMOS) Update on the diagnosis and treatment of neuromyelitis optica rec-ommendations of the Neuromyelitis Optica Study Group (NEMOS) J Neurol20142611ndash16

20 Hacohen Y Wong YY Lechner C et al Disease course and treatment responses inchildren with relapsing myelin oligodendrocyte glycoprotein antibody-associateddisease JAMA Neurol 201875478ndash487

21 Ramanathan S Mohammad S Tantsis E et al Clinical course therapeutic responsesand outcomes in relapsing MOG antibody-associated demyelination J Neurol Neu-rosurg Psychiatry 201889127ndash137

22 Zhou J LuX ZhangY et al Follow-up study onChinese childrenwith relapsingMOG-IgG-associated central nervous system demyelination Mult Scler Relat Disord 2019284ndash10

23 Hacohen Y Banwell B Treatment approaches forMOG-Ab-associated demyelinationin children Curr Treat Options Neurol 2019212

24 Montcuquet A Collongues N Papeix C et al Effectiveness of mycophenolate mofetilas first-line therapy in AQP4-IgG MOG-IgG and seronegative neuromyelitis opticaspectrum disorders Mult Scler 2017231377ndash1384

25 Jarius S Ruprecht K Kleiter I et al MOG-IgG in NMO and related disordersa multicenter study of 50 patients Part 1 frequency syndrome specificity influence ofdisease activity long-term course association with AQP4-IgG and originJ Neuroinflammation 201613279

26 Song H Zhou H Yang M et al Clinical characteristics and prognosis of myelinoligodendrocyte glycoprotein antibody-seropositive paediatric optic neuritis in ChinaBr J Ophthalmol 2019103831ndash836

27 Hennes EM Baumann M Schanda K et al Prognostic relevance of MOG antibodiesin children with an acquired demyelinating syndrome Neurology 201789900ndash908

28 Choi SJ Kim B Lee HJ Kim SJ Kim SM Sung JJ Rebound of relapses afterdiscontinuation of rituximab in a patient with MOG-IgG1 positive highly relapsingoptic neuritis a case report BMC Neurol 201818216

29 Nagashima M Osaka H Ikeda T et al Rituximab was effective for acute disseminatedencephalomyelitis followed by recurrent optic neuritis with anti-myelin oligoden-drocyte glycoprotein antibodies Brain Dev 201840607ndash611

30 Kothur K Wienholt L Tantsis EM et al B cell Th17 and neutrophil related cere-brospinal fluid cytokinechemokines are elevated in MOG antibody associated de-myelination PLoS One 201611e0149411

31 Waters PJ Komorowski LWoodhall M et al Amulticenter comparison ofMOG-IgGcell-based assays Neurology 201992e1250ndashe1255

32 Aljebab F Choonara I Conroy S Systematic review of the toxicity of long-course oralcorticosteroids in children PLoS One 201712e0170259

33 Perez-Aytes A Marin-Reina P Boso V Ledo A Carey JC Vento M Mycophenolatemofetil embryopathy a newly recognized teratogenic syndrome Eur J Med Genet20176016ndash21


DOI 101212NXI000000000000070520207 Neurol Neuroimmunol Neuroinflamm

Shengde Li Haitao Ren Yan Xu et al antibody-associated disorders A prospective study

Long-term efficacy of mycophenolate mofetil in myelin oligodendrocyte glycoprotein

This information is current as of March 13 2020

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Myelin oligodendrocyte glycoprotein (MOG) which isexpressed on the surface of myelin sheaths in the CNS istargeted by antibodies (MOG-immunoglobulin G [IgG]) ininflammatory demyelinating disorders12 including MS acutedisseminated encephalomyelitis (ADEM) neuromyelitisoptica spectrum disorder (NMOSD) and optic neuritis al-though positive rate is very low in MS134 However clinicalradiologic CSF and prognostic features in patients with se-ropositive MOG-IgG are distinct from those in patients withseropositive AQP4-IgG NMOSD seronegative NMOSD orMS5ndash7 With the aid of serum MOG-IgG detected by trans-fected cell-based assay seropositive MOG-IgG demyelinatingdisorders are now classified as a separate disease entity withdistinct diagnostic criteria28

Patients with MOG-IgG-associated disorders (MOGADs)exhibit a predominantly relapsing and often severe diseasecourse from 36 relapse rate in a median 16-month to 80 ina mean 75-month follow-up period910 Many patients do notcompletely recover from the onset attack with 47 ofpatients having permanent disability10 Although the long-term immunosuppression therapy seemed to reduce relapserisk there is a lack of prospective data and large samplestudies910 In view of the heterogeneity of the treatmentsgiven there is still a need to define an optimal strategy es-pecially considering that the relapse rate of treated patients isstill too high9 Therefore prophylactic long-term treatmentsremain insufficiently effective with little evidence for theability of long-term therapy to reduce relapse risk amongpatients with MOGAD Here we conducted a prospectiveobservational cohort study of patients with MOGAD to de-termine the association of relapse risk and the use of myco-phenolate mofetil (MMF) because the efficiency and safety ofMMF has been confirmed in patients with NMOSD1112

MethodsStudy design and patientsPatients enrolled in the Peking Union Medical College hospitalMSNMOBase database12 were followed up prospectively in theperiod of 2017ndash2019 after undergoing a MOG-IgG laboratorytest (figure 1) Participating patients were included into theMOG cohort when they met all the following criteria (1)clinical presentation of ADEM optic neuritis (including chronicrelapsing inflammatory optic neuropathy) transverse myelitisandor brain or brainstem syndrome compatible with de-myelination (2) serum positive for MOG-IgG by a fixed cell-based indirect immunofluorescence test (IIFT) (3) exclusion

of alternative diagnoses based on clinical features serum andCSF results and imaging findings and (4) diagnosis of MOG-IgG-associated disorder confirmed by a neurologist

The Institutional Review Board of Peking Union MedicalCollege Hospital approved this study and confirmed that itdid not meet the definition of human subjects research underthe common law because deidentified data were analyzedwhich waived the need for informed consent

ProceduresPatient data including sociodemographic information clinicalevents medical history Expanded Disability Status Scale(EDSS) score prescriptions imaging and results of serumand CSF tests were prospectively collected at the time ofMSNMOBase enrollment If a patient was suspected of hav-ing a MOGAD by a neurologist serum MOG-IgG wasdetected by IIFT (FA 1156-1010-50 Euroimmun AGLuebeck Germany) using full-length human MOG trans-fected into EUROIMMUN 90 cells13 Owing to the recom-mended semiquantitative evaluation for the IIFTmethodology MOG-IgG titers were determined according totheir fluorescence of the different sample dilutions

On January 1 2017 the board of neurologists (leader)ophthalmologists and pediatricians on MOGAD wasestablished Participating patients in the MOG cohort re-ceived either MMF or non-MMF on to the decisions of thepatient or their guardians after a complete and thoroughdiscussion with the board According to the purpose of thisstudy patients who rejected MMF but chose azathioprine(AZA) as an alternative were excluded Thus the partici-pating patients in the MOG cohort were divided into 2therapeutic groups those with and without MMF therapyie MMF + and MMFminus respectively (figure 1) Besides allpatients in the MOG cohort were given standard of care(see below) The index date (ie start of the follow-up) wasdefined as the date when the patient was diagnosed with anMOGAD We regarded the onset prior and closest to theindex date as the ldquoindex onsetrdquo

We did clinic follow-up every 6 months after index date In-formation was collected at each time on relapse EDSS andresults of serum tests Images of the brain and spinal cord werescanned annually Adverse effects were also monitored regu-larly All available information gathered from assessments wasreviewed by the neurologist The endpoint of a follow-up inour analysis was on April 30 2019

GlossaryADEM = acute disseminated encephalomyelitis ARR = annualized relapse rate AZA = azathioprine EDSS = expandeddisability status scale HR = hazard ratio IgG = immunoglobulin G IIFT = indirect immunofluorescence test IQR =interquartile range MMF = mycophenolate mofetil MOG = myelin oligodendrocyte glycoprotein MOGAD = MOG-IgG-associated disorders NMOSD = neuromyelitis optica spectrum disorder


























Characteristic

Median (IQR)


Patients n () 79 25 (316) 54 (684) NA





Female n () 47 (595) 16 (640) 31 (574) 0579


None 21 (266) 5 (200) 16 (296)


Othera 10 (127) 2 (80) 8 (148)





Otherb 22 (278) 7 (280) 15 (278)




0 22 (278) 9 (360) 13 (241)

lt30 35 (443) 7 (280) 28 (519)

ge30 22 (278) 9 (360) 13 (241)


110 6 (78) 3 (125) 3 (57)

132 23 (299) 6 (250) 17 (321)

1100 32 (416) 11 (458) 21 (396)

1320 16 (208) 4 (167) 12 (226)


72 (911) 25 (1000) 47 (870) 0091


0143

lt3 mo 14 (194) 6 (240) 8 (170)

3ndash6 mo 4 (56) 3 (120) 1 (21)

ge6 mo 54 (750) 16 (640) 38 (809)






1173 (1134) 1185 (1239) 1143 (940) 0952


Continued







Characteristic

Median (IQR)


EDSS score gt1 n ()i 7 (89) 1 (40) 6 (111) 0422


















Therapy Events n ()





























Appendix Authors


ShengdeLi MD



HaitaoRen BS



Yan XuMD PhD





Tao XuMD


Analyzed the data

YaoZhangMD



HexiangYin MD



WeihuaZhangMD



Jiuwei LiMD



XiaotunRen MD



FangFangMD



WenhanLi MD



YichengZhu MD



BinPengMD



JingWangMD



YongZhongMD



LiyingCui MD















































Reprints




























Characteristic

Median (IQR)


Patients n () 79 25 (316) 54 (684) NA





Female n () 47 (595) 16 (640) 31 (574) 0579


None 21 (266) 5 (200) 16 (296)


Othera 10 (127) 2 (80) 8 (148)





Otherb 22 (278) 7 (280) 15 (278)




0 22 (278) 9 (360) 13 (241)

lt30 35 (443) 7 (280) 28 (519)

ge30 22 (278) 9 (360) 13 (241)


110 6 (78) 3 (125) 3 (57)

132 23 (299) 6 (250) 17 (321)

1100 32 (416) 11 (458) 21 (396)

1320 16 (208) 4 (167) 12 (226)


72 (911) 25 (1000) 47 (870) 0091


0143

lt3 mo 14 (194) 6 (240) 8 (170)

3ndash6 mo 4 (56) 3 (120) 1 (21)

ge6 mo 54 (750) 16 (640) 38 (809)






1173 (1134) 1185 (1239) 1143 (940) 0952


Continued







Characteristic

Median (IQR)


EDSS score gt1 n ()i 7 (89) 1 (40) 6 (111) 0422


















Therapy Events n ()





























Appendix Authors


ShengdeLi MD



HaitaoRen BS



Yan XuMD PhD





Tao XuMD


Analyzed the data

YaoZhangMD



HexiangYin MD



WeihuaZhangMD



Jiuwei LiMD



XiaotunRen MD



FangFangMD



WenhanLi MD



YichengZhu MD



BinPengMD



JingWangMD



YongZhongMD



LiyingCui MD















































Reprints


















Characteristic

Median (IQR)


Patients n () 79 25 (316) 54 (684) NA





Female n () 47 (595) 16 (640) 31 (574) 0579


None 21 (266) 5 (200) 16 (296)


Othera 10 (127) 2 (80) 8 (148)





Otherb 22 (278) 7 (280) 15 (278)




0 22 (278) 9 (360) 13 (241)

lt30 35 (443) 7 (280) 28 (519)

ge30 22 (278) 9 (360) 13 (241)


110 6 (78) 3 (125) 3 (57)

132 23 (299) 6 (250) 17 (321)

1100 32 (416) 11 (458) 21 (396)

1320 16 (208) 4 (167) 12 (226)


72 (911) 25 (1000) 47 (870) 0091


0143

lt3 mo 14 (194) 6 (240) 8 (170)

3ndash6 mo 4 (56) 3 (120) 1 (21)

ge6 mo 54 (750) 16 (640) 38 (809)






1173 (1134) 1185 (1239) 1143 (940) 0952


Continued







Characteristic

Median (IQR)


EDSS score gt1 n ()i 7 (89) 1 (40) 6 (111) 0422


















Therapy Events n ()





























Appendix Authors


ShengdeLi MD



HaitaoRen BS



Yan XuMD PhD





Tao XuMD


Analyzed the data

YaoZhangMD



HexiangYin MD



WeihuaZhangMD



Jiuwei LiMD



XiaotunRen MD



FangFangMD



WenhanLi MD



YichengZhu MD



BinPengMD



JingWangMD



YongZhongMD



LiyingCui MD















































Reprints





Characteristic

Median (IQR)


Patients n () 79 25 (316) 54 (684) NA





Female n () 47 (595) 16 (640) 31 (574) 0579


None 21 (266) 5 (200) 16 (296)


Othera 10 (127) 2 (80) 8 (148)





Otherb 22 (278) 7 (280) 15 (278)




0 22 (278) 9 (360) 13 (241)

lt30 35 (443) 7 (280) 28 (519)

ge30 22 (278) 9 (360) 13 (241)


110 6 (78) 3 (125) 3 (57)

132 23 (299) 6 (250) 17 (321)

1100 32 (416) 11 (458) 21 (396)

1320 16 (208) 4 (167) 12 (226)


72 (911) 25 (1000) 47 (870) 0091


0143

lt3 mo 14 (194) 6 (240) 8 (170)

3ndash6 mo 4 (56) 3 (120) 1 (21)

ge6 mo 54 (750) 16 (640) 38 (809)






1173 (1134) 1185 (1239) 1143 (940) 0952


Continued







Characteristic

Median (IQR)


EDSS score gt1 n ()i 7 (89) 1 (40) 6 (111) 0422


















Therapy Events n ()





























Appendix Authors


ShengdeLi MD



HaitaoRen BS



Yan XuMD PhD





Tao XuMD


Analyzed the data

YaoZhangMD



HexiangYin MD



WeihuaZhangMD



Jiuwei LiMD



XiaotunRen MD



FangFangMD



WenhanLi MD



YichengZhu MD



BinPengMD



JingWangMD



YongZhongMD



LiyingCui MD















































Reprints









Characteristic

Median (IQR)


EDSS score gt1 n ()i 7 (89) 1 (40) 6 (111) 0422


















Therapy Events n ()





























Appendix Authors


ShengdeLi MD



HaitaoRen BS



Yan XuMD PhD





Tao XuMD


Analyzed the data

YaoZhangMD



HexiangYin MD



WeihuaZhangMD



Jiuwei LiMD



XiaotunRen MD



FangFangMD



WenhanLi MD



YichengZhu MD



BinPengMD



JingWangMD



YongZhongMD



LiyingCui MD















































Reprints
















Therapy Events n ()





























Appendix Authors


ShengdeLi MD



HaitaoRen BS



Yan XuMD PhD





Tao XuMD


Analyzed the data

YaoZhangMD



HexiangYin MD



WeihuaZhangMD



Jiuwei LiMD



XiaotunRen MD



FangFangMD



WenhanLi MD



YichengZhu MD



BinPengMD



JingWangMD



YongZhongMD



LiyingCui MD















































Reprints


























Appendix Authors


ShengdeLi MD



HaitaoRen BS



Yan XuMD PhD





Tao XuMD


Analyzed the data

YaoZhangMD



HexiangYin MD



WeihuaZhangMD



Jiuwei LiMD



XiaotunRen MD



FangFangMD



WenhanLi MD



YichengZhu MD



BinPengMD



JingWangMD



YongZhongMD



LiyingCui MD















































Reprints



















Appendix Authors


ShengdeLi MD



HaitaoRen BS



Yan XuMD PhD





Tao XuMD


Analyzed the data

YaoZhangMD



HexiangYin MD



WeihuaZhangMD



Jiuwei LiMD



XiaotunRen MD



FangFangMD



WenhanLi MD



YichengZhu MD



BinPengMD



JingWangMD



YongZhongMD



LiyingCui MD















































Reprints















































Reprints






















Reprints
















Reprints




Documents

Long-term efficacy of mycophenolate mofetil in myelin ...diagnosis, we used IIFT with a MOG antibody in this real-world clinical study. The imbalance follow-up times is a bias that