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Neuro- inflammation

Original research

Oral corticosteroid dosage and taper duration at
onset in myelin oligodendrocyte glycoprotein
antibody- associated disease influences time to
first relapse
Benjamin P Trewin      ,1 Russell C Dale      ,2,3 Jessica Qiu,1 Melissa Chu,4,5
Niroshan Jeyakumar,1 Fionna Dela Cruz,4,5 Jane Andersen,1,6 Pakeeran Siriratnam,7
Kit Kwan M Ma,4,5 Todd A Hardy      ,3,8 Anneke van der Walt      ,7,9
Jeanette Lechner- Scott,10 Helmut Butzkueven,7,9 Simon A Broadley      ,11,12
Michael H Barnett      ,3,13 Stephen W Reddel      ,3,8 Fabienne Brilot      ,6,14
Tomas Kalincik      ,4,5 Sudarshini Ramanathan      ,1,8 On behalf of the Australasian
MOGAD Study Group

ABSTRACT
Background  We sought to identify an optimal oral
corticosteroid regimen at the onset of myelin oligodendrocyte
glycoprotein antibody- associated disease (MOGAD), which
would delay time to first relapse while minimising cumulative
corticosteroid exposure.
Methods  In a retrospective multicentre cohort
study, Cox proportional hazards models examined
the relationship between corticosteroid course as a
time- varying covariate and time to first relapse. Simon-
Makuch and Kaplan- Meier plots identified an optimal
dosing strategy.
Results  We evaluated 109 patients (62 female, 57%; 41
paediatric, 38%; median age at onset 26 years, (IQR 8–38);
median follow- up 6.2 years (IQR 2.6–9.6)). 76/109 (70%)
experienced a relapse (median time to first relapse 13.7
months; 95% CI 8.2 to 37.9). In a multivariable model,
higher doses of oral prednisone delayed time to first relapse
with an effect estimate of 3.7% (95% CI 0.8% to 6.6%;
p=0.014) reduced hazard of relapse for every 1 mg/day dose
increment. There was evidence of reduced hazard of relapse
for patients dosed ≥12.5 mg/day (HR 0.21, 95% CI 0.07 to
0.6; p=0.0036), corresponding to a 79% reduction in relapse
risk. There was evidence of reduced hazard of relapse for
those dosed ≥12.5 mg/day for at least 3 months (HR 0.12,
95% CI 0.03 to 0.44; p=0.0012), corresponding to an 88%
reduction in relapse risk compared with those never treated
in this range. No patient with this recommended dosing
at onset experienced a Common Terminology Criteria for
Adverse Events grade >3 adverse effect.
Conclusions  The optimal dose of 12.5 mg of
prednisone daily in adults (0.16 mg/kg/day for children)
for a minimum of 3 months at the onset of MOGAD
delays time to first relapse.

WHAT IS ALREADY KNOWN ON THIS TOPIC
 ⇒ Myelin oligodendrocyte glycoprotein antibody-
associated disease (MOGAD) patients may
experience early relapses, with increasing
evidence that an active early disease course is
associated with a more chronically relapsing
trajectory. There is currently no consensus
on the optimal therapeutic management of
MOGAD at disease onset, with significant
clinical equipoise related to the role of
corticosteroids as a therapeutic strategy.

WHAT THIS STUDY ADDS
 ⇒ In this multicentre cohort study of 109 children
and adults with MOGAD, there was evidence
that patients treated with at least 12.5 mg/day
(0.16 mg/kg in children) of oral prednisone for
at least 3 months had an 88% reduction in the
risk of relapse compared with those who did
not receive this regimen.

HOW THIS STUDY MIGHT AFFECT RESEARCH,
PRACTICE OR POLICY
 ⇒ This study highlights the need for effective early
treatment after MOGAD onset to modify the
long- term disease trajectory, and for the first
time provides recommendations to clinicians on
the corticosteroid dosing regimen and duration
at disease onset to minimise relapsing disease,
while minimising cumulative corticosteroid
exposure. This study represents an important
step forward in improving treatment and
outcomes for children and adults with MOGAD.

INTRODUCTION
Myelin  oligodendrocyte  glycoprotein  antibody-
associated disease (MOGAD) is a distinct antibody-
associated  demyelinating  disorder.1  2  MOGAD

commonly  presents  as  bilateral  or  recurrent
optic  neuritis  (ON)  and  transverse  myelitis  (TM)
in  children  and  adults,  and  acute  disseminated
encephalomyelitis  (ADEM)  in  children.3–5  Less
common  manifestations  encompass  brainstem  or
cerebellar  involvement,  cortical  encephalitis  and

 ► Additional supplemental
material is published online
only. To view, please visit the
journal online (https:// doi. org/
10. 1136/ jnnp- 2024- 333463).

For numbered affiliations see
end of article.

Correspondence to
Associate Professor Sudarshini
Ramanathan;  sudarshini.
ramanathan@ sydney. edu. au

TK and SR contributed equally.

Received 22 January 2024
Accepted 3 April 2024
Published Online First 14 May
2024

© Author(s) (or their
employer(s)) 2024. Re- use
permitted under CC BY.
Published by BMJ.

To cite: Trewin BP, Dale RC,
Qiu J, et al. J Neurol
Neurosurg Psychiatry
2024;95:1054–1063.

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Trewin BP, et al. J Neurol Neurosurg Psychiatry 2024;95:1054–1063. doi:10.1136/jnnp-2024-333463

leptomeningeal involvement.4–6 Demyelination due to MOGAD
has the potential to cause permanent visual, motor and sphincter
dysfunction.4 7–9 The recent publication of consensus diagnostic
criteria represents an important step in expediting early recogni-
tion of this condition.10

We  previously  identified  MOGAD  as  a  condition  that  exhibits
significant  and  often  rapid  responsiveness  to  corticosteroids  and
can  be  corticosteroid  dependent.3  4  Relapses  were  associated  with
rapid tapering of oral prednisone at doses <10 mg daily or within
the first 2–3 months following cessation.3 4 Subsequent studies have
supported  the  modulating  effect  of  corticosteroids  on  inducing
remission and identified longer courses of treatment may be asso-
ciated  with  reduced  relapses  with  suggested  treatment  durations
ranging from 5 weeks to 6 months.11–13 There is emerging evidence
that reduced relapse rates in the first year after onset may be asso-
ciated with a reduction in the long- term relapse risk.14 Such insights
magnify the critical nature of interventions during this nascent phase
and  suggest  therapeutic  decisions  at  onset  might  influence  subse-
quent disease course. Yet, the well- documented impact of long- term
corticosteroid  exposure  encompassing  neuropsychiatric,  metabolic
and bone health- related adverse effects across the ages,15 underscores
the complexity of therapeutic decision- making in MOGAD.

At  present,  there  is  equipoise  regarding  optimal  therapeutic
approaches in MOGAD, with variable clinician preference and expe-
rience.16 While retrospective studies and systematic reviews report
intravenous immunoglobulin and rituximab may reduce activity in
relapsing MOGAD,17–19 there is currently no consensus on optimal
treatment  at  onset.  Our  objective  was  to  explore  potential  thera-
peutic strategies for MOGAD patients at disease onset in a retrospec-
tive cohort, by evaluating whether a specific oral prednisone regimen
could effectively delay time to first relapse (TTFR), while minimising
cumulative corticosteroid exposure.

MATERIALS AND METHODS
Study design and participants
This was a retrospective, observational, multicentre cohort study of
24  centres  from  the  Australasian  MOGAD  Study  Group.  Patients
were included if they were seropositive for MOG immunoglobulin
G by a live cell- based assay and had a clinical phenotype compat-
ible  with  MOGAD  as  per  proposed  diagnostic  criteria.10  Patients
were required to have detailed clinical, therapeutic (including dose
and  timing  of  corticosteroids  and  other  treatment),  and  outcome
(including  Expanded  Disability  Status  Scale  and  visual  acuities)
data available, and a minimum follow- up of 12 months. An inves-
tigator- led national MOGAD REDCap electronic data registry was
developed in 2020. Predetermined fields relevant to this study were

Neuro- inflammation

identified, and required data were extracted from detailed review of
clinical information.

An onset clinical episode or relapse was defined as new focal or
multifocal central nervous system symptoms and/or signs lasting
at  least  24  hours,  supported  clinically  and/or  radiologically  as
attributable to MOGAD, in the absence of concurrent infection
and  following  exclusion  of  an  alternate  diagnosis.  A  relapse
included  neurological  symptoms  and/or  signs  separated  from
initial presentation by a period of recovery of at least 2 weeks.

Patients ≤16 years of age at onset were classified as paediatric.
Doses of intravenous and oral corticosteroids in children were
evaluated in conjunction with adult patients using a weight- based
conversion,  where  each  paediatric  patient’s  dose  was  multi-
plied  by  the  ratio  of  the  median  weight  of  an  Australian  adult
(76.35 kg)20 to the patient’s weight at dosing.21 All corticosteroid
doses were converted into the equivalent dose of prednisone.22

‘Acute therapy’ refers to treatment within the first month of
a  clinical  episode  including  pulsed  intravenous  corticosteroids,
intravenous
induction  or  plasmapheresis.
‘Maintenance therapy’ is defined as a non- corticosteroid treat-
ment continued for ≥6 months.

immunoglobulin

Study outcomes
The exposure of interest was the daily dosage of oral corticoste-
roids following disease onset until first relapse or last follow- up,
whichever  occurred  first.  The  primary  outcome  was  TTFR.
Secondary  outcomes  included  annualised  relapse  rate,  disease
course at last follow- up and adverse event frequency as defined
by  Common  Terminology  Criteria  for  Adverse  Events  grade
(CTCAE V.5.0).23 The potential variables affecting the relation-
ship between oral corticosteroids and TTFR are highlighted in a
directed acyclic graph (figure 1).

Statistical analyses
Descriptive  summary  statistics  were  used  for  demographics,
clinical  characteristics  and  treatment  details.  Medians  and
IQRs were calculated for continuous variables, and frequencies
and  percentages  were  calculated  for  categorical  variables.  The
standardised  mean  difference  (SMD)  was  used  to  examine  the
balance of covariate distribution between children and adults.

The relationship between oral corticosteroid dose and TTFR
was  visualised  in  Simon- Makuch  survival  plots,  which  allow
for  a  time- dependent  covariate  (oral  corticosteroid  dose)  to
be used as a stratifying variable.24 The association between the
dose of oral corticosteroids and TTFR was analysed using Cox

Figure 1  Directed acyclic graph examining potential variables that may influence the relationship between oral corticosteroid treatment and time to
first relapse. Pseudorandomising factors (on the left) are variables that lead to heterogeneity in the exposure of interest (dose/duration of initial oral
corticosteroid course). Potentially confounding covariates (above) are also listed with their relationship to exposure and outcome (time to first relapse).
MOGAD, myelin oligodendrocyte glycoprotein antibody- associated disease.

Trewin BP, et al. J Neurol Neurosurg Psychiatry 2024;95:1054–1063. doi:10.1136/jnnp-2024-333463

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Neuro- inflammation

proportional hazards models adjusted for potential confounding
variables, identified based on plausible contribution (as outlined
in figure 1) or a univariate association at α≤0.1.

The  relationship  between  time  spent  above  the  optimal  oral
corticosteroid dose and risk of a relapse was visualised in a series
of Kaplan- Meier curves using different duration cut- offs to cate-
gorise patients into groups. A subgroup analysis was planned to
assess  for  the  presence  of  a  differential  response  between  chil-
dren and adults. The annualised relapse rate during each of the
first 6 months from MOGAD onset was compared between the
cumulative time that patients spent treated with oral corticoste-
roids above versus below the nominated threshold oral cortico-
steroid dose.

Patients  with  a  follow- up  <12  months  were  excluded.  The
only  variable  with  missing  data  referred  specifically  to  onset
episode severity in 20/109 patients. When stratifying this vari-
able, one stratum was designated for missing data, which enabled
us to include it in the multivariable analysis.

Statistical analyses were performed with R statistical software

(V.4.3.1).25

RESULTS
Between 1 July 2009 and 31 August 2023, 745 patients tested
positive  for  MOG  IgG  using  a  flow  cytometry  live  cell- based
assay as previously described.26 27 Detailed clinical data meeting
predefined inclusion criteria was available from 109 patients.

Demographics,  disease  duration  and  course,  initial  episode
phenotype  and  immunotherapy  in  109  patients  with  MOGAD
are  summarised  in  table 1.  Patients  had  a  median  age  of  onset
of  26  years  (IQR  8–38).  41/109  (38%)  were  paediatric  onset,
62/109 (57%) were assigned female at birth, 76/109 (70%) expe-
rienced a relapsing course and median duration of follow- up was
6.2 years (IQR 2.6–9.6). Sex assigned at birth, a relapsing disease
course  and  duration  of  follow- up  were  similar  between  the
paediatric and adult groups (SMD<0.14). Patients who had not
experienced relapse at the last follow- up had a shorter median
duration  of  follow- up  (2.6  years,  IQR  2–4.6),  compared  with
those who had relapsed (6.9 years, IQR 4.8–10.3, SMD=0.75).
The most common presentation phenotype was isolated ON
in 58 patients (53%), followed by isolated ADEM in 19 (17%),
and then isolated TM in 10 (9%) (table 1). 35 of 58 ON patients
were clinically bilateral at onset. There was a higher incidence of
isolated ON at onset for adults compared with children (63% vs
37%, SMD=0.26). ADEM was exclusively identified in paedi-
atric patients.

18/109  (17%)  patients  did  not  receive  any  immunotherapy
at  onset  while  91/109  (83%)  received  oral  and/or  intravenous
corticosteroids  (table  1).  Nine  (8%)  patients  received  intrave-
nous immunoglobulin and/or plasmapheresis as acute treatment,
in  addition  to  corticosteroids.  Intravenous  corticosteroids  in
isolation  were  more  commonly  used  in  adults  (children  10%,
adults  32%,  SMD=0.54)  while  a  combination  of  intravenous

Table 1  Demographic, clinical, therapeutic and outcome data in the total cohort and stratified by age

n

Onset age, years median (IQR)

Sex assigned at birth, n females (%)

Disease course, n of relapsing patients (%)

Duration of follow- up, years median (IQR)

Onset episode phenotype
n of patients (%)

Onset episode treatment
n of patients (%)

Total cohort

Paediatric onset

Adult onset

109

26 (8–38)

62 (57)

76 (70)

41

7 (5–9)

25 (61)

28 (68)

68

34 (29–46)

37 (54)

48 (71)

6.2 (2.6–9.6)

5.9 (2.7–10.1)

6.3 (2.6–9.2)

Isolated optic neuritis (% of total phenotypes)

58 (53)

15 (37)

Bilateral (n)

Unilateral (n)

Isolated transverse myelitis (TM) (% of total
cohort)

Longitudinally extensive (n)

Short segment only (n)

Acute disseminated encephalomyelitis

Cerebral cortical encephalitis

Mixed phenotypes*

Nil

IV corticosteroids only

Oral corticosteroids only

IV and oral corticosteroids

35

23

10 (9)

4

6

19 (17)

2 (2)

19 (17)

18 (17)

26 (24)

12 (11)

53 (49)

10

5

1 (2)

1

0

19 (46)

1 (2)

5 (12)

5 (12)

4 (10)

6 (15)

26 (63)

43 (63)

25

18

9 (13)

3

6

0

1 (1)

14 (21)

13 (19)

22 (32)

6 (9)

27 (40)

Initial oral corticosteroid dose (mg/kg)

0.96 (0.65–1.31)

1.28 (1.04–1.92)

0.65 (0.65–0.65)

Maintenance treatment instituted at
disease onset

IVIg/PLEX

Other immunotherapies†

Corticosteroids and IVIg/PLEX

9 (8)

0

5 (5)

5 (12)

0

0

4 (6)

0

5 (7)

Standardised
mean difference

–

2.99

0.13

0.05

0.02

0.55

0.26

–

0.38

0.1

–

1.5

0.07

0.22

0.19

0.54

0.18

0.48

1.78

0.23

–

0.35

Data are summarised as n (%) or median (IQR).
*Other presentation phenotypes: 1 UON+STM (adult); 1 UON+LETM (paediatric); 1 BON+LETM (adult);1 UON+STM+area postrema syndrome (adult); 1
BON+LETM+diencephalic+intracranial hypertension; 4 cerebral syndrome (adults); 1 BON+LGI1 antibody encephalitis (adult); 1 ADEM+BON (paediatric); 1 ON+cerebellum
(adult); 1 TM+cerebellum (adult); 1 LETM+cerebral (adult); 2 LETM+brainstem (adults); 1 CCE+brainstem (adult); 1 brainstem+cerebellum (paediatric); 1 aseptic meningitis
(adult).
†Other maintenance immunotherapies: 3 rituximab; 1 azathioprine; 1 mycophenolate mofetil.
ADEM, acute disseminated encephalomyelitis; BON, bilateral optic neuritis; CCE, cerebral cortical encephalitis; IV, intravenous; IVIg, Intravenous immunoglobulin; LETM,
longitudinally extensive transverse myelitis; LGI1, Leucine rich glioma- inactivated 1; PLEX, Therapeutic plasma exchange; STM, short transverse myelitis; UON, unilateral optic
neuritis.

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Table 2  Univariate and multivariable Cox proportional hazard models of time to first relapse

Covariate

Onset age (years)

Sex assigned at birth

Initial phenotype

Onset episode severity

Onset episode severity (VFSS)

Time from initial symptoms to corticosteroids

Cumulative IV corticosteroid dose (g)

Oral corticosteroid dose (mg/day)

IVIg or PLEX given as acute immunotherapy

Female

Male

No ON

ON

No TM

TM

No ADEM

ADEM

EDSS<3

EDSS≥3

Missing

<7 days

≥7 days

No treatment

Not given

Given

Univariate

HR (95% CI)

1 (0.99 to 1.01)

1.00 (reference)

1.25 (0.79 to 1.97)

1.00 (reference)

1.24 (0.78 to 1.96)

n

109

62

47

51

58

100

1.00 (reference)

0.54 (0.2 to 1.48)

1.00 (reference)

0.83 (0.45 to 1.54)

1.00 (reference)

0.71 (0.39 to 1.3)

0.58 (0.27 to 1.23)

1.06 (0.86 to 1.31)

1.00 (reference)

1.09 (0.62 to 1.93)

1.72 (0.86 to 3.4)

0.96 (0.9 to 1.02)

10

90

19

18

71

20

54

41

62

18

109

109

100

9

Neuro- inflammation

Multivariable

P value

HR (95% CI)

P value

0.80

–

0.34

–

0.36

–

0.23

–

0.56

–

0.27

0.15

0.56

–

0.76

0.12

0.18

1 (0.98 to 1.01)

1.00 (reference)

1.45 (0.9 to 2.34)

–

–

–

–

–

–

1.00 (reference)

0.75 (0.38 to 1.46)

0.49 (0.21 to 1.11)

–

1.00 (reference)

1.04 (0.59 to 1.85)

1.71 (0.81 to 3.62)

–

0.48

–

0.13

–

–

–

–

–

–

–

0.40

0.088

–

–

0.89

0.16

–

0.014

–

–

0.96 (0.93 to 0.99)

0.0078

0.96 (0.93 to 0.99)

1.00 (reference)

0.8 (0.32 to 1.99)

–

0.63

–

–

ADEM, acute disseminated encephalomyelitis; EDSS, Expanded Disability Status Score; IVIg, intravenous immunoglobulin; ON, optic neuritis; PLEX, therapeutic plasma exchange;
TM, transverse myelitis; VFSS, Visual Functional System Score.

and  oral  corticosteroids  was  more  frequently  administered  in
children (children 63%, adults 40%, SMD=0.48). Maintenance
immunotherapy  outside  of  intravenous  immunoglobulin  and
plasmapheresis instituted for the first clinical episode was used
in a minority of adults (7%; rituximab n=3, azathioprine n=1,
mycophenolate n=1) and in none of the children.

Timing of clinical episodes relative to corticosteroids
76  relapses  occurred  in  109  patients  with  a  median  survival
TTFR  of  13.7  months  (95% CI  8.2  to  37.9).  The  relationship
between oral prednisone courses and the first relapse was eval-
uated.  40/65  patients  treated  with  oral  prednisone  went  on  to
experience  a  relapse  (online  supplemental  figure  1),  of  which
21/40  relapsed  on  prednisone  doses  <10 mg/day  or  within  10
weeks of cessation. The median time from first symptoms of the
onset episode to initiation of oral prednisone was 13 days (IQR
9–22 days) and the median oral prednisone course duration was
47 days (IQR 30–140). The rate of steroid taper is visualised in
online supplemental figure 2.

Multivariable modelling of TTFR
The  univariate  and  multivariable  associations  between  patient
and  disease  characteristics,  and  cumulative  hazard  of  a  relapse
are  shown  in  table  2.  The  univariate  models  identified  that
higher oral prednisone doses were associated with a lower risk
of a relapse (HR 0.96 (95% CI 0.93 to 0.99); p=0.0078). The
univariate  models  did  not  provide  evidence  for  an  association
with other covariates including onset age, sex assigned at birth,
onset  phenotype  (inclusive  of  ON,  TM  and  ADEM  presenta-
tions), time from onset to initiation of corticosteroids, episode
severity, the use of intravenous corticosteroids inclusive of total
dosage  or  concurrent  intravenous  immunoglobulin  or  plas-
mapheresis.  This  association  was  confirmed  in  a  multivariable
model (HR 0.96 (95% CI 0.93 to 0.99); p=0.014) adjusted for
onset age, sex, time from onset to initiation of prednisone and

episode severity. The estimated effect size was a 3.7% (95% CI
0.8%  to  6.6%)  reduction  in  the  hazard  of  a  relapse  for  every
1 mg/day increment in oral prednisone dose. This equated to a
17.2%  (95%  CI  3.8%  to  28.8%)  reduction  in  the  hazard  of  a
relapse for every 5 mg/day oral prednisone dose increment.

Specifying the optimal dose and duration of oral
corticosteroids which delays TTFR
A series of Cox proportional hazard analyses and visualisations
were  performed  to  identify  the  optimal  dose  and  duration  for
prednisone  courses.  The  association  of  oral  prednisone  (as
a  time- dependent  variable)  with  TTFR  was  visualised,  using
a  Simon- Makuch  plot,  which  displayed  the  outcome  among
patients  treated  at  or  above  a  particular  daily  oral  prednisone
dose vs below this dose. We predefined candidate threshold doses
ranging from 50 mg/day to 0 mg/day in 2.5 mg/day decrements
(representative examples in online supplemental figure 3). The
minimum effective dose was identified as 12.5 mg/day in adults
(or  0.16 mg/kg/day  in  children),  as  this  plot  demonstrated  the
best separation of the groups while maintaining precision of the
estimate (HR 0.21 (95% CI 0.07 to 0.6); p=0.0036; figure 2).
Patients treated with oral prednisone dosed ≥12.5 mg/day expe-
rienced a 79.1% reduction in the risk of a relapse compared with
patients treated with oral prednisone doses <12.5 mg/day, when
controlling for age, sex, time to treatment and clinical episode
severity.

Next, a similar approach was taken to find the optimal dura-
tion to be spent at or above the recommended oral prednisone
dose of 12.5 mg/day. A series of Cox proportional hazard anal-
yses  and  visualisations  explored  binary  cutoffs  from  6  months
to  0  months  in  0.5- month  decrements  (representative  exam-
ples  in  online  supplemental  figure  4).  Based  on  the  separation
of the outcomes between the oral prednisone dose groups, the
effect  estimates  and  their  CIs,  the  minimum  effective  duration
of  oral  prednisone  dose  of  ≥12.5 mg/day  was  identified  as

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Neuro- inflammation

Figure 2  Time to first relapse according to daily oral corticosteroid dose. Simon- Makuch plot of the association of oral corticosteroid dose (as a time-
dependent covariate) with time to first relapse, using the dosing threshold of 12.5 mg/day. This plot visualises the comparison of the cumulative hazards
of a relapse while patients were treated with oral corticosteroid doses at or above 12.5 mg daily compared with the time they were treated with oral
corticosteroid doses lower than 12.5 mg daily. Number censored exceeds total event number because in this analysis, censoring events occur when patients
cross the dose threshold and at relapse.

3 months from MOGAD onset (HR 0.15 (95% CI 0.04 to 0.48);
p=0.0016). This equated to an absolute risk reduction of 42%
and  a  number  needed  to  treat  of  three  to  prevent  one  patient
from having relapsed at 12 months.

Effective  oral  prednisone  dosing  lasting  less  than  3 months
resulted in a substantially smaller estimated effect size (HR≥0.54)
with weaker evidence of an association with TTFR. This point
estimate  of  the  ≥3 months  persistence  on  the  oral  prednisone
dose of ≥12.5 mg/day corresponded to an 85.4% reduction in
the hazard of a relapse compared with a shorter duration of effec-
tive oral prednisone therapy, and an 87.7% reduction (HR 0.12
(95% CI 0.03 to 0.44); p=0.0012) when compared with those
who never spent any time on effective oral prednisone therapy.
Figure 3A visualises this relationship by dividing the cohort into
four groups that spent different durations of time at or above the
oral prednisone dose of 12.5 mg/day. The median (IQR) cumula-
tive oral prednisone dose (mg) for the <1.5 months, 1.5 to <3
months  and  ≥3 months  groups  were  1085  (631–1807),  2540
(1722–3538)  and  4345  (3761–5965),  respectively.  The  superi-
ority of the ≥3 months group was maintained in both paediatric
and adult subgroups (online supplemental figure 5). Analysis of
patients  diagnosed  in  epochs  before  2014,  between  2014  and
2018 and after 2018 did not reveal any significant differences in
either oral corticosteroid dose or duration.

To  evaluate  the  optimal  duration  of  oral  prednisone  treat-
ment using a different approach, annualised relapse rates were
compared  during  the  time  when  patients  were  treated  with
≥12.5 mg/day  oral  prednisone  and  <12.5 mg/day  oral  predni-
sone during each of the initial 6 months after onset (figure 3B).
The differences in annualised relapse rate in patients in these two
groups  were  largest  in  the  first  3 months  (0.81,  3.06  and  1.44
relapses, respectively) and consistently smaller thereafter (0.58,
0.45  and  0.64).  This  suggests  3 months  might  be  an  adequate
duration  for  this  regimen,  without  marked  additional  benefits
with longer durations of corticosteroids.

Finally, the influence of oral corticosteroid treatment at disease
onset  and  the  likelihood  of  exhibiting  a  monophasic  disease

course was evaluated. MOGAD remained monophasic in 13/16
(81.3%) patients who spent ≥3 months treated with ≥12.5 mg/
day  oral  corticosteroids,  compared  with  12/49  (24.5%)  of
patients  who  were  treated  with  ≥12.5 mg/day  oral  cortico-
steroids  for  less  than  3 months,  and  8/44  (18.2%)  of  patients
who were never treated with ≥12.5 mg/day oral corticosteroids
(figure 4, p<0.001).

Adverse events from corticosteroid exposure during onset
clinical episode
Adverse events related to prednisone exposure during the onset
episode were reported in 8/65 (12.3%) patients. These included
six  grade  1  events,  one  grade  2  event  and  one  grade  3  event
(table 3). There were no grade 4 or 5 events reported. The one
grade 3 event occurred in a patient who had been on 8 months
of  oral  prednisone  (cumulative  dose  5574 mg),  and  who  expe-
rienced cholecystitis requiring a cholecystectomy. We note that
long- term  steroid- related  adverse  events  associated  with  the
treatment  of  subsequent  relapses  with  oral  prednisone  were
documented in some patients (online supplemental table 1).

DISCUSSION
Factors  at  MOGAD  onset  which  influence  the  induction  and
maintenance of disease remission remain to be fully elucidated.
MOGAD patients at disease onset may be prone to ‘very early
relapses’  (<3  months  after  onset)  and  ‘delayed  early  relapses’
(3–12  months  after  onset).14  A  recent  publication  found  an
association  of  very  early  relapses  in  adults,  and  delayed  early
relapses in children and adults, with an increased risk of long-
term  relapsing  disease.14  This  provides  a  compelling  argument
for  effective  early  treatment  after  onset  to  modify  long- term
disease course.

A key historic study related to the duration of corticosteroid
treatment following ON in 448 adults, the Optic Neuritis Treat-
ment  Trial,  identified  a  14- day  course  of  oral  prednisone  was
associated  with  a  higher  risk  of  further  ON  compared  with  a

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Neuro- inflammation

Figure 3  Relapse activity over time since first clinical episode with respect to threshold dosing (≥12.5 mg daily). (A) Kaplan- Meier survival time to first
relapse curves with patients stratified by time spent above threshold dosing. Adjusted Cox proportional hazard ratios, with ‘never’ stratum as the reference
group, are annotated. The median (IQR) cumulative oral corticosteroid dose (mg) for the <1.5 months, 1.5 to <3 months and ≥3 months groups are 1085
(631–1807), 2540 (1722–3538) and 4345 (3761–5965), respectively. (B) Annualised relapse rates were compared for each month after onset clinical
episode, between patients above threshold dose and those below. Data for each group were aggregated from multiple patient- days in their respective
months. The number of patients and patient- days contributing to each group are tabulated.

Trewin BP, et al. J Neurol Neurosurg Psychiatry 2024;95:1054–1063. doi:10.1136/jnnp-2024-333463

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Neuro- inflammation

Figure 4  Disease course outcome according to time above threshold dosing. Alluvial plot of the disease course outcome for patients with different
durations spent above threshold dosing of oral corticosteroids (≥12.5 mg/day) for their initial episode of MOGAD. 13/17 (76%) of patients remaining above
threshold dosing for more than 3 months had not experienced a relapse at last follow- up, compared with 12/48 (25%) of those who spent time above
threshold dosing that was less than 3 months, and 8/45 (18%) of those who never received above threshold dosing. MOGAD, myelin oligodendrocyte
glycoprotein antibody- associated disease.

group  receiving  3 days  of  intravenous  methylprednisolone  and
11 days of oral prednisone, or placebo.28 However, subsequent
evaluation  of  177  patients’  available  sera  from  this  trial  iden-
tified  only  three  were  seropositive  for  MOG  antibodies.29  A
publication from 2019 surveying 52 neurologists from 22 coun-
tries  revealed  that  there  was  significant  equipoise  with  respect
to clinical practice at disease onset in MOGAD.16 All clinicians
surveyed used pulsed intravenous methylprednisolone for acute
clinical  episodes  of  MOGAD.  Of  interest,  our  univariate  anal-
yses showed that the use of intravenous corticosteroids did not
appear to influence the risk of a relapse. 60% usually or always
prescribed ≥3 months course of oral corticosteroid therapy, 23%
sometimes did and 17% rarely or never did.16 Paediatric neurol-
ogists were more likely to never have treated with ≥3 months of
corticosteroids compared with adult neurologists. The duration
of  preferred  oral  corticosteroid  treatment  varied  significantly
and ranged from less than 3 months to ≥18 months.16

Our cohort is of value as it included patients with clinical onset
before widespread knowledge of MOGAD as a distinct syndrome,
with  18  patients  who  did  not  receive  any  immunotherapy  for
their  first  clinical  episode,  enabling  direct  comparisons  with  a

Table 3  Adverse events in patients exposed to oral corticosteroids
(n=65)

Number (% of
patients exposed to
oral corticosteroids)

Type

CTCAE

1

2

3

4

5

6 (9.2)

1 (1.5)

1 (1.5)

0

0

5 Cushingoid appearance;
2 Irritability; 1
hyperglycaemia; 1 HTN
worsening

Weight gain, severe acne
and insomnia requiring
medication

Cholecystitis requiring
surgery

–

–

Median
cumulative oral
corticosteroid
dose (mg)

5583 (IQR 4158–
6395)

1750

5574

–

–

Data are summarised as n (%) or median (IQR).
CTCAE, Common Terminology Criteria for Adverse Events; HTN, hypertension.

‘never  treated’  at  onset  group.  Additionally,  the  current  study
reiterates our prior findings that up to 55% of relapsers experi-
encing their first relapse, do so on prednisone doses <10 mg/day
or within 10 weeks of cessation of prednisone.3 4

MOGAD  episodes  have  been  demonstrated  to  be  extremely
responsive  to  corticosteroids  with  prior  studies  demonstrating
varying  durations  of  corticosteroid  treatment  ranging  from
2 weeks to 6 months identified as being associated with a reduced
propensity  to  relapses.3  4  9  11–13  There  are  publications  which
query  the  role  of  corticosteroids  in  children  beyond  a  short
intravenous  course  at  disease  onset,30  31  while  others  identi-
fied that corticosteroid treatment for ≥5 weeks in children was
associated  with  a  lower  risk  of  relapse.12  A  prospective  cohort
study of 276 patients revealed an HR of 0.33 for developing a
relapsing  course  in  those  treated  with  prednisone  as  a  mainte-
nance therapy, compared with those who were not.32 However,
there remains a lack of consensus on the optimal dose and dura-
tion of corticosteroids at MOGAD onset.

There is accumulating evidence of increased relapse- associated
disability  in  MOGAD,  particularly  with  visual  and  sphincter
dysfunction,  reinforcing  relapse  prevention  remains  a  critical
therapeutic  goal.4  9  12  33  While  relapse  rates  are  reported  as
30%–60%  in  MOGAD,8  11  13  34  35  this  may  be  in  the  order  of
70% when patients are followed up for over 5 years,9 as in our
cohort. This brings to question whether there is a role for intro-
ducing  corticosteroid- sparing  maintenance  immunosuppression
at disease onset in order to minimise relapse- associated deficits
as  well  as  corticosteroid  exposure.  However,  while  treatment
of MS and NMOSD highlights the need for ongoing immuno-
therapy from diagnosis, in MOGAD there remains a proportion
of patients who have a monophasic illness who may be unneces-
sarily exposed to long- term immunosuppression if this approach
was uniformly adopted at disease onset.

The  most  salient  finding  of  this  study  is  the  79%  reduction
in  the  hazard  of  relapse  at  or  above  a  dose  threshold  of  pred-
nisone  12.5  mg/day  (0.16  mg/kg/day  for  children),  compared
to those below this dose threshold. The other key finding was
strong evidence of an 88% reduced hazard of relapse for those
spending at least 3 months at or above this threshold compared
to  those  that  never  received  this  dosing.  Furthermore,  the
annualised relapse rate reduction was not as striking when the

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prednisone  regimens  extended  beyond  3 months.  While  many
patients are commenced initially on intravenous methylprednis-
olone or high doses of prednisone in the range of 1 mg/kg/day,
our findings suggest that this high dose may be rapidly reduced
to  our  recommended  dose  of  12.5 mg/day  in  adults  (0.16 mg/
kg/day in children) for 3 months, in order to minimise total oral
corticosteroid exposure while still maintaining relapse freedom.
Given there were 16 patients in the ≥3 months treatment group,
further  prospective  studies,  with  larger  cohorts  following  the
proposed  dosing  and  duration  protocol,  will  be  essential  to
corroborate our findings.

None of the patients in this cohort on prednisone were docu-
mented to have CTCAE grade 4 or 5 adverse events related to
their onset treatment. No patient experienced a CTCAE grade
>2  adverse  event  with  a  cumulative  dose  of  <5000  mg  of
oral  prednisone.  The  suggested  optimal  dose  and  duration  at
onset  that  our  results  recommend  accumulates  to  a  total  dose
that resides below this limit. Moreover, the reduction in future
relapses evident in our study also would be expected to have a
corticosteroid- sparing effect, by avoiding high cumulative doses
associated with treatment of relapses.15

Our  study  is  retrospective,  with  inherent  limitations  such  as
the potential for selection bias, treatment indication bias, infor-
mative  censoring  and  unmeasured  confounding  factors.  Our
statistical models were refined to adjust for known confounders.
Neurological  and  visual  assessments  were  not  standardised
across  centres  due  to  the  retrospective  nature  of  this  study.  It
is  likely  that  among  patients  with  a  documented  monophasic
disease course, some will develop a relapsing course given suffi-
cient time. This, however, does not affect our primary finding of
TTFR, or treatment recommendations within the first 12 months
after  onset.  In  order  to  analyse  paediatric  and  adult  patients
concurrently,  we  weight- adjusted  doses  of  oral  prednisone.
While this is considered a reasonable conversion method,21 and
weight- based  dosing  is  an  established  convention  in  paediatric
medicine,  we  acknowledge  that  adult  body  weight  data  for  all
patients in this retrospective study were not available for inclu-
sion  in  this  analysis.  Addressing  immortal  time  bias  presented
an  analytical  challenge,  especially  when  assessing  a  time- based
outcome  (TTFR),  with  the  exposure  stratified  by  a  time  based
criterion  (time  above  threshold  dosing).  In  our  approach,  we
accounted for all above- threshold dosing durations, even when
this  extended  past  the  point  of  the  first  relapse,  to  reflect  the
intention to treat with a certain oral prednisone course. Finally,
documentation  of  adverse  events  following  prednisone  expo-
sure, while likely accurate for severe short- term adverse events,
could  underestimate  more  minor  adverse  events  and  the  long-
term consequences of corticosteroid use for the onset episode.

This study provides evidence supporting the use of oral corti-
costeroids at the onset of MOGAD. We propose evidence- based
recommendations  highlighting  that  patients  at  disease  onset
should  be  treated  with  a  minimum  effective  dose  of  12.5 mg
daily  of  oral  prednisone  (0.16 mg/kg/day  for  children)  for  a
minimum  duration  of  3 months  in  order  to  delay  TTFR  and
minimise cumulative corticosteroid exposure.

Author affiliations
1Translational Neuroimmunology Group, Kids Neuroscience Centre and Brain and
Mind Centre, Sydney Medical School, Faculty of Medicine and Health, University of
Sydney, Sydney, New South Wales, Australia
2Clinical Neuroimmunology Group, Institute for Neuroscience and Muscle Research,
Kids Research Institute at the Children’s Hospital at Westmead, University of Sydney,
Sydney, New South Wales, Australia
3Sydney Medical School, Faculty of Medicine and Health, University of Sydney,
Sydney, New South Wales, Australia

Neuro- inflammation

4Department of Medicine, The University of Melbourne, Melbourne, Victoria, Australia
5Department of Neurology, The Royal Melbourne Hospital, Parkville, Victoria, Australia
6Brain Autoimmunity, Kids Neuroscience Centre, Kids Research at the Children’s
Hospital at Westmead, Sydney, New South Wales, Australia
7Department of Neuroscience, Monash University Central Clinical School, Melbourne,
Victoria, Australia
8Department of Neurology, Concord Hospital, Concord, New South Wales, Australia
9Alfred Hospital, Melbourne, Victoria, Australia
10The University of Newcastle, Newcastle, New South Wales, Australia
11School of Medicine, Griffith University, Nathan, Queensland, Australia
12Department of Neurology, Gold Coast University Hospital, Southport, Queensland,
Australia
13Brain and Mind Centre, The University Of Sydney, Camperdown, New South Wales,
Australia
14School of Medical Science, Faculty of Medicine and Health, University of Sydney,
Sydney, New South Wales, Australia

X Benjamin P Trewin @Benjamin_Trewin, Russell C Dale RussellCDale@, Fabienne
Brilot @FabienneBrilot and Sudarshini Ramanathan @darshi_r

Collaborators  Australasian MOGAD Study Group: Robert Adam, Ian Andrews,
Jayne Antony, Patrick Aouad, Monica Badve, Joshua Barton, Heidi Beadnall, Stefan
Blum, Michael Boggild, David A Brown, Jim Burrow, Katherine Buzzard, Ann Bye,
Anita Cairns, Sophie Calvert, Shabeed Chelakkadan, Damian R Clark, Marzena J
Fabis- Pedrini, Deborah Field, Anthony Fok, Clare L Fraser, Victor SC Fung, Justin
Garber, Serge Geara, Deepak Gill, Sachin Gupta, Simon Hawke, Andrew PD
Henderson, Nevin A John, Dean L Jones, Hannah F Jones, Allan Kermode, Matthew
Kiernan, Trevor Kilpatrick, Andrew J Kornberg, Mitchell Lawlor, Fiona XZ Lee, Richard
J Leventer, Vivien Li, Simon Ling, Ganesha Liyanage, Joseph A Lopez, Stephen
Malone, Mark P Marriot, Pamela McCombe, Alan McDougall, Manoj P Menezes,
Vera Merheb, Christina Miteff, Mastura Monif, Gopinath Musuwadi Subramanian,
Ai- Lan Nguyen, Gina O’Grady, John O’Neill, Robert Ouvrier, Mark Paine, John Parratt,
Sekhar Pillai, Jane Prosser, Sean DS Riminton, Izanne Roos, Jennifer Sandbach, Ingrid
E Scheffer, Ubaid Shah, Neil Shuey, Adriane Sinclair, Mark Slee, Claire G Spooner, Ian
Sutton, Sanjay Swaminathan, Esther Tantsis, James Thomas, Terrence Thomas, Julia
Thompson, Christopher Troedson, Steve Vucic, Justine Wang, Tyson Ware, Richard
Webster, Ming Wei Lin, Owen White, Wei Yeh, Con Yiannikas, Eppie M Yiu, Michael
Zong.

Contributors  BPT and SR had full access to all of the data in the study and SR is
responsible for the overall content as guarantor. SR, TK, RCD and BPT contributed to
the conception, design of the study and statistical analyses. All authors contributed
to acquisition, analysis and interpretation of data. Authors from the Australasian
MOGAD Study Group have contributed to acquisition, analysis and interpretation
of data. BPT and SR contributed to drafting the text and preparing the figures. All
authors contributed to the critical review of the manuscript for important intellectual
content. SR obtained funding and supervised BPT.

Funding  Research funding CIA Ramanathan: National Health and Medical
Research GNT1141169, GNT2008339; Royal Australasian College of Physicians
Research Establishment Fellowship; University of Sydney SOAR Prize and Rewarding
Research Success Grants. Research Funding Trewin: University Postgraduate Award
(University of Sydney).

Disclaimer  The funders had no role in study design, data collection, data analysis,
data interpretation, manuscript writing, or submission for publication.

Competing interests  BPT receives a University of Sydney postgraduate
scholarship and a stipend from CIA Ramanathan’s Royal Australasian College
of Physicians Research Establishment Fellowship. RCD has received research
funding from the Star Scientific Foundation, The Trish Multiple Sclerosis Research
Foundation, Multiple Sclerosis Research Australia, the Petre Foundation and the
NHMRC (Australia; Investigator Grant). He has also received honoraria from Biogen
Idec as an invited speaker, and is on the IDMC for a Roche RCT in paediatric MS.
He is on the medical advisory board (non- remunerated position). TAH has received
research funding from MS Australia, the NHMRC Medical Research Future Fund
(Australia), the Brain Foundation and has received honoraria for talks, advisory
boards or support for scientific meetings from Bayer- Schering, Novartis, Biogen Idec,
Merck, Teva, Alexion, Bristol Myers Squibb and Sanofi- Genzyme. AVDW receives
funding from MS Australia, the NHMRC and the Trish Foundation. She has received
research support from Roche pharmaceuticals, Biogen, Novartis and Merck. She
has received honoraria for talks, advisory boards, and travel support from Novartis
and Merck. She serves as the COO of the MSBase Foundation. JLS received travel
compensation from Biogen, Merck, Novartis; has been involved in clinical trials with
Biogen, Novartis, Roche; her institution has received honoraria for talks and advisory
board service from Biogen, Merck, Novartis, Roche. She is on the board of directors
for MSPlus. HB has received institutional compensation (To Monash University) for
advisory board or trial steering committee membership or speaker bureaus from
Biogen, Merck, Novartis, Roche, and UCB Pharma. Institutional Research Support to
Monash University or MSBase Foundation from Merck, Biogen, Roche, Novartis, UCB

Trewin BP, et al. J Neurol Neurosurg Psychiatry 2024;95:1054–1063. doi:10.1136/jnnp-2024-333463

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Neuro- inflammation

Pharma, Alexion, Teva, NMHRC (Australia), MRFF (Australia), MS Australia, TRISH
MS Research Foundation, Pennycook Foundation and Monash University. SAB has
received honoraria for attendance at advisory boards and travel sponsorship from
Bayer- Schering, Biogen- Idec, Merck- Serono, Novartis, and Sanofi- Genzyme, has
received speaker’s honoraria from Biogen- Idec and Genzyme, is an investigator in
clinical trials sponsored by Biogen Idec, Novartis and Genzyme, and was the recipient
of an unencumbered research grant from Biogen- Idec. MB received research
grants from Genzyme- Sanofi, Novartis, Biogen, Merck and BMS; and is a Research
Consultant for RxMx and Research Director for the Sydney Neuroimaging Analysis
Centre. He is on the board of the Research Management Council of MS Australia,
or the Trish Foundation Board. SWR has received travel support, honoraria, trial
payments, research and clinical support to the neurology department or academic
projects from NHMRC, MRFF, NBA, Myasthenia Alliance Australia, Lambert Initiative,
Beeren foundation, anonymous donors; and from pharmaceutical / biological
companies: Alexion, Biogen, CSL, Genzyme, Grifols, Merck, Novartis, Roche, Sandoz,
Sanofi, UCB. He is cofounder/shareholder of RxPx health, National IVIG Governance
Advisory Council & Specialist Working Group Australia (Neurology) (paid), Australian
Medical Services Advisory Committee ad hoc subcommittee on IVIG (paid), Australian
Technical Advisory Group on Immunisation Varicella Zoster working party (unpaid),
Medical advisor (unpaid) to various patient and advocacy groups. Funds over the
last 5 years including but not limited to travel support, honoraria, trial payments,
research and clinical support to the neurology department or academic projects
from: NHMRC, MRFF, NBA, Myasthenia Alliance Australia, Lambert Initiative, Beeren
foundation, anonymous donors; and from pharmaceutical/biological companies:
Alexion, Biogen, CSL, Genzyme, Grifols, Merck, Novartis, Roche, Sandoz, Sanofi,
UCB. FB has received research funding from NSW Health, MS Australia, the NHMRC
(Australia), the Medical Research Future Fund (Australia), The MOG Project (Apollo
Grant) and Novartis. She was on an advisory board for Novartis and Merck, and has
been an invited speaker for Biogen, Novartis and Limbic Neurology. She is on the
medical advisory board (non- remunerated positions) of The MOG Project and the
Sumaira Foundation. TK served on scientific advisory boards for MS International
Federation and World Health Organisation, BMS, Roche, Janssen, Sanofi Genzyme,
Novartis, Merck and Biogen, steering committee for Brain Atrophy Initiative by Sanofi
Genzyme, received conference travel support and/or speaker honoraria from WebMD
Global, Eisai, Novartis, Biogen, Roche, Sanofi- Genzyme, Teva, BioCSL and Merck and
received research or educational event support from Biogen, Novartis, Genzyme,
Roche, Celgene and Merck. SR has received research funding from the National
Health and Medical Research Council (NHMRC, Australia), the Petre Foundation, the
Brain Foundation, the Royal Australasian College of Physicians, and the University
of Sydney. She is supported by an NHMRC Investigator Grant (GNT2008339). She
serves as a consultant on an advisory board for UCB and Limbic Neurology and has
been an invited speaker for educational/research sessions coordinated by Biogen,
Alexion, Novartis, Excemed and Limbic Neurology. She is on the medical advisory
board (non- remunerated positions) of The MOG Project and the Sumaira Foundation.
All other authors have no relevant disclosures.

Patient consent for publication  Not applicable.

Ethics approval  This study involves human participants and ethics approval was
granted by Sydney Children’s Hospitals Network Human Ethics Committee (2019/
ETH06041) and affiliated sites. Participants gave informed consent to participate in
the study before taking part.

Provenance and peer review  Not commissioned; externally peer reviewed.

Data availability statement  Data are available on reasonable request.
Anonymised data and datasets that support the findings of the current study are
available from the corresponding author on reasonable request.

Supplemental material  This content has been supplied by the author(s). It
has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have
been peer- reviewed. Any opinions or recommendations discussed are solely those
of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and
responsibility arising from any reliance placed on the content. Where the content
includes any translated material, BMJ does not warrant the accuracy and reliability
of the translations (including but not limited to local regulations, clinical guidelines,
terminology, drug names and drug dosages), and is not responsible for any error
and/or omissions arising from translation and adaptation or otherwise.

Open access  This is an open access article distributed in accordance with the
Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits
others to copy, redistribute, remix, transform and build upon this work for any
purpose, provided the original work is properly cited, a link to the licence is given,
and indication of whether changes were made. See: https://creativecommons.org/
licenses/by/4.0/.

ORCID iDs
Benjamin P Trewin http://orcid.org/0000-0001-6452-6229
Russell C Dale http://orcid.org/0000-0002-2495-1826
Todd A Hardy http://orcid.org/0000-0003-4145-3172
Anneke van der Walt http://orcid.org/0000-0002-4278-7003

Simon A Broadley http://orcid.org/0000-0002-9429-4307
Michael H Barnett http://orcid.org/0000-0002-2156-8864
Stephen W Reddel http://orcid.org/0000-0002-0169-3350
Fabienne Brilot http://orcid.org/0000-0002-7025-2276
Tomas Kalincik http://orcid.org/0000-0003-3778-1376
Sudarshini Ramanathan http://orcid.org/0000-0002-0294-9768

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Supplemental Online Content

Supplementary Figure 1. Relationship between oral corticosteroid treatment and relapses
Supplementary Figure 2. Temporal dynamics of prednisone dosing for all treated patients
Supplementary Figure 3. Representative examples of a series of Simon-Makuch plots in descending thresholds
to find the optimal oral corticosteroid dose
Supplementary Figure 4. Representative examples of a series of Kaplan-Meier plots in descending duration
cutoffs above threshold dose to find the optimal duration of above threshold dosing
Supplementary Figure 5. Time to first relapse stratified by months spent above threshold oral corticosteroid
dose in paediatric (A) and adult patients (B)
Supplementary Table 1. Long term adverse events possibly related to corticosteroids
Supplementary References

1

BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any relianceSupplemental materialplaced on this supplemental material which has been supplied by the author(s)J Neurol Neurosurg Psychiatry doi: 10.1136/jnnp-2024-333463–10.:10 2024;J Neurol Neurosurg Psychiatry, et al. Trewin BP

Supplementary Figure 1. Relationship between oral corticosteroid treatment and
relapses

Histogram of the relationship between oral corticosteroid course and relapse in patients who relapsed and had
been  exposed  to  oral  corticosteroids  (n=40).  The  x-axis  left  of  the  dashed  vertical  line  indicate  the  oral
corticosteroid dose at which patients relapsed, and the values to the right indicate the time from oral corticosteroid
cessation to relapse. There is a break in the x-axis from 80-120 months with a 10-fold change in scale above 120
months to include three outliers with very late relapses. OCS, oral corticosteroid.

2

BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any relianceSupplemental materialplaced on this supplemental material which has been supplied by the author(s)J Neurol Neurosurg Psychiatry doi: 10.1136/jnnp-2024-333463–10.:10 2024;J Neurol Neurosurg Psychiatry, et al. Trewin BP

Supplementary Figure 2. Temporal dynamics of prednisone dosing for all treated patients

Prednisone dose over the first year for each of the patients treated with oral corticosteroids (n=65, 60%) for their first clinical episode
of  MOGAD  is  indicated  above.  Raw  doses  are  provided  (A)  stratified  by  age.  The  median  (solid  line)  and  interquartile  range
(shading) dose for prednisone over time is shown for paediatric patients (B) and adult patients (C). Panel A is then re-presented with
the paediatric doses weight-adjusted to adult equivalent doses (D), as used in our analysis. The treated patients in our cohort were
given corticosteroids for a median (IQR) of 47 days (30-140), with an initial adult equivalent dose of 73 mg (50-100). There was
no statistically significant difference in the mean total prednisone dose between females and males (p-value 0.81).

3

BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any relianceSupplemental materialplaced on this supplemental material which has been supplied by the author(s)J Neurol Neurosurg Psychiatry doi: 10.1136/jnnp-2024-333463–10.:10 2024;J Neurol Neurosurg Psychiatry, et al. Trewin BP

Supplementary  Figure  3.  Representative  examples  of  a  series  of  Simon-Makuch  plots  in  descending
thresholds to find the optimal oral corticosteroid dose

These six survival plots are representative of a series performed with the dosing cutoff reducing by 2.5 mg/day from 50 mg/day to
0 mg/day. They are presented in descending order from 50mg/day dosing cutoff in the top left of the figure (A) down to 5mg/day in
the bottom right (F). The shading represents the 95% confidence interval. In Simon-Makuch plots of time-varying covariates, the
number of subjects at risk is very small in at least one stratum at early time points, therefore it is common practice to move the
starting  time  point  from  study  time  0  to  the  median  time  to  switch  membership  of  groups  (Day  13)1. The  number  of  censored
observations in these plots is larger than the total number of patients in the study as censoring events occur at last follow up for
those  who  did  not  experience  the  event  (a  relapse)  and  when  patients  cross  the  dosing  threshold.  The  survival  curve  and  the
annotation are confounder-adjusted effect estimates. We identified 12.5mg/day as the optimal dosing threshold as the separation
between the two lines over the follow-up period, and the confidence interval are the most favourable at this dose cutoff. The x-axis
range is 18 months as there is insufficient data for patients on any continuous dose of oral corticosteroids beyond this point. CI,
confidence interval; HR, hazard ratio.

4

BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any relianceSupplemental materialplaced on this supplemental material which has been supplied by the author(s)J Neurol Neurosurg Psychiatry doi: 10.1136/jnnp-2024-333463–10.:10 2024;J Neurol Neurosurg Psychiatry, et al. Trewin BP

Supplementary Figure 4. Representative examples of a series of Kaplan-Meier plots in descending
duration cutoffs above threshold dose to find the optimal duration of above threshold dosing

These six survival plots are representative of a series performed with the dosing duration cutoff reducing by 0.5 month from 6
months to 0 months. They are presented in descending order from 6 months duration cutoff in the top left of the figure (A) down to
0 months in the bottom right (F). The shading represents the 95% confidence interval. The annotation is the confounder-adjusted
effect estimate. We identified three months as the optimal threshold dosing duration as the separation between the two groups over
the follow-up period, and the confidence interval are the most favourable at this duration cutoff. CI, confidence interval; HR, hazard
ratio.

5

BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any relianceSupplemental materialplaced on this supplemental material which has been supplied by the author(s)J Neurol Neurosurg Psychiatry doi: 10.1136/jnnp-2024-333463–10.:10 2024;J Neurol Neurosurg Psychiatry, et al. Trewin BP

Supplementary Figure 5. Time to first relapse stratified by months (m) spent above threshold oral
corticosteroid dose in paediatric (A) and adult patients (B)

Kaplan-Meier survival curves for paediatric patients (A) and adult patients (B) of time to first relapse according to time spent above
threshold dosing (≥12.5mg/day). Adjusted Cox proportional hazard ratios are annotated next to their respective curves. The “Never”
stratum who never received oral corticosteroids above threshold dosing, are the reference group. CI, confidence interval; HR, hazard
ratio.

6

BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any relianceSupplemental materialplaced on this supplemental material which has been supplied by the author(s)J Neurol Neurosurg Psychiatry doi: 10.1136/jnnp-2024-333463–10.:10 2024;J Neurol Neurosurg Psychiatry, et al. Trewin BP

Supplementary Table 1. Long term adverse events possibly related to corticosteroids

Timing
relative to
onset episode

Onset episode

Adverse
event
severity
(CTCAE)

No
adverse
events

Onset episode

Onset episode

Onset episode
Onset episode

Onset episode

Relapses <3y

1

2

3
4

5
No
adverse
events

Relapses <3y

Relapses <3y
Relapses <3y
Relapses <3y

Relapses <3y

1

2
3
4

5

No. of
patients

Adverse event  (AE) descriptions
(Possibly related to corticosteroids)

Cumulative IV
corticosteroid dose
[Median (Q1-Q3)] for the
clinical episode associated
with the AE (grams)

Cumulative prednisone
dose [median (Q1-Q3)]  for
the clinical episode
associated with the AE
(grams)

Days above threshold
dose [median (Q1-Q3)] of
prednisone for the clinical
episode associated with
the AE

98

7

3

1
0

0

59

7

4
1
0

0

-
Irritability; Steroid-induced
hyperglycaemia; Cushingoid
appearance; Weight gain and mild
irritability; Slightly cushingoid and mild
worsening of HTN; Mild cushingoid
appearance; Weight gain and irritability
Anxiety and paranoia; Weight gain,
Severe acne and insomnia; Primary VZV
infection
Cholecystitis requiring cholecystectomy
-

-

-
Irritability; Insomnia, irritability;
Irritability, acne; "Some undesirable
effects"; Significant weight gain;
Osteopaenia; Irritability with IV steroids
Osteopaenia; Osteopenia and central
adiposity; Irritability and insomnia;
Obstructive sleep apnoea
Bilateral cataracts requiring surgery
-

-

5.77 (3.75-7.19)

1.83 (1.05-3.67)

18 (0-47)

9.54 (8.66-12.66)

5.58 (4.16-6.39)

78 (47-152)

3.75 (3.75-5.81)

6.25 (6.25-6.25)
-

-

1.75 (1.75-1.75)

5.57 (5.57-5.57)
-

-

0 (0-22)

154 (154-154)
-

-

5.96 (3.75-7.82)

5.34 (2.53-8.48)

14 (0-138)

6.25 (5.62-6.25)

3.19 (1.85-4.52)

69 (12-99)

3.75 (3.38-3.75)
3.75 (3.75-3.75)
-

-

17.48 (11.34-22.63)
8.81 (8.81-8.81)
-

-

237 (61-534)
343 (343-343)
-

-

7

BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any relianceSupplemental materialplaced on this supplemental material which has been supplied by the author(s)J Neurol Neurosurg Psychiatry doi: 10.1136/jnnp-2024-333463–10.:10 2024;J Neurol Neurosurg Psychiatry, et al. Trewin BP
Relapses ≥3 to
<5y

Relapses ≥3 to
<5y
Relapses ≥3 to
<5y
Relapses ≥3 to
<5y
Relapses ≥3 to
<5y
Relapses ≥3 to
<5y

Relapses ≥5y

No
adverse
events

1

2

3

4

5
No
adverse
events

Relapses ≥5y

1

Relapses ≥5y

Relapses ≥5y
Relapses ≥5y
Relapses ≥5y

2

3
4
5

17

4

1

0

0

0

24

5

8

0
1
0

-
Weight gain and irritability; Dyspepsia,
irritability, insomnia; Irritability; Weight
gain; Weight gain

6.25 (3.93-8.58)

1.73 (0.34-3.58)

2 (0-27)

8.59 (6.17-9.07)

2.47 (1.33-12.56)

55 (34-366)

Osteopaenia

6.09 (6.09-6.09)

4.10 (4.10-4.10)

0 (0-0)

-

-

-

-

-

-

-

-

-

-

-

-

3.75 (3.75-6.25)

1.19 (0.59-3.83)

0 (0-18)

Anxiety, nausea and insomnia;
Dyspepsia; Weight gain, irritability;
Dyspepsia, mood changes and
insomnia; Dyspepsia, irritability and
insomnia with IV steroids; Acne; Mild
central adiposity
Osteopaenia; Cholelithiasis requiring
surgery; Osteopaenia; Obesity; Weight
gain and headache; Osteopaenia;
Glaucoma; Weight gain; HTN

-
Depression and suicidality
-

3.75 (2.50-4.38)

2.20 (1.91-5.17)

39 (2-62)

3.75 (3.75-3.75)

-
6.25 (6.25-6.25)
-

7.44 (5.02-14.87)

-
3.35 (3.35-3.35)
-

21 (0-161)

-
35 (35-35)
-

CTCAE = Common terminology for criteria for adverse events; HTN = hypertension; Q = quartile; VZV = varicella zoster virus; y = years.

8

BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any relianceSupplemental materialplaced on this supplemental material which has been supplied by the author(s)J Neurol Neurosurg Psychiatry doi: 10.1136/jnnp-2024-333463–10.:10 2024;J Neurol Neurosurg Psychiatry, et al. Trewin BP

Supplementary References

1. Schultz LR, Peterson EL, Breslau N. Graphing survival curve estimates for time‐dependent covariates. Int J Methods Psychiatr Res. 2002;11(2):68-74. doi:10.1002/mpr.124

9

BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any relianceSupplemental materialplaced on this supplemental material which has been supplied by the author(s)J Neurol Neurosurg Psychiatry doi: 10.1136/jnnp-2024-333463–10.:10 2024;J Neurol Neurosurg Psychiatry, et al. Trewin BP



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