Predictors of a relapsing course in myelin oligodendrocyte glycoprotein antibody-associated disease

Abstract

Background:

Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is a recently described demyelinating disorder, and children represent about 50% of all cases. Almost half of the patients experience relapses, but very few studies have evaluated predictors of relapse risk, challenging clinical management. The study aimed to identify predictors at MOGAD onset that are associated with a relapsing course.

Methods:

Prospectively collected data from pediatric patients with MOGAD seen by the US Network of Pediatric MS Centers were leveraged. Univariable and adjusted multivariable models were used to predict recurrent disease.

Results:

We identified 326 MOGAD cases (mean age at first event 8.9 years (SD 4.3), 57% female, 77% White, 74% non-Hispanic), and 46% relapsed during a mean follow-up of 3.9 years (SD 4.1). In the adjusted multivariable model, female sex (HR 1.66, 95% CI 1.17–2.36, p=0.004), and Hispanic/Latino ethnicity (HR 1.77, 95% CI 1.19–2.64, p=0.005) were associated with a higher risk of relapsing MOGAD. Maintenance treatment initiated before a second event with rituximab (HR 0.25, 95% CI 0.07 – 0.92, p=0.037) or intravenous immunoglobulin (IVIG) (HR 0.35, 95% CI 0.14–0.88, p=0.026) was associated with lower risk of a second event in multivariable analyses. Conversely, maintenance steroids were associated with a higher estimated relapse risk (HR 1.76, 95% CI 0.90–3.45, p=0.097).

Conclusion:

Sex and ethnicity are associated with relapsing MOGAD. Use of rituximab or IVIG therapy shortly after onset is associated with a lower risk of second event. Preventive treatment after a first event could be considered in those with a higher relapse risk.

Funding:

National Institute of Neurological Disorders and Stroke - 5R01NS113828–04; National Multiple Sclerosis Society - FAN-2107–38301 & SI-210–38420.

Introduction

Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is a relatively newly identified demyelinating disorder; much is still unknown about its clinical course and optimal management. Multiple studies have helped to distinguish MOGAD from multiple sclerosis (MS) and aquaporin-4 positive neuromyelitis optica spectrum disorder (AQP4+ NMOSD), focusing on clinical and imaging features in children and adults.^1–5 MOGAD can exhibit either a monophasic or relapsing pattern. In fact, MOGAD patients are more likely to have a monophasic disease course,³ compared to those with MS and AQP4+ NMOSD.^4,6 The proportion of patients with recurrent disease varies from 27 to 53% of all MOGAD cases.^2,4,7–10 While high-dose corticosteroids are often used to treat acute MOGAD events, there is currently no consensus on the optimal long-term management strategy.² This is primarily due to limited literature regarding predictors of relapsing disease and drug efficacy for relapse prevention.^2,4 Identifying prognostic factors at disease onset is critical to predict the risk of relapse, to inform long-term treatment decisions and to design clinical trials to test new preventive agents.

Methods

Study design and participants:

Data from pediatric-onset MOGAD patients were extracted from the prospective Network of Pediatric Multiple Sclerosis Centers (NPMSC) registry, which includes thirteen participating pediatric MS clinics in the USA.¹¹ Participating centers included: Boston Children's Hospital, Children's Hospital Colorado, Loma Linda University, Massachusetts General Hospital for Children, Mayo Clinic Rochester, State University of New York at Buffalo, Stony Brook University Medical Center, Texas Children's Hospital Baylor, University of Alabama at Birmingham, University of California San Francisco, and Washington University School of Medicine in St. Louis. The Network maintains a centralized database, and demographic, clinical, cerebrospinal fluid (CSF), and imaging characteristics have been entered prospectively since 2011 for patients with demyelinating disease onset before the age of 18 years. The institutional review board approved the study protocols at each participating institution, and informed consent was obtained from all participants/legal guardians before enrollment as required.

Inclusion criteria:

Patients with disease onset before the age of 18 between November 1, 2011, and August 15, 2023, were enrolled in the study. Additional criteria were as follows:

• Positive for MOG IgG via CBA at any time during the disease course with titer ≥1:20.

• Negative for AQP4+ IgG via CBA.

• Diagnosis of central nervous system (CNS) acquired demyelinating disease that is not MS or AQP4+ MOSD.

MOG-IgG serostatus:

The determination of MOG IgG1 serostatus was carried out by the Mayo Clinic laboratory for clinical serum samples from November 2017 onwards, utilizing a commercially available CBA assay. Research samples collected before 2017 were tested as a batch by the Mayo Clinic laboratory with the same assay.¹²

Study variables and definitions at baseline:

Mother's education was used as a proxy of socioeconomic status as previously reported.¹³ Additional variables included a family history of autoimmune disease in first-degree relatives and acute illness within the 30 days before MOGAD onset. Body mass index (BMI) was calculated using weight and height and converted to age- and sex-specific z-scores based on CDC growth charts. BMI was classified as underweight (z-score <5th percentile), healthy weight (5th-<85th percentile), overweight (85th-94th percentile), or obese (≥95th percentile).¹⁴

The severity of the first event was defined as mild (no change in daily activities), moderate (interferes with some daily activities), or severe (major interference with daily activities) based on the extent to which activities of daily living (ADL) were affected and were estimated by the treating neuroimmunologist. Onset phenotypes included isolated acute disseminated encephalomyelitis (ADEM), isolated optic neuritis (ON), isolated transverse myelitis (TM), combination (a combination of ADEM, ON, and/or TM), and other (no ADEM, TM, or ON). A clinical relapse was defined as a new clinical attack occurring more than 30 days following the onset of a previous attack.^4,15

Acute treatment for the initial event was categorized as either receiving or not receiving treatment (pulse steroids, intravenous immunoglobulin [IVIG], plasma exchange [PLEX], cyclophosphamide, tocilizumab) initiated within 45 days of disease onset and administered for less than 90 days. Pulse steroid treatment was defined as daily methylprednisolone ≥500 mg or ≥20 mg/kg of body weight or an equivalent dose of other glucocorticoids, such as dexamethasone; this was further classified as pulse without oral taper or pulse followed by oral taper. In cases where the precise start dates for acute treatment were unavailable, but month was known, start date, by default, was set as the first of that month.

Preventive maintenance disease-modifying therapies (DMT) were defined as long-term (≥90 days) treatment including steroid use, IVIG, anti-CD20 therapy (rituximab), immunosuppressants (mycophenolate, azathioprine, cyclophosphamide), and other maintenance therapies (interferon, glatiramer acetate, tocilizumab).

Baseline MRI variables (abnormal brain and/or orbit MRI, presence/absence of T2 lesions, and presence/absence of gadolinium-enhancing lesions) were assessed using the earliest brain MRI scan performed within three months of disease onset (i.e., baseline MRI). CSF variables were assessed using the first spinal tap results obtained within one year of onset.

Statistical Analysis:

Baseline characteristics between demyelinating disorder groups or between first-event phenotypes were compared with the use of Kruskal-Wallis test for continuous variables and chi-square tests or Fisher's Exact tests for categorical variables. To identify predictors that distinguish monophasic from relapsing course in MOGAD, we utilized univariable and multivariable Cox regression models to analyze time to first relapse. Those without a recorded relapse event were considered censored at the last record update. Predictors tested were selected based on clinical relevance and included age, sex, race, ethnicity, mother's education, BMI, onset phenotype, presence of oligoclonal bands (OCB) in CSF, presence of at least one T2 lesion on baseline brain MRI, presence of at least one gadolinium-enhancing lesion on baseline brain MRI, use of acute pulse steroids, use of acute IVIG, and maintenance DMT use before the first relapse. The multivariable model was constructed using standard demographic variables with the potential addition of clinically important variables that were identified as significant in univariable analyses. A p-value less than 0.05 was considered statistically significant for all analyses. Multiple Imputation (MI) using chained equations was employed for multivariate analysis due to over 10% missingness in several variables.^16,17 Twenty imputed datasets were created using age, sex, race, ethnicity, BMI, mother’s education, clinical features at disease onset, acute treatment, baseline MRI, and phenotype as predictors. Pooled results were provided using PROC MI ANALYZE in SAS.

Results

Characteristics of MOGAD cases:

We identified 326 (19.29%) MOGAD cases in the registry who met criteria for this study. Table 1 provides a comprehensive overview of the demographic and clinical characteristics of MOGAD cases at onset. 46% relapsed during a mean follow-up time of 3.9 years (SD 4.1). The mean time to first relapse was 1.41 years (SD 2.13). The following variables displayed missingness: Race 35 (10.7%), ethnicity 36 (11.0%), mother’s education 84 (25.8%), history of auto-immune disease in first-degree relatives 130 (39.9%), first event severity 23 (7.1%), BMI at disease onset 107 (32.8%), presence of OCB 145 (44.5% of the patients either did not have a spinal tap or did not have OCB measured), baseline MRI 28 (8.6%), baseline T2 lesion: 28 (8.6%) and baseline Gadolinium lesion: 28 (8.6%). Subjects with missing data are categorized based on the presence or absence of relapse in the Supplementary Table S1a.

Table 1:

Summary of demographics and clinical characteristics in MOGAD

Baseline variables	n= 326
Sex: Female	188 (58%)
Race
White	223 (77%)
Black	24 (8%)
Asian	20 (7%)
Other	24 (8%)
Ethnicity
Hispanic or Latino	76 (26%)
Not Hispanic or Latino	214 (74%)
Mother’s Education
None	22 (9%)
High School or Associate's	109 (45%)
Bachelor's or Graduate	111 (46%)
BMI at disease onset
Underweight (z-score <5th %ile)	4 (2%)
Healthy (5th - <85th %ile )	116 (53%)
Overweight (85th - 94th %ile )	44 (20%)
Obese (≥95th %ile)	55 (25%)
History of autoimmune disease in first-degree relatives: Yes	63 (32%)
Age at first event: Mean (SD)	8.9 (4.3)
Follow-up years: Mean (SD)	3.9 (4.1)
Time to first relapse (years): Mean (SD)	1.41 (2.13)

The variable Race had 35 missing values.

The variable Ethnicity had 36 missing values.

The variable Mother’s Education had 84 missing values.

The variable BMI at onset had 107 missing values.

The variable History of autoimmune disease on first-degree relatives had 130 missing values.

The variable Follow-up time had 5 missing values.`

MOGAD characteristics based on clinical phenotype at onset:

Isolated ON at onset was the most common phenotype (Supplementary Table S1). No significant sex or race differences were noted across phenotypic subgroups. Onset age varied across phenotypes (p < 0.0011), with isolated ADEM showing the youngest (5.9 years, SD = 3.3) and isolated ON the oldest (10.5 years, SD = 3.5) (Table S1). Across phenotypes, 83% of the MOGAD cases received acute pulse steroid treatment at onset (Table S2). The distribution of the phenotypes who did not receive acute pulse steroids at onset is provided in Table S3. Table S4 provides detailed information on treatment patterns for MOGAD who had a relapse and were not on preventive maintenance treatment.

Predictors of relapse in MOGAD:

Of the 152 MOGAD cases who experienced a relapse during follow-up, 52% had received maintenance therapy before the first relapse. Univariable and multivariable survival analyses identified several significant factors at onset associated with the risk to have a relapse.

Univariable analyses:

Female sex (HR 1.58, 95% CI 1.13–2.21, p=0.007), non-White race (HR 1.49, 95% CI 1.03–2.16, p=0.031), and Hispanic/Latino ethnicity (HR 1.58, 95% CI 1.10–2.27, p=0.012) were associated with a higher risk of having a relapse (Figure 1). The lack of acute pulse steroid treatment at onset was also associated with increased relapse risk (HR 1.60, 95% CI 1.11–2.30, p=0.01) compared to those who did receive pulse steroids (Figure 2). Other baseline factors such as clinical onset phenotype, mother's education level, first event severity, MRI features (presence of T2 lesion, presence of gadolinium-enhancing lesions), BMI, use of acute IVIG, and presence of CSF oligoclonal bands were not associated with relapse risk.

Figure 1:

Forest Plot displaying the unadjusted univariable analysis of factors correlated with relapsing course in MOGAD.

Figure 2:

2A-2B shows Kaplan-Meier curves displaying the probability of remaining relapse-free over time based on sex (2A), ethnicity (2B) in MOGAD. Vertical ticks indicate censoring times.

Multivariable analyses:

Adjusting for potential confounders, female sex (HR 1.66, 95% CI 1.17–2.36, p=0.004), and Hispanic/Latino ethnicity (HR 1.77, 95% CI 1.19–2.64, p=0.005) remained independently associated with higher risk of having a relapse (Table 2). In addition, non-Whites had a higher estimated risk of relapse (HR 1.44, 95% CI 0.96–2.16, p=0.08). Of note, in multivariable analyses, use of acute pulse steroids was no longer associated with relapse risk (HR 0.79, 95% CI 0.53–1.20, p=0.27). Other factors at onset such as age, first event severity, presence of OCB did not affect relapse risk (Table 2).

Table 2:

Multivariable analysis with hazard ratios for time to relapse

Variables	Hazard Ratio	95% CI	p
Sex: Female	1.66	1.17–2.36	0.004
Ethnicity: Hispanic or Latino	1.77	1.19–2.64	0.005
Race: non-White	1.43	0.96–2.16	0.08
Age at first event	1.02	0.98–1.06	0.37
First event severity: Moderate	0.66	0.37–1.16	0.15
First event severity: Severe	0.74	0.42–1.31	0.30
Oligoclonal bands: Positive	1.31	0.74–2.35	0.35
Acute pulse steroid treatment at onset: Yes	0.80	0.52–1.20	0.27
Maintenance steroids before first relapse: Yes	1.76	0.90–3.44	0.097
Anti-CD20* before first relapse: Yes	0.25	0.06–0.92	0.037
Maintenance IVIG before first relapse: Yes	0.35	0.14–0.88	0.026
Other DMTs^ before first relapse: Yes	1.89	0.55–6.46	0.306
Immunosuppressants# before first relapse: Yes	0.54	0.18–1.64	0.28

^*Anti-CD20: rituximab

^{^}Immunosuppressants: mycophenolate, azathioprine, cyclophosphamide

^#Other: interferon, glatiramer acetate, tocilizumab

From the same multivariable model, we estimate that maintenance treatment initiated before a second event with an rituximab (HR 0.25, 95% CI 0.07–0.92, p=0.037) or IVIG (HR 0.35, 95% CI 0.14–0.88, p=0.026) was associated with lower risk of a second event compared to patients who did not receive maintenance therapy. Conversely, maintenance steroids had a higher estimated relapse risk compared to patients who did not receive maintenance therapy, though this effect was not statistically significant (HR 1.76, 95% CI 0.90–3.45, p=0.097). Finally, there was no effect of the use of immunosuppressant or other treatment used for MS on the risk of relapse (Table 2).

Discussion:

This work provides critical new information regarding the risk factors associated with relapsing MOGAD as well as the effect of various early preventive treatments. Although no predictor of a relapsing course has been consistently reported across studies, MOG-IgG serostatus one year after onset and possibly age, sex or clinical phenotype at onset have been suggested to be possible predictors of relapse in smaller and/or shorter studies with retrospective data collection.^7,10,18–21 We identify strong predictors of a relapsing disease at the time of onset, namely female sex, and Hispanic ethnicity in multivariable analyses adjusted for possible confounders, including use of DMT before a second event, leveraging prospectively collected data. In addition, we report that the use of rituximab, an anti-CD20 agent or IVIG as maintenance therapies initiated shortly after disease onset was associated respectively with a 75% and 65% decrease in the hazard of having a relapse. Our findings have important implications for managing pediatric patients shortly after MOGAD onset but also for understanding biological factors underlying the risk of a relapsing course.

Except for the higher racial and ethnic diversity of our cohort, our demographic and clinical baseline characteristics align with previous studies.^7,18,22,23 Consistent with other investigations, MOGAD patients were more likely to be white, less likely to be Hispanic/Latino, had mothers with higher levels of education, and had a younger age of onset compared to MS and NMOSD.²⁴ Isolated ON was the most common presentation, accounting for 52% and half of our MOGAD cases experienced a relapse during a mean follow-up of almost four years, which is in keeping with previous studies.^2,4,7

While sex differences play a role in susceptibility to autoimmune diseases such as MS, it may also modulate disease course.^25–27 For example, females with MS have a higher relapse rate than males.^27–29 The reason for the overall increased risk of relapse in females with MOGAD is unclear but could relate to immunomodulatory differences related to sex. Furthermore, in alignment with previous studies in CNS autoimmunity, women with MS display robust peripheral immune responses and harbor a blood-brain barrier that tends to have greater permeability.³⁰ Such distinct characteristics, in turn, may create a conducive environment for heightened transmigration of autoreactive lymphocytes into the CNS. This may be a plausible explanation for the elevated relapse rates observed among females with MS in contrast to their male counterparts.^30–32

The association between Hispanic/Latino ethnicity and increased risk of relapse in MOGAD is intriguing. This trend has also been observed in other autoimmune diseases, with Hispanic and Latino individuals demonstrating higher age-standardized prevalence, and higher disease activity in conditions such as lupus.^33–36 Proposed reasons for this include genetic factors and social determinants of health like socio-economic status, and access to care.^35–37 It is possible that Hispanics with a monophasic MOGAD course may be less likely to present to specialized referral centers, thereby underestimating the proportion of non-relapsing cases in this population. Similarly, non-white race tended to be associated with higher risk to have relapses, though this did not reach statistical significance in the multivariable analysis, likely due to insufficient power related to the sample size. In addition, the sample size did not allow for a more in-depth examination of specific racial associations with the risk of relapse. The underlying drivers of racial differences in MOGAD course could be similar to those proposed for ethnicity. Further research is needed to elucidate the biological and socioeconomic mechanisms underlying the association of ethnicity and race with MOGAD course. Additionally, concerted efforts should be made to enroll minorities in ongoing and future MOGAD clinical trials, given traditionally lower rates of participation among these populations.³⁸ Ensuring adequate representation of ethnic and racial groups seemingly at higher risk of relapse will be important to maximize generalizability of trial findings and developing therapeutic strategies that benefit all MOGAD patients. As our results suggest certain demographics may portend more active disease, recruiting these groups for studies of novel agents or treatment approaches could aid discovery of more effective treatments for recurrent MOGAD.

MOGAD clinical phenotype is age-dependent, very young children commonly presenting with an ADEM-like phenotype, while ON or TM is more frequently observed in older patients.^4,8,39,40 A few studies have reported that TM phenotype may be associated with a lower risk of relapse.^10,18 Our study, encompassing a larger and more diverse group of pediatric MOGAD, did not find a significant association between clinical onset phenotype and the risk of relapse (Figure S3).

No consensus currently exists on the optimal steroid regimen to treat a first event of MOGAD, but some experts recommend using pulse steroids and, for those using a taper, limiting corticosteroid use to less than four weeks, especially in children, to minimize adverse effects.² In our study, pulse steroid therapy was the most commonly administered acute treatment across all MOGAD phenotypes. The proportion of cases receiving pulse steroids at onset was higher than in other studies.^18,22 Although in univariate analyses, those who received pulse dosing at onset, especially those whose pulse was not followed by oral taper, had a lesser risk of having a relapse than those who did not receive pulse steroids, the finding did not hold in multivariate analyses; thus, there is no basis to recommend a change in acute management of first MOGAD events. Furthermore, the use of acute IVIG for first event was not associated with a change in the risk of subsequent events.

While most physicians would not start a DMT after the first event due to the high proportion of patients that do not relapse, in some cases with severe presentation or poor onset recovery a preventive therapy is initiated.² A few retrospective studies have suggested that maintenance rituximab, IVIG or tocilizumab may decrease relapse rate in relapsing MOGAD, although analyses were not adjusted for potential confounders.^40–45 Our study addresses more specifically the effect of various treatment strategies initiated shortly after disease onset in preventing a second clinical event, adjusting for potential confounders. We report that rituximab and maintenance IVIG both prevent a second event. While maintenance steroids appear to increase the risk of a second event, immunosuppressive and other drugs used in MS do not appear to affect that risk. These findings are novel and will help establish treatment recommendations at disease onset, especially in patients with higher risk to have a relapse.

The limitations of our study should be acknowledged. First, relying on data from tertiary referral pediatric MS centers within the NPMSC network may have introduced a referral bias, as less severe or monophasic MOGAD cases might be underrepresented; however, our rate of relapsing disease is similar to other published cohorts. Additionally, serial MOG antibody titers and status were unavailable to correlate with relapse timing and risk. While pediatric patients comprise nearly 50% of all MOGAD cases, our findings may not fully generalize to adult populations. Of note, this study focused on predicting factors at onset that were associated with a relapsing course, and precludes causal inference and assessment of the overall efficacy of different therapies on relapse rates. The study did not employ the newly proposed MOGAD diagnostic criteria due to limited published literature on its validity in children.^4,46–48 Given the observational nature of this registry-based investigation, there were missing data which was handled through imputation, and dosages of maintenance immunosuppressive therapies were unavailable.

Our major strengths include the large, multicenter, longitudinal nature of this study, leveraging one of the largest pediatric MOGAD cohorts reported. Standardized prospective data collection with quality control through our data coordinating center enabled robust analysis of potential relapse predictors including appropriate adjustments. Our diverse population allowed to analyze the contribution of race/ethnicity to disease course which was not possible to tease out in prior reports. The high representation of Hispanic patients (26%) is a notable strength, as this ethnic group has been historically underrepresented in prior MOGAD studies. Our findings related to the Hispanic/Latino subgroup may provide important generalizable insights about MOGAD course in this population. In addition, the mean follow-up of almost four years provided sufficient observation time to reliably assess relapse risk. Finally, the use of adjusted multivariate models including use of various DMT before a second event helped to address as best as possible confounding and reveals important treatment effect for second event prevention.

In summary, the study represents an important step toward prognosis prediction at disease onset. This may not only enable to individualize management for patients at highest risk of relapsing MOGAD but also improve the design of future trials.

Supplementary Material

Figure S1

Figure S1-3: Kaplan-Meier curves displaying the probability of remaining relapse-free over time based on race (S1), acute pulse steroid treatment (S2), and phenotype (S3) in MOGAD. Vertical ticks indicate censoring times.

Key messages:

1. What is already known on this topic

Very few studies have evaluated predictors of relapse risk in MOGAD. Previous studies have identified persistence of MOG seropositivity as predictors of relapse. However, evidence on demographic and clinical factors at disease onset that predict relapsing disease course is limited.

2. What this study adds

The study aimed to identify factors at onset in patients with MOGAD that are associated with a relapsing course. This is the largest pediatric cohort of MOGAD patients to date and the first study to take into account confounders when analyzing relapse predictors, more specifically the effect of disease modifying therapies in predicting relapse. Key findings include identifying female sex and Hispanic ethnicity as associated with increased relapse risk and showing that CD20 agent (rituximab) or IVIG maintenance therapy shortly after onset lowers relapse risk while steroids do not appear to benefit.

3. How this study might affect research, practice or policy

These data can help guide management and prognostic decisions for MOGAD patients at highest risk of recurrence, with implications for relapse prevention through tailored treatment approaches based on demographic factors. The findings also highlight the need to further investigate reasons underlying demographic disparities in MOGAD prognosis.

Data Sharing:

Participant data is securely stored electronically at the Data Coordinating and Access Center (DCAC) of the NPMSC registry, which is located at the University of Utah in Salt Lake City, United States. Anonymous raw data can be accessed upon reasonable request to the corresponding author, subject to approval from DCAC.