The Treatment of Myelin Oligodendrocyte Glycoprotein Antibody Disease: A State-of-the-Art Review

Background: Myelin oligodendrocyte glycoprotein antibody disease (MOGAD) is an important etiology of neurologic morbidity and specifically, atypical, and relapsing optic neuritis. This review summarizes acute treatment and long-term prevention approaches in MOGAD. Evidence acquisition: PubMed and Google Scholar databases were manually searched and reviewed. Results: We review the evidence base for acute treatment of MOGAD with corticosteroids and adjunct therapies, such as intravenous immunoglobulin (IVIg) and plasma exchange. We discuss the utility of prolonged corticosteroid tapering after the acute attack. We then summarize the commonly used disease-modifying treatments for relapsing MOGAD, including chronic low-dose corticosteroids, classic antirheumatic immune suppressants, biologic agents, and IVIg. Conclusions: While acute MOGAD attacks are usually treated with high-dose IV corticosteroids, longer oral corticosteroid tapers may prevent rapid relapse. Multiple long-term treatment strategies are being employed in recurrent MOGAD, with IVIg is emerging as probably the most effective therapy.

State-of-the-Art Review Section Editors: Fiona Costello, MD, FRCP(C) Sashank Prasad, MD The Treatment of Myelin Oligodendrocyte Glycoprotein Antibody Disease: A State-of-the-Art Review Bart K. Chwalisz, MD, Michael Levy, MD, PhD Background: Myelin oligodendrocyte glycoprotein antibody disease (MOGAD) is an important etiology of neurologic morbidity and specifically, atypical, and relapsing optic neuritis. This review summarizes acute treatment and long-term prevention approaches in MOGAD. Evidence Acquisition: PubMed and Google Scholar databases were manually searched and reviewed. Results: We review the evidence base for acute treatment of MOGAD with corticosteroids and adjunct therapies, such as intravenous immunoglobulin (IVIg) and plasma exchange. We discuss the utility of prolonged corticosteroid tapering after the acute attack. We then summarize the commonly used disease-modifying treatments for relapsing MOGAD, including chronic low-dose corticosteroids, classic antirheumatic immune suppressants, biologic agents, and IVIg. Conclusions: While acute MOGAD attacks are usually treated with high-dose IV corticosteroids, longer oral corticosteroid tapers may prevent rapid relapse. Multiple longterm treatment strategies are being employed in recurrent MOGAD, with IVIg is emerging as probably the most effective therapy. Journal of Neuro-Ophthalmology 2022;42:292–296 doi: 10.1097/WNO.0000000000001684 © 2022 by North American Neuro-Ophthalmology Society M yelin oligodendrocyte glycoprotein antibody disease (MOGAD) has recently emerged as an important cause of neuro-ophthalmic morbidity that is distinct from other demyelinating disorders, such as multiple sclerosis and neuromyelitis optica spectrum disorder (NMOSD) associated with aquaporin 4 antibodies (AQP4). Department of Neurology (BKC, ML), Massachusetts General Hospital, Harvard Medical School, Boston Massachusetts; and Department of Ophthalmology (BKC), Massachusetts Eye and Ear, Harvard Medical School, Boston, Massachusetts. The authors report no conflicts of interest. Address correspondence to Bart K. Chwalisz, MD, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02130; E-mail: [e-mail] 292 MOGAD: CLINICAL PHENOTYPE AND MORBIDITY MOGAD has broad phenotypic expression that prominently includes optic neuritis, transverse myelitis, acute demyelinating encephalomyelitis (ADEM) and other cerebral syndromes. In adults, optic neuritis (ON) is the most common manifestation of MOGAD, whereas ADEM is most common in children. Clinical characteristics suggestive of MOGAD optic neuritis include recurrent ON, including chronic relapsing inflammatory optic neuritis (CRION), prominent optic disc edema, bilateral disease, and radiologic features of longitudinally extensive optic nerve as well as perineural enhancement on MRI (1). Compared with NMOSD, the optic chiasm and tracts are less commonly involved. Importantly, similar to NMOSD and in contradistinction to MS, accumulation of disability in MOGAD appears to be driven primarily by relapses. Early studies suggested that MOGAD may have a more favorable prognosis compared with AQP4-seropositive NMOSD, leading to a lower EDSS and reduced overall risk of visual and motor disability. However, severe disability has been reported in 47% of adult MOGAD patients, with more than 70% resulting from the onset attack. Although vision loss in MOGAD ON at nadir can be severe, the recovery is typically better than in NMOSD optic neuritis. Nevertheless, a high attack frequency can lead to significant cumulative visual morbidity. In addition, MOGAD patients with transverse myelitis tend to experience more severe residual deficits (2). Although the clinical course can be monophasic, approximately 50% of MOGAD patients will experience a recurrence of demyelination, most commonly ON (3). Indeed, more recent studies from different cohorts strongly argue against the conceptualization of MOGAD as a generally monophasic and mild disease. MOGAD: ACUTE TREATMENT Patients with MOGAD ON tend to present with severely comprised visual function during the acute phase of the Chwalisz and Levy: J Neuro-Ophthalmol 2022; 42: 292-296 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. State-of-the-Art Review disease. Treatment with corticosteroids is almost universally used in the acute period to aid in visual recovery. The treatment of acute ON with high-dose corticosteroids has historically been informed by the results of the Optic Neuritis Treatment Trial (ONTT). Notably, in the typical and MS-associated ON patients who were represented in the ONTT, IV corticosteroids do not affect the ultimate visual outcome (4), and patients are not typically steroid refractory or become steroid dependent. However, when serum samples from 177 of 448 patients enrolled in the ONTT were assayed for AQP4- and MOG-IgG, only 4 MOG-IgG–seropositive patients were identified (5). Therefore, the results of the ONTT cannot be extrapolated to assess the impact of high-dose corticosteroids on visual recovery in MOG-ON. Compared with optic neuritis associated with MS, MOGAD-associated optic neuritis appears to be highly steroid responsive and, in some cases, steroid dependent. New onset disease or acute relapses in MOGAD are typically initially treated with high-dose IV methylprednisolone or equivalent for 3–5 days. In many cases, a rapid return to baseline can be observed within 48 hours following steroid initiation. Observational data have shown that, similarly to NMOSD, shorter time to treatment of MOGAD-associated optic neuritis correlated with better visual outcomes (6). This is also supported by evidence that loss of retinal nerve fiber layers is an early event in ON, including in MOGAD (7). Acute attacks that respond poorly to steroids can be treated with intravenous immunoglobulin (IVIg), plasma exchange (PLEX), or immunoadsorption (8). Thus, in antibody-associated optic neuritis, NMOSD and MOGAD both, ‘’time equals vision.’’ This represents a radical shift from the ONTT paradigm of the treatment of optic neuritis: it can no longer be assumed that the treatment of acute optic neuritis only leads to faster recovery. Rather, fast appropriate treatment can be essential to improve clinical outcomes. Although some studies in NMOSD have supported the concurrent initiation of PLEX with corticosteroids during acute relapses (9,10), it is currently unknown whether such an approach should also be considered in sever MOGAD attacks. STEROID TAPER AFTER INITIAL ATTACK Typically, MOGAD optic neuritis relapses respond well to steroids, but patients are often vulnerable to relapses on tapering or withdrawal of steroids. A slow taper of corticosteroids has been recommended based on observational studies. The Australasian and New Zealand MOG Study Group recently showed that relapses commonly occurred with doses of ,20 mg of prednisone per day in adults and that a duration of treatment less than 3 months was associated with a 2-fold higher risk of relapses, compared with patients treated for a longer time Chwalisz and Levy: J Neuro-Ophthalmol 2022; 42: 292-296 (2). Another study from China demonstrated that early tapering or discontinuation of oral steroids within 30 days had as outcome a relapse in 59% of patients (11). In conclusion, a prolonged steroid taper may reduce the chance of early relapses and provide a good maintenance option, with close monitoring during and after steroid cessation. In some cases, initial corticosteroids treatment may be the only therapy that is needed after a first MOGAD attack. A subgroup of MOGAD patients may remain relapse free on no immunotherapy for a long time after initial treatment with steroids or only experience a relapse after many years (2). THE ROLE OF ANTIBODY TESTING IN GUIDING TREATMENT To some extent, the treatment of MOGAD can be informed by antibody testing (12). A relapsing or chronic course is associated with higher titers of MOG-IgG during the first months and/or maintenance of seropositive status despite treatment. In contrast, low titers or seroconversion to negativity in early course represents a reliable predictor of monophasic course. Persistent titers may be more meaningful because serology may transiently be positive during an initial relapse but negative during follow-up. THE TREATMENT OF RELAPSING MOGAD Given that MOGAD is an antibody-mediated inflammatory demyelinating disorder of the CNS with high likelihood of relapse and a propensity to cause relapse-related morbidity, it is imperative to potentially consider an early secondary prevention treatment strategy. The longer-term treatment of MOGAD has been largely extrapolated from AQP4-seropositive NMOSD. It is currently not standardized, still based on clinical experience and observational studies (Class IV evidence). To date, there are no Food and Drug Administration (FDA)–approved medications for long-term relapse prevention in adult patients. No Phase III, multicenter, randomized, clinical trials have been completed to assess treatment effectiveness in MOGAD. The lack of high-class clinical studies is related to the novelty of the disease, its low prevalence, the wide age range, and broad clinical spectrum. Maintenance therapies that have been used in MOGAD include low-dose oral corticosteroids, IVIg, classic steroidsparing antirheumatic immune suppressants, such as azathioprine and mycophenolate mofetil, and B-cell-depleting therapies, such as rituximab. Retrospective evidence suggests that long-term immunosuppressant therapy may reduce the frequency of recurrent attacks, while most disease-modifying agents used to treat MS have not demonstrated usefulness in preventing relapses in MOGAD. 293 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. State-of-the-Art Review LOW-DOSE MAINTENANCE CORTICOSTEROIDS In addition to supporting the use of a very slow steroid taper, it has been shown that concomitant use of oral steroids as an adjunct to immunosuppressive drugs was accompanied by reduced risk of relapses (5% vs. 38% on immunosuppressive monotherapy) (2). Some patients on maintenance low-dose prednisone alone had a relapse-free course, indicating efficacy of steroids in sustaining remission. However, the significant long-term metabolic and bone health–related adverse effects warrant caution and careful monitoring. ANTIRHEUMATIC IMMUNOSUPPRESSANTS IN CHRONIC MOGAD Azathioprine (AZA) and mycophenolate mofetil (MMF) have an established safety record and display some efficacy as therapeutic strategies for long-term immunosuppression in adult MOGAD patients. However, treatment failure and intolerance can lead to their discontinuation. These agents can be used as monotherapy or in combination with oral steroids. Azathioprine A review of studies of the use of long-term immunotherapy in adult MOGAD (13) reported that AZA (2–3 mg/kg/day divided into 2–3 doses) achieves reduction of mean and median annualized relapse rate (ARR), as well as stabilization or improvement of the EDSS. In 2019, in a European cohort of 125 adults with relapsing MOGAD patients, Cobo-Calvo et al reported a significant reduction in relapses in patients treated with AZA and MMF (14). The interval between the initiation of AZA and the first relapse ranged from 3 to 9 months (median of 6 months). In a North American Study, AZA found to have the second lowest posttreatment ARR after IVIG (3); in that study, however, the slightly lower pretreatment ARR for recipients of azathioprine compared with patients receiving the other therapies could have led to a bias because AZA may have been preferentially used in more benign cases. In addition, patients on AZA were more frequently on concomitant maintenance prednisone, which may have contributed to the apparently greater efficacy of azathioprine. Mycophenolate Mofetil Efficacy of MMF, typically given 1,500–3,000 mg/day divided into 2 doses, was demonstrated in a sample of 96 patients treated with the agent, both in terms of ARR and EDSS indices (13). Similarly, a recent prospective study from China evaluating MMF showed improved outcomes, especially in a subset of patients with isolated optic neuritis or high MOG-IgG titers, with 86% of patients having a 294 reduced risk of relapse (15). In the Australian cohort, MMF also appeared to be effective, but treatment failure rates were higher and relapses were often associated with steroid taper, suggesting that the steroid was producing the benefit in these patients (2). Consistent findings were reported in the study by Chen et al, where MMF use in 13 patients documented a more modest reduction of relapse rates compared with the others immunosuppressive agents (3). Cyclophosphamide There is limited information about the potential utility of cyclophosphamide in MOGAD, as the number of reported patients so far is low. The Australian cohort had a 50% failure rate (2), and similarly, in the study by Chen et al, 2 of 3 patients had relapses during treatment with the agent (3). Chen et al commented that although the lack of apparent efficacy could be attributed to the small total number of patients treated with IV cyclophosphamide or to the fact that this more toxic agent may have been employed to treat the most severe and refractory cases, the findings may indicate that cytotoxic CD8 T cells are not key effectors of MOGAD pathogenesis. Potentially supporting the lack of efficacy of cyclophosphamide in MOGAD patients may be that when the 2 patients who relapsed early on cyclophosphamide switched to rituximab, they stabilized without further relapse (3). B-CELL-DEPLETING THERAPIES B-cell-depleting therapies have been employed with great success in the treatment of AQP4-positive NMOSD. In the clinical experience with MOGAD so far, these therapies also have some efficacy, but in comparison with NMOSD, it may be more modest. The systematic review of studies by Lu et al in 2020, reporting 253 adult MOGAD patients in total, concluded that, similar to AQP4-ab-positive NMOSD patients, new relapses within the few weeks after the first rituximab infusion occurred in about 30% of MOGAD patients, despite a correct biological effect, with a median time from the most recent infusion to the first relapse of 2.6 (range: 0.6–5.8) months (13). At a multicenter study that involved patients treated with rituximab (RTX), Whittam et al (16) showed that the agent reduces the relapse rate for MOGAD, but the benefit did not appear to be as great as for AQP4-positive NMOSD. Recently, in a study of 121 adult MOGAD patients on RTX, the same authors demonstrated an improvement in relapse rate of 42%, with median followup time of 12.7 months (16). Interestingly, the investigators found that MOG-specific B cells were only detected in about 60% of these patients, indicating that MOGspecific B cells are not linked to levels of serum MOG antibodies. This has cast doubt on whether B-celldepleting treatments should be used in MOG-seropositive patients. Chwalisz and Levy: J Neuro-Ophthalmol 2022; 42: 292-296 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. State-of-the-Art Review Although the response to B-cell depletion in MOGAD may not be as robust as in NMOSD, regular CD19+ cell count monitoring and proactive redosing in the event of B-cell repopulation might reduce the incidence of relapses, as has been demonstrated in NMOSD. Inebilizumab is a novel, humanized monoclonal antibody that binds to and depletes CD19+ B cells, leading to a greater reduction in cell population as compared with the CD20+ inhibitor rituximab. It is now FDA approved for use in NMOSD. The NMomentum trial, which compared inebelizumab vs. placebo administration in NMOSD patients, also enrolled 7 adult MOGAD patients, but separate outcomes for the MOGAD subgroup were not specifically reported (17). IL6 INHIBITION IL6 inhibition is another therapeutic strategy that has been successful in NMOSD. The IL6 inhibitor tocilizumab has been used with varied effectivity in some patients with rituximab-refractory MOGAD (18). Because of limited numbers of patients, it is difficult to draw firm conclusions. MAINTENANCE IVIg IVIg is emerging as a promising maintenance therapy for patients with relapsing MOGAD. Based on data from a recent, large, multicenter cohort of MOGAD patients, maintenance IVIg at 3- or 4-week intervals, applied in 10 patients (5 children), demonstrated the lowest relapse rate compared with other immunomodulators; only 20% of patients had a relapse, compared relapse rates of greater than 50% in alternative (59% for azathioprine, 73% for mycophenolate mofetil, 62% for RTX) (3). The authors suggest that IVIg’s efficacy in suppressing attacks is independent of any bias toward using IVIg in patients with more benign disease. They concluded that long-term IVIG is an effective maintenance immunotherapy for patients with MOGAD. Previous small retrospective studies support these results, especially in children. By contrast, in the Australian cohort, a higher relapse rate in 3 of 7 patients receiving long-term IVIG was seen, but the median annualized relapse rate (ARR) for the cohort was 0, and the relapse rate in patients receiving IVIg was still the lowest among the treatments evaluated (range, 0–0.75) (2). EMERGING THERAPIES Emerging therapeutic approaches that have been used successfully in the treatment of NMOSD could also be evaluated in MOGAD. Novel, future, potential treatments that are currently being investigated in NMOSD include, for instance, efgartigimod, a synthetic IgG1 Fc analog, which has been shown efficacy as a substitute for IVIg in treating the IgG-mediated neuromuscular disorder myasthenia gravis. Rozanolixizumab is an inhibitor of the Chwalisz and Levy: J Neuro-Ophthalmol 2022; 42: 292-296 neonatal Fc receptor and also has such potential. The use of Bruton tyrosine kinase inhibitors is also being considered. DECISION MAKING IN CLINICAL PRACTICE The prognosis in each individual MOG case is uncertain. It may depend on demographics, previous attack frequency, MOG IgG seropositivity, and prior medication exposure. In clinical practice, the decision-making process to initiate long-term relapse prevention treatment should consider a number of features, including severity and recovery from the acute attack, relapse recurrence, the level and persistence of MOG IgG titers, and patient preferences. Long-term preventive treatment is generally recommended for adults patients with either a relapsing course or significant disability derived from a previous relapse. There is currently limited data on the question how long to treat MOGAD patients for. This is an important consideration given the potential morbidity of long-term immunosuppression for what could be a monophasic disease. Thus, the appropriate duration of immunosuppressive maintenance after a first relapse is not well established. The most commonly used therapeutic approach after a first debilitating event or the first relapse of MOGAD and following high-dose IV steroids is a maintenance protocol of oral prednisone slow taper. Different treatment durations have been suggested for oral steroids, ranging from 1 to 12 months. A panel of experts recently recommended oral corticosteroids for at least 6 months of treatment after the initial relapse, based on the fact that the risk of relapse is higher during the first months of disease onset (17). If MOG-IgG becomes negative at 6 months, these experts suggested that treatment could be tapered and discontinued, given the evidence that persistent MOG antibody seropositivity may predict relapse. In case of persistent seropositivity at 6 months, oral steroids can be maintained for 12 months; when they should be retested and if seroconversion to negativity occurs and there are no relapses, initial immunosuppressive treatment could be slowly discontinued. Alternatively, AZA or MMF could be introduced if new relapses occur (recurrent MOGAD) and/or MOG-IgG persist at 12 months. However, a bridging therapy is recommended until these immunosuppressive agents take full biologic effect, that is, for at least 3–6 months. Oral steroids in a dose of around 20 mg per day is the recommended approach. Modification of initial steroid immunosuppressive treatment should be considered in case of adverse effects and/or intolerance to oral steroids. As summarized above, IVIg may be the most efficacious therapy for relapse prevention in MOGAD. One effective approach consists early induction with IVIg followed by weekly or monthly repeat dosing. The clinical evidence so far supports the need for flexibility in management. In particular, the option of switching maintenance immunotherapy following 295 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. State-of-the-Art Review treatment failure on the initial agent may significantly reduce relapse rates and improve treatment outcomes. FUTURE DIRECTIONS Although there has been substantial progress in the clinical experience of the treatment of MOGAD, there is an urgent need to improve the evidence base for treatment. The need for randomized controlled trials in MOGAD is also underscored by the fact that relapses occur with almost all available immunotherapy modalities. 9. 10. CONCLUSIONS MOGAD has emerged as an important demyelinating disease that has the potential for high relapse rates and significant morbidity. While acute MOGAD attacks are usually treated with high-dose IV corticosteroids, longer oral steroid tapers may be required to prevent rapid relapse. Less certainty exists regarding the optimal long-term treatment strategies in recurrent MOGAD, although IVIg is emerging as probably the most effective therapy. 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