Building the Archetype for MOGAD Care: Introducing Mayo’s New Clinic

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Mayo's MOGAD Clinic represents a new type of novel, multidisciplinary care, incorporating multiple different backgrounds of neurology, neuroimmunology, neuro—ophthalmology, and urology, among others.

Eion Flanagan, MB, BCh, an expert neurologist within the MOGAD clinic

Eion Flanagan, MB, BCh

Although it is a rare disease, myelin oligodendrocyte glycoprotein antibody disease (MOGAD)’s inflammatory pathology of demyelination of the optic nerves, brain, and spinal cord affect a global patient population numbering more than 20 million. In the United States alone, this CNS disease has an annual incidence of 3.4 to 4.8 per million individuals. In addition, it poses challenges in diagnosis, as its presenting features are similar to other demyelinating diseases, such as MS and NMOSD.1

In 2007, after nearly 4 decades since the study of MOG antibodies in animal models began, researchers detected antibodies known as MOG-immunoglobulin (IgG) in a subset of patients with acute disseminated encephalomyelitis (ADEM).2 Using a tetramer radioimmunoassay, these specific autoantibodies were rarely found in adult-onset MS cases, indicating that MOG was a more prominent target antigen in ADEM than MS. As the availability of cell-based assays to detect MOG has increased over the past decade, MOGAD has become more formally recognized, with diagnostic criteria published in 2023.3

Earlier this year, Mayo Clinic launched its MOGAD Clinic, a first-of-its-kind specialty clinic devoted toward the care of patients with this rare disease. The clinic, driven by a multidisciplinary approach, offers expert services from Mayo locations in Jacksonville, Florida; Phoenix and Scottsdale, Arizona; and Rochester, Minnesota.

Expertise in multidisciplinary care

Over the years, the experts at Mayo Clinic have seen hundreds of cases of MOGAD, far more than most institutions in the United States and across the globe. Having that experience and being able to distinguish differences between MOGAD and other similarly-presenting disorders is important to the long-term treatment approach, Sebastian Lopez-Chiriboga, MD, told NeurologyLive®.

Sebastian Lopez-Chiriboga, MD

Sebastian Lopez-Chiriboga, MD

"As opposed to aquaporin-4-positive patients, those with MOGAD are not always relapsing," he said. "When they have a first attack, we don’t put them on immunosuppressive therapy because their chances of relapsing are 50/50. Our current approach is to utilize drugs that have been used for similar conditions like NMO (neuromyelitis optica) for patients that have proven to have relapses."

Chiriboga-Lopez, an assistant professor of neurology and director of the Multiple Sclerosis and Autoimmune Neurology Division at the Jacksonville site, is one of many involved in the large-scale MOGAD clinic. He and his colleagues stress that access to validated cell-based assays to be able to diagnose patients in a timely manner is critical to establishing a proper paradigm.

MOGAD has been largely considered a monophasic disease, meaning that patients will only incur relapse once in their lifetime. This has been especially true in younger patients. Further studies with follow-up have shown that, in adults, the disease usually causes multiple attacks, with relapses more frequent in those who present with optic neuritis (ON).4

"About half of patients go on to develop relapsing disease, and we don’t want to put a young child, teenager, or young adult on long-term, immune-lowing medication for the rest of their life if they’re never destined to have another attack,” Eion Flanagan, MB, BCh, an expert neurologist within the MOGAD clinic, told NeurologyLive. "One of the major things we’re looking for is, how do we predict who’s going to have just one attack and who’s going to have future attacks?"

Flanagan, a professor of neurology and chief of the Division of Multiple Sclerosis and Autoimmune Neurology at Mayo Clinic Rochester, has been a part of dozens of research projects on MOGAD, including serving as part of the international panel that published the aforementioned formal diagnosis criteria in 2023. He believes the clinical community, and Mayo Clinic specifically, are following a model similar to NMOSD, where "we went from a disease taught to be a subtype of MS, which is similar to MOG; to now, [when we] have multiple different FDA-approved medications."

"We’re only halfway there in MOGAD. We have the diagnosis part, but we don’t have the treatment yet," he added. "We’re really pushing forward ahead to try and bring patients in to learn more about the disease and bring FDA-approved treatments for these patients for the future."

MOGAD requires high-quality multidisciplinary care because of the ongoing complications patients face in addition to the risk of relapse. Some possible complications may include permanent paralysis in the arms and legs; long-term bowel and bladder difficulties; blindness; and trouble with language, memory, and thinking.

Patients with the disease can face a number of common bladder problems, including incontinence, frequency, nocturia, hesitancy, and retention.5 In fact, urinary issues are more common in patients with MOGAD than MS. At the MOGAD Clinic, there are several different types of specialists on staff to help address the complications patients endure, including urologists, which may help patients who have difficulties emptying their bladder or who may need assistance with a urinary catheter.

The clinic also has a physical rehabilitation department where patients can undergo both cognitive rehab and physical rehab to help with residual symptoms in the arms or legs. Each week, specialists from various departments, including those in neurology, neuroimmunology, urology, physical rehabilitation, and neuro–ophthalmology, discuss perplexing cases of MOGAD and similar-related disorders to establish formal diagnosis, even in some of the most difficult scenarios. The ability to bring in all different specialties allows those in the clinic to confirm and validate diagnoses and ultimately start patients on the right treatment path for long-term success.

Advancing MOGAD testing capabilities

"It’s critical to have access to a good, validated assays to be able to diagnose patients, and we’re lucky that we have access to the Mayo Clinic Immunomodulatory Laboratory, which is the reference center for these disorders that use live cell-based assays," Lopez-Chriboga added. "These are the standard of care for MOGAD diagnosis. Those assays have proven to be much more sensitive and specific compared with other assays."

Cristina Valencia-Sanchez, MD, PhD

Cristina Valencia-Sanchez, MD, PhD

The technology and ability to have conveniently test for serum autoantibodies directed against MOG using cell-based assays is something that sets Mayo Clinic apart from other institutions. As mentioned, this is a relatively newer disease to medical history, with few areas that have the clinical experience to properly diagnose and treat patients at their earliest stage.

"Some patients can actually have low levels of the MOG antibody which could potentially be a false positive," Cristina Valencia-Sanchez, MD, PhD, said. "For this reason, it’s very important for these patients to see a neurologist who has expertise in the disease."

Valencia-Sanchez, a senior associate consultant and assistant professor of neurology at Mayo Clinic in Arizona, added that the ability to quickly receive and interpret the results is beneficial for patients and clinicians alike. Furthermore, she noted that access to research testing is another additional feature patients can take advantage of.

As of currently, MOG-IgG testing has primarily been observed in serum. Despite this, a recently published study led by Flanagan and others from Mayo suggest that testing for MOG-IgG in cerebrospinal fluid (CSF) may have beneficial diagnostic utility in patients with a suspicious phenotype but negative serum MOG-IgG.6

The study retrospectively identified patients for CSF MOG-IgG testing at Mayo Clinic and other medical centers comprising 282 controls, serum MOG-IgG positive MOGAD (n = 74) samples, serum MOG-IgG negative high-risk phenotypes (n = 73), and those with serum false positive MOG-IgG with alternative diagnoses (n = 18). Overall, the pan-IgG Fc-specific secondary was optimal, yielding CSF MOG-IgG sensitivity of 90% and specificity of 98% (Youden index, 0.88).

In the trial, CSF MOG-IgG was positive in 1.4% of controls (4 of 282) controls; 89% (66 of 74) of patients with serum MOG-IgG positive MOGAD; and 12% (9 of 73) of patients with serum MOG-IgG negative with high-risk phenotypes. A subgroup analysis of serum MOG-IgG low-positives revealed CSF MOG-IgG positivity more in MOGAD (13 of 16; 81%) than other diseases with false positive serum MOG-IgG (3 of 15; 20%; P = .001). Of note, findings also showed CSF MOG-IgG IgG-binding-index and CSF MOG-IgG titer to be correlated (Spearman r = 0.64; P <.001).

"The other thing is to determine [is], well, why do people just have antibodies in the spinal fluid? And what does that mean?" Flanagan said regarding the next steps. "Does that mean that they have immune cells within the CSF compartment that are making antibodies that are not present in the blood and so forth, or in the rest of the body? We need to better understand what's happening there and what the mechanisms are and what are the implications for treatment in those patients."

Importance of neuro–ophthalmologists in clinic

Optic neuritis (ON) is a major clinical attack phenotype in demyelinating neurological diseases of the central nervous system, including MS, AQP4-antibody-positive NMOSD, and MOGAD. Compared with MS, ON in MOGAD is bilateral and lengthier. Relative to NMOSD, the anterior optic pathway is more commonly involved in MOGAD. Optic nerve head swelling and perineural sheath enhancement are other typical features of MOGAD, indicating increased blood–optic nerve barrier breakdown.7

MOGAD has several different presentations, most commonly as bilateral ON, transverse myelitis, ADEM, or less commonly, cerebral cortical encephalitis, thus raising the importance of having neuro–ophthalmologists readily available. At the MOGAD clinic, there are several highly trained neuro–ophthalmologists who work with neurologists to perform specialized testing on patients’ eyes to help distinguish differences in these disorders.

John Chen, MD, PhD, a neuro–ophthalmologist and leader within the MOGAD clinic, has been at the forefront of optic-related MOGAD research. A 2022 study conducted by Chen and others showed that retinal nerve fiber layer (RNFL) thickness observed through optical coherence tomography (OCT) can help differentiate acute ON in MOGAD from MS.8 OCT, a noninvasive eye exam that uses light waves to create 3D images of the retina and optic nerve, are commonly used by those at the MOGAD clinic to help understand the severity of ON.

OCT angiography has also been proposed as a way to quantify the retinal structural thickness and microvascular density changes to help differentiate MOGAD from NMOSD. "[Chen] has done some sophisticated work looking at the blood vessels using OCT angiography and trying to match those with MRI changes, because sometimes we can see some thinning in the visual parts of the brain related to optic neuritis. So, we’re working closely with our neuroradiologists to look at those visual pathways very closely," Flanagan noted.

Mayo’s work to advance MOGAD research and treatment

About 20 years ago, researchers at Mayo discovered a critical serum autoantibody biomarker, the NMO antibody.9 This antibody, and its target, the AQP4 water channel, represented a breakthrough in the diagnosis and treatment for patients with autoimmune disorders, which were plagued by high rates of misdiagnosis for years.

The advancement of antibody biomarkers, specifically AQP4, led to several notable therapeutic developments, some of which were led by researchers at Mayo. Notable experts Sean Pittock, MD, and Dean M. Wingerchuk, MD, both of Mayo Clinic, were the primary investigators of one of the early studies of eculizumab (Soliris; Alexion), the first approved therapy for NMOSD in 2019.

MOGAD, a condition with no approved therapies, is primarily managed through corticosteroids, plasma exchange, and IV immune globulin (IVIG). Other oral immunosuppressants and IV medicines have been used as well to prevent attacks of the disease. At the MOGAD clinic, Mayo is a part of several notable ongoing studies, including 2 assessing potential therapies for the disease.

One of these includes METEOROID (NCT05271409), a first of its kind study to evaluate satralizumab (Enspryng; Genentech), a humanized monoclonal recycling antibody that targets the interleukin (IL)-6 receptor, in patients with MOGAD. Previous research has suggested that IL-6 has a role in the pathogenesis of MOGAD, and that IL-6-directed therapy has shown to provide clinical benefit for relapse protection in this patient population.10 METEROID, a phase 3 study, assesses the efficacy, safety, pharmacokinetics, and pharmacodynamics of satralizumab, an FDA-approved therapy for NMOSD, as either a monotherapy or add-on to baseline immunosuppressive therapy.

"These studies are really important because all the data we have right now comes from retrospective studies," Valencia-Sanchez told NeurologyLive. "We are putting our patients with MOGAD on immunosuppressants that we use for other autoimmune neurological conditions, but we don’t have any targeted therapies yet. We don’t have results from clinical trials saying ‘yes, this is effective,’ and how effective the medication is. Hopefully we will have those results soon once these trials are completed."

Mayo is also a part of a large-scale trial dubbed cosMOG (NCT05063162) that assesses the efficacy and safety of rozanolixizumab (Rystiggo; UCB Pharma) in patients with MOGAD. Rozanolixizumab, also referred to as rozimab, is a monoclonal antibody that blocks the activity of the FcRn molecule, which preserves antibodies in the bloodstream from being destroyed. The agent remains the only approved therapy to treat anti-acetylcholine receptor (AChR) or anti-muscle-specific tyrosine kinase (MuSK) antibody-positive myasthenia gravis, another autoimmune disorder.

"Rozanolixizumab is an agent that works similar to IVIG," Valencia-Sanchez added. "It’s an infusion that is given subcutaneously every 2 weeks, and we’ll see whether that’s an effective, targeted therapy for MOGAD in this trial."

Because autoantibodies like MOG are found in low frequency in the blood, the hope is that rozanolixizumab will deplete autoantibodies, thus quieting the immune system. The phase 3 study uses time to first independently centrally adjudicated relapse as the primary outcome, with other secondary outcomes that include change in low-contrast monocular visual acuity and disability, as measured using the Expanded Disability Status Scale score, among others.

Outside of these studies, there are several other ongoing initiatives the clinic is conducting with the help of patients with MOGAD.

"We’re quite interested in finding what drives relapses," said Lopez-Chiriboga. "It’s a big question that’s poorly understood. We also have a lot of interest in trying to understand what is important for patients in terms of quality-of-life assessment, as well as finding additional biomarkers of disease activity. We’re one of the few centers that is actively enrolling clinical trials for MOGAD."

Mayo Clinic researchers were one of the earliest to receive funding from the National Institutes of Health to study how common MOGAD is around the world. This group also has had a major hand in the development of MOGAD diagnostic criteria, and were the first to show that MOGAD does not form scars in the brain like MS and that most lesions resolve over time.11

"These multidisciplinary clinics are so important for patients with MOGAD. The disease is new—so I think this is the first ever designated MOGAD clinic—and many other centers will follow along,” Flanagan said. “It’s important for most patients to get that multidisciplinary care. We have many multidisciplinary clinics for multiple sclerosis, autoimmune neurology, and NMO for transverse myelitis, but for MOGAD, we need to have a representative clinic that looks after patients in a holistic way, including neuro–ophthalmology [in that care paradigm]."

REFERENCES
1. Hor JY, Fujihara K. Epidemiology of myelin oligodendrocyte glycoprotein antibody-associated disease: a review of prevalence and incidence worldwide. Front Neurol. 2023;14. doi:10.3389/fneur.2023.1260358
2. O’Connor KC, McLaughlin KA, De Jager PL, et al. Self-antigen tetramers discriminate between myelin autoantibodies to native or denatured protein
3. Banwell B, Bennett JL, Marignier R, et al. Diagnosis of myelin oligodendrocyte glycoprotein antibody-associated disease: International MOGAD Panel proposed criteria. Lancet Neuro. 2023;22(3):268-282. doi:10.1016/S1474-4422(22)00431-8
4. Flanagan E, Tillema JM. Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD): Clinical features and diagnosis. UpToDate. Updated April 2024. Accessed May 14, 2024.
5. MOG Antibody Disease: MOGAD. SRNA. https://wearesrna.org/living-with-myelitis/disease-information/mog-antibody-disease/long-term-care/ Accessed May 14, 2024
6. Redenbaugh V, Fryer JP, Cacciaguerra L, et al. Diagnostic utility of MOG antibody testing in cerebrospinal fluid. Annals of Neurol. Published online April 4, 2024. Doi:10.1002/ana.26931
7. Corbali O, Chitnis T. Pathophysiology of myelin oligodendrocyte glycoprotein antibody disease. Front Neurol. 2023;14;1137998. doi:10.3389/fneur.2023.1137998
8. Chen JJ, Sotirchos ES, Henderson AD, et al. OCT retinal nerve fiber layer thickness differentiates acute optic neuritis from MOG antibody-associated disease and Multiple Sclerosis: rNFL thickening in acute optic neuritis from MOGAD vs MS. Mult Scler Relat Disord. 2022;58:103525. doi:10.1016/j.msard.2022.103525.
9. Lennon VA, Wingerchuk DM, Kryzer TJ, et al. A serum autoantibody marker of neuromyeltis optica: distinction from multiple sclerosis. Lancet. 2004;364(9451):2106-12. doi:10.1016/S0140-6736(04)17551-X.
10. Ringelstein M, Ayzenberg I, Lindenblatt G, et al. Interleukin-6 receptor blockade in treatment-refractory MOG-IgG-associated disease and neuromyelitis optica spectrum disorders. Neurol Neuroimmunol Neuroinflamm. 2021;9(1):e1100. doi:10.1212/NXI.0000000000001100
11. Sechi E, Krecke KN, Messina SA, et al. Comparison of MRI lesion evolution in different central nervous system demyelinating disorders. Neurology. 2021;97:e1097-e1109. doi:10.1212/WNL.0000000000012467
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