Implications of Low-Titer MOG Antibodies

Abstract

Disclosures: None The MOG antibody was thought initially to be associated with MS in a widely-discussed article published in the New England Journal of Medicine (Berger et al., 2003Berger T. Rubner P. Schautzer F. Egg R. Ulmer H. Mayringer I. Dilitz E. Deisenhammer F. Reindl M. Antimyelin antibodies as a predictor of clinically definite multiple sclerosis after a first demyelinating event.N Engl J Med. 2003; 349: 139-145Crossref PubMed Scopus (523) Google Scholar). Those findings could not be reproduced, leading to another New England Journal of Medicine article claiming that the antibody is actually not associated with MS at all (Kuhle et al., 2007Kuhle J. Pohl C. Mehling M. Edan G. Freedman M.S. Hartung H.P. Polman C.H. Miller D.H. Montalban X. Barkhof F. Bauer L. Dahms S. Lindberg R. Kappos L. Sandbrink R. Lack of association between antimyelin antibodies and progression to multiple sclerosis.N Engl J Med. 2007; 356: 371-378Crossref PubMed Scopus (197) Google Scholar). The confusion at the time was due to the high false-positive rate of the MOG antibody assays. Later, in 2015, the Oxford University Neuroimmunology Lab demonstrated much higher specificity using a cell-based assay with the full extracellular portion of the MOG protein that detected only IgG1 MOG antibodies (Waters et al., 2015Waters P. Woodhall M. O'Connor K.C. Reindl M. Lang B. Sato D.K. Jurynczyk M. Tackley G. Rocha J. Takahashi T. Misu T. Nakashima I. Palace J. Fujihara K. Leite M.I. Vincent A. MOG cell-based assay detects non-MS patients with inflammatory neurologic disease.Neurol Neuroimmunol Neuroinflamm. 2015; 2: e89Crossref PubMed Scopus (239) Google Scholar). This protocol has since been adopted as the standard MOG-IgG assay for recognition of MOGAD as an autoimmune disease that is distinct from MS. MOG antibody disease (MOGAD) is an autoimmune demyelinating condition that is defined by antigen specificity to myelin oligodendrocyte glycoprotein (MOG) that is expressed on the outer surface of the myelin sheath in the central nervous system (CNS) (Narayan et al., 2018Narayan R. Simpson A. Fritsche K. Salama S. Pardo S. Mealy M. Paul F. Levy M. MOG antibody disease: A review of MOG antibody seropositive neuromyelitis optica spectrum disorder.Mult Scler Relat Disord. 2018; 25: 66-72Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar). Several clinical criteria for MOGAD have been proposed but in general, the diagnosis is confirmed by detection of IgG1 antibody to MOG in patients with an episode of CNS inflammation (Jarius et al., 2018Jarius S. Paul F. Aktas O. Asgari N. Dale R.C. de Seze J. Franciotta D. Fujihara K. Jacob A. Kim H.J. Kleiter I. Kumpfel T. Levy M. Palace J. Ruprecht K. Saiz A. Trebst C. Weinshenker B.G. Wildemann B. MOG encephalomyelitis: international recommendations on diagnosis and antibody testing.J Neuroinflammation. 2018; 15: 134Crossref PubMed Scopus (324) Google Scholar; Levy, 2020Levy M. Expanding the spectrum of MOG antibody disease.Mult Scler. 2020; 26: 515-516Crossref PubMed Scopus (4) Google Scholar). The most common clinical phenotypes of MOG are optic neuritis which is often bilateral, and transverse myelitis. In children, MOGAD can present as acute disseminated encephalomyelitis (ADEM) (Marignier et al., 2021Marignier R. Hacohen Y. Cobo-Calvo A. Probstel A.K. Aktas O. Alexopoulos H. Amato M.P. Asgari N. Banwell B. Bennett J. Brilot F. Capobianco M. Chitnis T. Ciccarelli O. Deiva K. De Seze J. Fujihara K. Jacob A. Kim H.J. Kleiter I. Lassmann H. Leite M.I. Linington C. Meinl E. Palace J. Paul F. Petzold A. Pittock S. Reindl M. Sato D.K. Selmaj K. Siva A. Stankoff B. Tintore M. Traboulsee A. Waters P. Waubant E. Weinshenker B. Derfuss T. Vukusic S. Hemmer B. Myelin-oligodendrocyte glycoprotein antibody-associated disease.Lancet Neurol. 2021; 20: 762-772Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar). While the antibody appears to distinguish MS from MOGAD in most cases, one problem remains: low titers of MOG antibodies. Such low levels of MOG antibodies in the range of 1:20 – 1:40 may not be specific for MOGAD where MS is suspected. For example, in a Mayo Clinic series, MOG antibody values that fell in the low titer range in people with clinical features consistent with MS were considered false positives for MOGAD in more than half of cases (Sechi et al., 2021Sechi E. Buciuc M. Pittock S.J. Chen J.J. Fryer J.P. Jenkins S.M. Budhram A. Weinshenker B.G. Lopez-Chiriboga A.S. Tillema J.M. McKeon A. Mills J.R. Tobin W.O. Flanagan E.P. Positive Predictive Value of Myelin Oligodendrocyte Glycoprotein Autoantibody Testing.JAMA Neurol. 2021; 78: 741-746Crossref PubMed Scopus (18) Google Scholar). Higher titers of 1:100 were more specific for MOGAD, with only an 18% false-positive rate. Titers of 1:1,000 or 1:10,000 were 100% specific for MOGAD. In most instances in which low-titer MOG antibody was considered a false positive, MS was thought to be the correct diagnosis. In a binary view of this problem, the solution is to create criteria that separate MOGAD from MS with rules to weigh certain clues like MOG antibody titers, oligoclonal bands and periventricular MRI lesions. In this view, there is one diagnosis – either MOGAD or MS (Fig. 1A). Another approach is to consider the possibility that people with MS who have low MOG antibody levels may indeed harbor immunity to MOG as part of their MS. In this view, one could propose a spectrum of disease from classic MOGAD with high titer antibodies to MOG-MS with low titers to classic MS with no MOG antibodies (Fig. 1B). The extent of the overlap among these conditions may depend on the contribution of MOG antibodies to the clinical and immunological phenotype. For example, people with MOG-MS may have more optic neuritis attacks than classic MS, and perhaps they remyelinate better. As classic MOGAD appears to respond very well to intravenous immunoglobulin especially compared to MS, perhaps MOG-MS will benefit likewise. Similarly, B cell depletion therapy is very effective for MS whereas it is only partially successful in MOGAD. Perhaps low-titer MOG-MS cases respond well to B cell therapy, whereas classic MOGAD does not. By taking the spectrum view of MOG-MS, we can individualize therapy for patients rather than lumping them into an umbrella diagnosis. Low MOG titers in children may have a different meaning, given the higher rate of positivity in clinical syndromes that do not resemble MS. Children with a clinical diagnosis of ADEM test positive for MOG antibodies in approximately 40% of cases (Reindl et al., 2013Reindl M. Di Pauli F. Rostasy K. Berger T. The spectrum of MOG autoantibody-associated demyelinating diseases.Nat Rev Neurol. 2013; 9: 455-461Crossref PubMed Scopus (279) Google Scholar). Sustained seropositivity to MOG antibodies using the improved cell-based assay beyond 6-12 months has been associated with a much higher risk of relapse – usually optic neuritis or another ADEM attack (Lopez-Chiriboga et al., 2018Lopez-Chiriboga A.S. Majed M. Fryer J. Dubey D. McKeon A. Flanagan E.P. Jitprapaikulsan J. Kothapalli N. Tillema J.M. Chen J. Weinshenker B. Wingerchuk D. Sagen J. Gadoth A. Lennon V.A. Keegan B.M. Lucchinetti C. Pittock S.J. Association of MOG-IgG Serostatus With Relapse After Acute Disseminated Encephalomyelitis and Proposed Diagnostic Criteria for MOG-IgG-Associated Disorders.JAMA Neurol. 2018; 75: 1355-1363Crossref PubMed Scopus (149) Google Scholar). Titers in children who relapse are usually stable over time, while those who do not relapse become seronegative (Lopez-Chiriboga et al., 2018Lopez-Chiriboga A.S. Majed M. Fryer J. Dubey D. McKeon A. Flanagan E.P. Jitprapaikulsan J. Kothapalli N. Tillema J.M. Chen J. Weinshenker B. Wingerchuk D. Sagen J. Gadoth A. Lennon V.A. Keegan B.M. Lucchinetti C. Pittock S.J. Association of MOG-IgG Serostatus With Relapse After Acute Disseminated Encephalomyelitis and Proposed Diagnostic Criteria for MOG-IgG-Associated Disorders.JAMA Neurol. 2018; 75: 1355-1363Crossref PubMed Scopus (149) Google Scholar). Preventive treatment after an episode of ADEM is not recommended, but in cases of sustained immunity to MOG, it should be considered. Finally, there are reports of non-demyelinating diseases in which a low-titer MOG antibody is detected, such as encephalitis and glioblastoma (Amin et al., 2021Amin M. Mays M. Polston D. Flanagan E.P. Prayson R. Kunchok A. Myelin oligodendrocyte glycoprotein (MOG) antibodies in a patient with glioblastoma: Red flags for false positivity.J Neuroimmunol. 2021; 361577743Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar; Titulaer et al., 2014Titulaer M.J. Hoftberger R. Iizuka T. Leypoldt F. McCracken L. Cellucci T. Benson L.A. Shu H. Irioka T. Hirano M. Singh G. Cobo Calvo A. Kaida K. Morales P.S. Wirtz P.W. Yamamoto T. Reindl M. Rosenfeld M.R. Graus F. Saiz A. Dalmau J. Overlapping demyelinating syndromes and anti-N-methyl-D-aspartate receptor encephalitis.Ann Neurol. 2014; 75: 411-428Crossref PubMed Scopus (324) Google Scholar). One explanation for immunity to MOG in these circumstances is that under healthy conditions, MOG is confined to the CNS, where it is less accessible to the peripheral immune system. When the CNS is damaged and MOG protein is exposed to the vascular system, a non-specific immune reaction to MOG occurs. In these cases, there is no phenotypical MOGAD disease course warranting treatment. However, these reports help us understand how MOG protein is processed by the immune system and how immunity to MOG might lead to a relapsing demyelinating disease. Low-titer MOG antibodies may not be sufficient to make a diagnosis of MOG antibody disease with certainty, but the presence of MOG antibodies cannot be dismissed. This may provide insight into the immunopathogenesis of an individual patient. We do not propose a new disease entity but rather an overlap with features of both MS and MOG. It is our opinion that people with MS who test positive for low-titer MOG antibodies may lie on the spectrum between MS and MOG – so called, MOG-MS. The implications of this recognition could be important for treatment and should be considered in the eligibility criteria for specific clinical trials. Clearly more research is required on the pathogenesis of low-titer MOG-MS to determine if MOG antibodies are responsible for either driving MS disease activity or at least providing a relevant component of MS disease activity in this subgroup of patients.