Myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD) is the most recently defined inflammatory demyelinating disease of the central nervous system (CNS). Over the last decade, several studies have helped delineate the characteristic clinical-MRI phenotypes of the disease, allowing distinction from aquaporin-4 (AQP4)-IgG-positive neuromyelitis optica spectrum disorder (AQP4-IgG+NMOSD) and multiple sclerosis (MS). The clinical manifestations of MOGAD are heterogeneous, ranging from isolated optic neuritis or myelitis to multifocal CNS demyelination often in the form of acute disseminated encephalomyelitis (ADEM), or cortical encephalitis. A relapsing course is observed in approximately 50% of patients. Characteristic MRI features have been described that increase the diagnostic suspicion (e.g., perineural optic nerve enhancement, spinal cord H-sign, T2-lesion resolution over time) and help discriminate from MS and AQP4+NMOSD, despite some overlap. The detection of MOG-IgG in the serum (and sometimes CSF) confirms the diagnosis in patients with compatible clinical-MRI phenotypes, but false positive results are occasionally encountered, especially with indiscriminate testing of large unselected populations. The type of cell-based assay used to evaluate for MOG-IgG (fixed vs. live) and antibody end-titer (low vs. high) can influence the likelihood of MOGAD diagnosis. International consensus diagnostic criteria for MOGAD are currently being compiled and will assist in clinical diagnosis and be useful for enrolment in clinical trials. Although randomized controlled trials are lacking, MOGAD acute attacks appear to be very responsive to high dose steroids and plasma exchange may be considered in refractory cases. Attack-prevention treatments also lack class-I data and empiric maintenance treatment is generally reserved for relapsing cases or patients with severe residual disability after the presenting attack. A variety of empiric steroid-sparing immunosuppressants can be considered and may be efficacious based on retrospective or prospective observational studies but prospective randomized placebo-controlled trials are needed to better guide treatment. In summary, this article will review our rapidly evolving understanding of MOGAD diagnosis and management.

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Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease (MOGAD): A Review of Clinical and MRI Features, Diagnosis, and Management

The term neuromyelitis optica spectrum disorder (NMOSD) describes a group of clinical-MRI syndromes characterized by longitudinally extensive transverse myelitis, optic neuritis, brainstem dysfunction and/or, less commonly, encephalopathy. About 80% of patients harbor antibodies directed against the water channel aquaporin-4 (AQP4-IgG), expressed on astrocytes, which was found to be both a biomarker and a pathogenic cause of NMOSD. More recently, antibodies against myelin oligodendrocyte glycoprotein (MOG-IgG), have been found to be a biomarker of a different entity, termed MOG antibody-associated disease (MOGAD), which has overlapping, but different pathogenesis, clinical features, treatment response, and prognosis when compared to AQP4-IgG-positive NMOSD. Despite important refinements in the accuracy of AQP4-IgG and MOG-IgG testing assays, a small proportion of patients with NMOSD still remain negative for both antibodies and are called “seronegative” NMOSD. Whilst major advances have been made in the diagnosis and treatment of these conditions, biomarkers that could help predict the risk of relapses, disease activity, and prognosis are still lacking. In this context, a number of serum and/or cerebrospinal fluid biomarkers are emerging as potentially useful in clinical practice for diagnostic and treatment purposes. These include antibody titers, cytokine profiles, complement factors, and markers of neuronal (e.g., neurofilament light chain) or astroglial (e.g., glial fibrillary acidic protein) damage. The aim of this review is to summarize current evidence regarding the role of emerging diagnostic and prognostic biomarkers in patients with NMOSD and MOGAD.

Serum and Cerebrospinal Fluid Biomarkers in Neuromyelitis Optica Spectrum Disorder and Myelin Oligodendrocyte Glycoprotein Associated Disease

This analysis evaluated long-term safety findings from the SAkuraSky and SAkuraStar studies with satralizumab in patients with neuromyelitis optica spectrum disorder (NMOSD).SAkuraSky (satralizumab in combination with baseline immunosuppressive therapy; IST) and SAkuraStar (satralizumab monotherapy) are international, multicenter, randomized, placebo-controlled, phase 3 studies consisting of a double-blind (DB) period followed by an open-label extension (OLE). The overall satralizumab treatment (OST) period safety population comprised patients receiving ≥1 dose of satralizumab in the DB and/or OLE periods (cut-off date: 22 February 2021). Safety was evaluated in the DB and OST periods.In the SAkuraSky DB period, patients received satralizumab (n = 41) or placebo (n = 42) in addition to stable baseline IST; 75 patients were included in the OST population. In the SAkuraStar DB period, 63 patients received satralizumab monotherapy and 32 received placebo; 91 patients were included in the OST population. Median treatment exposure in the OST period was 4.4 years (range 0.1-7.0) in SAkuraSky and 4.0 years (range 0.1-6.1) in SAkuraStar. Rates of adverse events (AEs per 100 patient-years) and serious AEs in the OST period were comparable with satralizumab and placebo in the DB periods of both studies. Similarly, overall rates of infections and serious infections were consistent between the OST and DB periods with satralizumab, with no increase in rates of infections or serious infections over time. In the OST periods, longer exposure to satralizumab was not associated with a higher risk of severe (grade ≥3) laboratory changes versus the DB periods. No deaths or anaphylactic reactions to treatment with satralizumab were reported during the OST periods of both studies.The safety profile of satralizumab as a monotherapy or in combination with IST was maintained in the OLE, and no new safety concerns versus the DB period were observed.ClinicalTrials.gov identifiers: NCT02028884 (SAkuraSky) and NCT02073279 (SAkuraStar). 

Long-term safety of satralizumab in neuromyelitis optica spectrum disorder (NMOSD) from SAkuraSky and SAkuraStar.

ABSTRACT Introduction Autoimmune eye diseases (AED) are inflammatory eye conditions caused by dysregulation of the immune system at the ocular level. Among them, the most representative is noninfectious uveitis, which can be limited to the eye or associated with various systemic autoimmune diseases. Other conditions include peripheral ulcerative keratitis, Graves’ orbitopathy, and some forms of optic neuropathy. Glucocorticoids are the cornerstone of treatment for most AEDs. However, conventional and/or biologic immunosuppressive drugs are often required to achieve clinical remission and reduce adverse events related to long-term glucocorticoid therapy. Areas covered To summarize all the available evidence on the use of the anti-interleukin-6 tocilizumab receptor (TCZ) for the different AEDs. Expert opinion The heterogeneity of the reported studies and the relatively small number of prospective randomized clinical trials make it difficult to establish robust guidelines on the positioning of TCZ in the treatment of AEDs. However, based on our own experience and the growing number of published studies, we are in favor of the use of TCZ as an effective and safe alternative for patients with severe and/or refractory AEDs. We highlight the efficacy of TCZ in patients with optic neuropathy related to giant cell arteritis, noninfectious uveitis, and Graves´ orbitopathy.

Utility of tocilizumab in autoimmune eye diseases

Neuromyelitis optica spectrum disorders (NMOSD) are rare neurologic autoimmune diseases that have a poor prognosis if left untreated. For many years, generic oral immunosuppressants and repurposed monoclonal antibodies that target the interleukin-6 pathway or B cells were the mainstays of drug treatment. Recently, these drug treatments have been complemented by new biologics developed and approved specifically for NMOSD. In principle, all of these drugs are effective, but treatment recommendations that take this into account are still pending. Instead, the choice of a drug may depend on other criteria such as drug safety or tolerability. In this review, we summarise current knowledge on the adverse effects of azathioprine, mycophenolate mofetil, rituximab, tocilizumab, eculizumab, satralizumab, and inebilizumab in NMOSD. Infections, cytopenias, and infusion-related reactions are most common, but the data are as heterogeneous as the manifestations are diverse. Nevertheless, knowledge of safety issues may facilitate treatment choices for individual patients.

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Adverse Events in NMOSD Therapy

BACKGROUND AND OBJECTIVES To evaluate the long-term safety and efficacy of tocilizumab (TCZ), a humanized anti-interleukin-6 receptor antibody in myelin oligodendrocyte glycoprotein-IgG-associated disease (MOGAD) and neuromyelitis optica spectrum disorders (NMOSD). METHODS Annualized relapse rate (ARR), Expanded Disability Status Scale score, MRI, autoantibody titers, pain, and adverse events were retrospectively evaluated in 57 patients with MOGAD (n = 14), aquaporin-4 (AQP4)-IgG seropositive (n = 36), and seronegative NMOSD (n = 7; 12%), switched to TCZ from previous immunotherapies, particularly rituximab. RESULTS Patients received TCZ for 23.8 months (median; interquartile range 13.0-51.1 months), with an IV dose of 8.0 mg/kg (median; range 6-12 mg/kg) every 31.6 days (mean; range 26-44 days). For MOGAD, the median ARR decreased from 1.75 (range 0.5-5) to 0 (range 0-0.9; p = 0.0011) under TCZ. A similar effect was seen for AQP4-IgG+ (ARR reduction from 1.5 [range 0-5] to 0 [range 0-4.2]; p < 0.001) and for seronegative NMOSD (from 3.0 [range 1.0-3.0] to 0.2 [range 0-2.0]; p = 0.031). During TCZ, 60% of all patients were relapse free (79% for MOGAD, 56% for AQP4-IgG+, and 43% for seronegative NMOSD). Disability follow-up indicated stabilization. MRI inflammatory activity decreased in MOGAD (p = 0.04; for the brain) and in AQP4-IgG+ NMOSD (p < 0.001; for the spinal cord). Chronic pain was unchanged. Regarding only patients treated with TCZ for at least 12 months (n = 44), ARR reductions were confirmed, including the subgroups of MOGAD (n = 11) and AQP4-IgG+ patients (n = 28). Similarly, in the group of patients treated with TCZ for at least 12 months, 59% of them were relapse free, with 73% for MOGAD, 57% for AQP4-IgG+, and 40% for patients with seronegative NMOSD. No severe or unexpected safety signals were observed. Add-on therapy showed no advantage compared with TCZ monotherapy. DISCUSSION This study provides Class III evidence that long-term TCZ therapy is safe and reduces relapse probability in MOGAD and AQP4-IgG+ NMOSD.

https://nn.neurology.org/content/nnn/9/1/e1100.full.pdf

Daniel Whittam

Papers

Interleukin-6 Receptor Blockade in Treatment-Refractory MOG-IgG-Associated Disease and Neuromyelitis Optica Spectrum Disorders.