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Abnormal albumin quotients are more common in patients with MOG-IgG than AQP4-IgG.
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BBB damage between MOG-IgG and AQP4-IgG patients in severe disability is similar.
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MOG-IgG-positive males were less able to improve from treatment than females.
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Females with AQP4-IgG were more likely to aggravate in disability than males.
Abstract
Background
The disruption of the blood–brain barrier (BBB) is common in patients with neuromyelitis optica spectrum disorder (NMOSD), causing pro-inflammatory immune cells to migrate into the central nervous system (CNS) and active demyelinating lesions. Albumin quotient is commonly used as an indicator for BBB permeability or dysfunction, but its potential clinical value in NMOSD treatment has never been explored. The present study investigated the differences in the albumin quotient level among NMOSD patients with different antibodies (AQP4-IgG and MOG-IgG) and the relationship between the albumin quotient and neurological dysfunction.
Methods
We retrospectively collected data from 141 patients with NMOSD (104 with AQP4-IgG and 37 with MOG-IgG) and reviewed their clinical features and albumin quotient levels.
Results
The percentage of patients with an abnormal albumin quotient was significantly higher in the MOG-IgG group than in the AQP4-IgG group (48.6% vs 27.9%, P = 0.026); albumin quotient levels in the AQP4-IgG-positive group were similar to those in the MOG-IgG groups (5.65 vs 5.8, P = 0.23). Among those with an abnormal quotient, no differences in the proportions of severe neurological disability across treatment were found between patients with AQP4-IgG and those with MOG-IgG (pre-treatment: AQP4-IgG group vs MOG-IgG group: 58.6% vs 38.9%, P = 0.24; post-treatment: AQP4-IgG group vs MOG-IgG group: 31.0% vs 22.2%, P = 0.74).
Conclusions
The BBB breakdown in NMOSD patients with MOG-IgG may be more common than in those with AQP4-IgG. AQP4-IgG-positive patients and MOG-IgG-positive patients with severe neurological disability tend to exhibit similar disruptions to the BBB.
Neuromyelitis optica spectrum disorder (NMOSD) is a rare inflammatory autoimmune disease of the central nervous system (CNS) that predominantly affects women and frequently leads to severe deficits in visual and motor functions. Antibodies against aquaporin 4 (AQP4-IgG) and myelin oligodendrocyte glycoprotein (MOG-IgG) are the most commonly detectable antibodies of value in diagnosis of NMOSD (
). Facilitated by a disrupted blood–brain barrier (BBB), the entry of these pathogenic antibodies and inflammatory immune cells into the CNS from the blood may partly account for the pathogenetic mechanism of NMOSD (
Soluble CD40 ligand contributes to blood-brain barrier breakdown and central nervous system inflammation in multiple sclerosis and neuromyelitis optica spectrum disorder.
). The albumin quotient (albumin in CSF/albumin in serum) level is used as a metric of BBB dysfunction and has become an indicator of BBB permeability (
Increased albumin quotient (QAlb) in patients after first clinical event suggestive of multiple sclerosis is associated with development of brain atrophy and greater disability 48 months later.
), suggesting more severe BBB dysfunction or breakdown. However, little evidence exists on the relationship between the albumin quotient and neurological dysfunction of NMOSD patients with different types of antibodies. The present study assessed the clinical value of the albumin quotient in the evaluation of disability in NMOSD patients with MOG-IgG or AQP4-IgG positive.
2. Methods
2.1 Participants
We retrospectively reviewed medical records of patients with NMOSD who had received AQP4-IgG and MOG-IgG serum and cerebrospinal fluid (CSF) tests in Tongji hospital of Tongji Medical College, Huazhong University of Science and Technology from Jul 1, 2015 to May 1, 2018. NMOSD was assessed in all cases according to diagnostic criteria established in 2015 (
). Only patients who tested positive for AQP4-IgG or MOG-IgG through assessments of the serum or CSF were included in our study. Data concerning the albumin quotient was collected within 7 days of the first attack of NMOSD and prior to glucocorticoid administration. All the patients were evaluated with the Expanded Disability Severity Scale (EDSS) twice: upon hospital admission and at 1 month after admission. Those who were double positive for AQP4-IgG and MOG-IgG were excluded from the study. A cell-based assay (CBA) was used to detect AQP4 and MOG antibodies in the serum or CSF.
2.2 Ethics statement
Our study was approved by the Institutional Review Board of Tongji hospital, which is affiliated with Tongji Medical College and Huazhong University of Science and Technology, with a waiver of informed consent obtained from the study subjects because of the retrospective and observational nature of the study and the de-identified data that were used. This study was conducted in accordance with the Declaration of Helsinki. All methods were performed in accordance with the relevant guidelines and regulations.
2.3 Definitions
Disability progression was evaluated by EDSS before and after treatment. Severe disability was defined as an EDSS score of ⩾ 6 at the nadir of the attack. The albumin quotient was defined as the ratio of the albumin concentration in the CSF divided by the albumin in the serum (albumin (CSF in mg/L)/albumin (serum in g/L)) (
). Patients with an elevated albumin quotient were considered to have abnormal BBB permeability:
2.4 Statistics
Statistical analysis was performed with IBM SPSS Statistics (version 23.0 for Windows; SPSS Inc., Chicago, IL) and GraphPad Prism (version 8.0). To compare the clinical characteristics of groups, the Mann–Whitney U test was used for continuous variables and Fisher's exact test was used for categorical data. Statistical significance was set at P < 0.05.
3. Results
3.1 Patient characteristics
A total of 982 patients who were suspected of having NMOSD received anti-AQP4 and anti-MOG antibody tests: 167 patients were positive for anti-AQP4 antibodies; 55 for anti-MOG antibodies; and for both. Of the 226 who tested positive, 141 were included in the final analysis:104 [70.3%] were positive for AQP4-IgG, and 37 [29.7%] for MOG-IgG; 63 and 18 patients who were positive for AQP4-IgG and MOG-IgG, respectively, were excluded due to lack of the necessary clinical data for further analysis. Four patients who were positive for both AQP4-IgG and MOG-IgG were also excluded (Fig. 1).
Fig. 1Enrollment and grouping of patients with NMOSD. MS: multiple sclerosis; ADEM: acute demyelinating encephalomyelitis.
3.2 Comparison of demographic and main clinical features of patients with NMOSD according to antibody status
The demographic and clinical features of patients who were NMOSD positive for AQP4-IgG or MOG-IgG are summarized in Table 1. The female-to-male ratio in the AQP4-IgG group was approximately 9:1 (92/12); this dropped to almost 4:5 (16/21) in the MOG-IgG group. Hence, the AQP4-IgG group was comprised predominantly of women (88.5% vs 43.2%; P < 0.01). The median age of onset was lower among patients with MOG antibodies than those with AQP4 antibodies (37 vs 47, P < 0.01). Patients with AQP4-IgG had significantly higher median pre-treatment and post-treatment EDSS scores than did those in the MOG-IgG group (pre-treatment: 5.0 vs. 4.0, P = 0.014; post-treatment: 4.0 vs. 3.0, P = 0.007). The number of patients with severe disability prior to or after treatment did not differ significantly between the AQP4-IgG and MOG-IgG groups: prior to treatment, (AQP4-IgG vs. MOG-IgG) 41 vs 10, P = 0.23; after treatment, 26 vs. 6, P = 0.36). Treatment affected similar levels of neurological improvement in NMOSD patients with AQP4-IgG and MOG-IgG. Of the 15 patients whose EDSS scores did not improve, 9/10 in the AQP4-IgG group were women, and 5/5 in the MOG-IgG group were men.
Table 1Comparison of demographic and main clinical features between NMOSD patients seropositive for MOG-IgG or AQP4-IgG.
Although the patients with NMOSD who were positive for MOG-IgG and AQP4-IgG had similar median albumin quotients (5.8 vs 5.65, respectively; P = 0.23), MOG-IgG-positive patients had a significant higher proportion of abnormal albumin quotients than did their AQP4-IgG-positive counterparts (48.6% vs 27.9%, respectively; P = 0.026) (Fig. 2). Subgroup analysis demonstrated that among those with abnormal albumin quotients, no statistical difference in severe neurological disability before or after treatment was found between the patients with AQP4-IgG and those with MOG-IgG (pre-treatment, 58.6% vs 38.9%, respectively, P = 0.24; post-treatment: 31.0% vs 22.2%, respectively, P = 0.74).
Fig. 2A-B. Albumin quotient in AQP4-IgG-positive or MOG-IgG-positive NMOSD patients *P < 0.05.
This retrospective study compared albumin quotient and other clinical characteristics between patients positive for AQP4-IgG and their MOG-IgG-positive counterparts during the acute period of NMOSD before and after treatment. We found that abnormal albumin quotient levels are more common in patients with MOG-IgG than in those with AQP4-IgG (P = 0.026).
NMOSD, a CNS demyelinating disorder, is mainly caused by pathogenic antibodies such as AQP4-IgG and to a lesser extent MOG-IgG. Attacks of these antibodies, along with complements, can result in demyelination and astrocyte death, which may produce NMO lesions (
), the passage of these pathogenic immunoglobulins from peripheral to circumventricular organs through a disrupted BBB may be the initial step to astrocyte death and myelin breakdown (
). Therefore, damage to the BBB might occur before the development of the NMO lesion and could correlate with neurological disability in patients with NMOSD. In addition, it has been thought, not without controversy, that the pathogenesis, clinical features, and outcomes of AQP4-IgG-positive and MOG-IgG-positive patients differ (
Increased albumin quotient (QAlb) in patients after first clinical event suggestive of multiple sclerosis is associated with development of brain atrophy and greater disability 48 months later.
Increased albumin quotient (QAlb) in patients after first clinical event suggestive of multiple sclerosis is associated with development of brain atrophy and greater disability 48 months later.
), suggesting a disrupted BBB. In relapsing-remitting MS (RRMS), an elevated albumin quotient at the time of the first attack is associated with higher EDSS scores and accelerated brain tissue loss in the subsequent 2 years (
Increased albumin quotient (QAlb) in patients after first clinical event suggestive of multiple sclerosis is associated with development of brain atrophy and greater disability 48 months later.
). Our study found that the MOG-IgG group featured a higher proportion of abnormal albumin quotients than did the AQP4-IgG group (48.6% vs 27.9%, respectively; P = 0.026); however, the difference in the median albumin quotients between the two groups was nonsignificant. Despite being insufficient for a direct comparison, the data obtained in a previous study suggested that the percentage of abnormal albumin quotients among NMOSD patients who were sero-positive for MOG-IgG was higher than among patients with MS, while the proportions of abnormal albumin quotients among AQP4-IgG-positive patients and those with MS were almost the same (MOG-IgG, MS, AQP4-IgG: 48.6%, 29.8%, 27.9%) (
). Among those with abnormal albumin quotients, although severe disability (EDSS ≥ 6) seemed more common among the patients that were positive for AQP4-IgG than among those that were positive for MOG-IgG before or after treatment, the difference between them was insignificant (before treatment: AQP4-IgG vs MOG-IgG, 58.6% vs 38.9%, P = 0.24; after treatment: AQP4-IgG vs MOG-IgG, 31.0% vs 22.2%, P = 0.74). These two results suggest that other factors may influence the final outcomes of BBB damage – the higher prevalence of the breakdown of the BBB among NMOSD patients with MOG-IgG relative to their AQP4-IgG-positive counterparts notwithstanding. Our findings can also be attributed to the vulnerability of MOG-IgG-positive patients to meningeal BBB involvement to the susceptibility of AQP4-IgG-positive patients to intraparenchymal injury. Indeed, like the prelaminar portion of the optic nerve and root entry zones in the spinal cord, some part of the normal BBB might not be fully developed, facilitating access of circulating IgG into the CNS (
). This would further account for why those with a normal BBB might also suffer severe dysfunction and also indicate that the disruption of the BBB may not be required for neuronal death. Supporting this hypothesis, our study found that more than 50% (24/41) of AQP4-IgG-positive patients and less than one third (3/10) of MOG-IgG-positive patients were severely disabled without having abnormal albumin quotients prior to treatment.
Nevertheless, as a measure of BBB dysfunction, the albumin quotient is influenced by multiple factors including the location of BBB leakage, the rate of albumin transport, and the timing of CSF collection during the course of the disease (
). While little of the currently available data helps to determine whether the albumin quotient is affected by these factors, their impact would not be sufficient to influence the albumin quotient in a substantial manner.
Moreover, although both of the antibodies (AQP4-IgG and MOG-IgG) are not directed against neurons, the relatively high EDSS scores in AQP4-IgG-positive patients before or after treatment (Table 1) observed in our study suggest that AQP-IgG triggers inflammatory reactions of higher severity and increasing neuronal death. This potential indication is supported by previous reports of less severe CNS lesions and more favorable prognoses among patients that are positive for MOG-IgG relative to their AQP4-IgG-positive counterparts (
), we observed a lower female-to-male ratio and an earlier age of onset in the MOG-IgG group during the acute period than in the AQP4-IgG group (Table 1). Notably, the neurological function of male patients with MOG-IgG was less able to improve from treatment than females (0 vs 5), while females with AQP4-IgG were more likely to be unimproved or even aggravate in disability than males (9 vs 1) (P < 0.01). This suggests that female patients who are positive for MOG-IgG and AQP4-IgG-positive males can benefit more from routine treatment, while combined immunotherapies may be required in the treatment of AQP4-IgG-positive women and MOG-IgG-positive men.
The present retrospective study was limited by a small size and its having been restricted to a single medical center, both of which made biases inevitable. A randomized, large scale control trial involving multiple centers is needed to further evaluate the discussed factors in NMOSD patients with AQP4-IgG or MOG-IgG.
Funding
This work was supported by the National Natural Science Foundation of China (81,571,132, 81,873,743 to D.S. Tian).
CRediT authorship contribution statement
Chen Bo: Investigation, Data curation, Methodology, Software, Formal analysis, Writing - original draft, Visualization. Qin Chuan: Data curation, Software, Formal analysis. Tao Ran: Investigation. Dong Yuan-Ji: Investigation. Ma Xue: Investigation. Chen Man: Investigation. Wu Long-Jun: Writing - review & editing. Bu Bi-Tao: Supervision, Writing - review & editing. Tian Dai-Shi: Supervision, Conceptualization, Validation, Writing - review & editing.
Declaration of Competing Interest
None declared.
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Soluble CD40 ligand contributes to blood-brain barrier breakdown and central nervous system inflammation in multiple sclerosis and neuromyelitis optica spectrum disorder.
Increased albumin quotient (QAlb) in patients after first clinical event suggestive of multiple sclerosis is associated with development of brain atrophy and greater disability 48 months later.
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