To our knowledge, this is the first large-scale cohort studies of ON in Asia. In this retrospective cohort of 11923 adult and 1365 pediatric ON patients with a median follow-up duration of 6.3 and 7.3 years respectively, MS occurred in 2.7% of adults and 3.1% of pediatric patients, and NMO occurred in 1.2% of adult and 1.2% of pediatric patients with ON. The incidence of ON in our study was comparable to other populations [1, 19], while the rate of conversion to MS was much lower compared with that reported from Caucasian populations. Together these findings were consistent with the low incidence rate of MS in Taiwan .
Although Sjogren syndrome and MG were uncommon (< 2% each) in ON patients in our study, they were significantly associated with subsequent development of NMO in adult patients with ON. Indeed, the association of Sjogren syndrome and NMO has been established [21, 22]. Coexistence of MG and NMO was also recognized to be more than chance, and MG usually preceded NMO . Our study corroborates these observations by providing population-level evidence of the associations. To date, cancer was the only comorbidity formally listed as one of the “red flag” features in patients with ON [14, 24]. Together with prior knowledge, our findings suggest that comorbid Sjogren syndrome or MG are also worth consideration as red flags that prompt further investigations such as aquaporin-4 serostatus in these patients. On the other hand, although SLE is also a common comorbidity of NMO, we found that it is associated with an increased risk of MS, rather than NMO, in both pediatric and adult ON. Another study in Taiwan revealed that female first-degree relatives of SLE patients are at higher risk for MS . Shared genetic predisposition (such as HLA-DRB1*1501) may partly account for the association between SLE and MS [26, 27], whereas their coexistence was rarely reported . SLE per se may also present with ON [6, 29], which is considered mechanistically different from MS-associated ON. Therefore, ON in patients with SLE could be either a manifestation of lupus or the forme fruste of MS. Nevertheless, the double dissociation of autoimmune comorbidity patterns between MS-associated and NMO-associated ON strongly hints at distinct immunological mechanisms underlying these two types of ON. The role of immune-related comorbidities, in combination with brain MRI and serum and CSF biomarkers [30–32], could be further explored in research concerning predictive modeling and risk-adapted management of ON patients .
Despite that high-dose methylprednisolone has been established as the standard treatment for ON, variations in real-world practice continue to be noted . This also appeared to be the case in our population, in which more than 20% of ON patients were given only corticosteroids other than methylprednisolone (Table 1). Our pharmacoepidemiological analysis showed that systemic steroid use after ON was associated with an increased risk of conversion to MS and NMO in a dose-dependent manner in adult population. At first sight this suggests that systemic steroid treatment for ON is detrimental in the long term, yet this interpretation incurs the risk of reverse causation, and it apparently contradicts existing knowledge . The more plausible explanation is that prescription of systemic steroid reflects the judgment of clinicians about the immune-mediated nature of ON in the particular patient, presumably based on clinical or paraclinical features. The association of immunomodulatory medication with subsequent MS was also observed in other retrospective studies of pediatric and adult ON [4, 7], which could be similarly explicated.
It is intriguing to note that use of systemic steroid during the 3 months preceding ON was associated with a modestly decreased risk of MS in adults. This phenomenon has not been reported, and the reason is open to speculation. One possibility is that ON developing in the immunological milieu sculpted by corticosteroid has a different pathogenesis, or MS-associated ON might have been more readily ameliorated by the fortuitous use of systemic steroid. More research is needed to clarify this issue.
Previous studies showed that pediatric ON has been distinguished from ON in adults in terms of sex ratio, laterality, associated diseases and rate of conversion to MS [13, 15]. We found that female patients in this population was associated with much increased risks of MS and NMO. Besides, comorbid SLE and higher cumulative dosage of systemic steroid use after ON were independently associated with increased risks of conversion of pediatric ON to MS. All of these findings were qualitatively similar to that in adults. In contrary to general notion, the rate of conversion to MS or NMO in pediatric ON was not lower than that in adults in our study. This could be partly accounted for by the age cutoff (20 years) used here, since adolescent ON may be more akin to adult as opposed to prepubertal ON , while they were included in the pediatric group in our study. On the other hand, if the prepubertal ON is specifically examined, analytical results would be less robust given the much smaller sample size.
The strength of this study lies in its national representativeness and unprecedented size of the cohort, making statistical modeling feasible. Although the findings are not directly generalizable to other populations, the clinical relevance herein deserves further research, as discussed above. Several limitations of this study should be considered. First, the diagnosis of individual case cannot be ascertained given the nature of datasets and the policy of the database provider. Second, although the temporal scale (spanning 15 years, median follow-up duration 6–7 years) is acceptable, it is insufficient to capture all cases of MS because some patients could run a more indolent course . Third, certain features of ON, such as laterality and ophthalmologic findings, were associated with differential risks of MS or NMO [24, 35], and these features could affect clinicians’ decision regarding steroid use. In other words, they were the potential sources of confounding-by-indication. However, these information were not available for this study. Similarly, relevant serologic data and neuroimaging findings were also unavailable. Therefore, caution should be exercised in the interpretation of treatment effects with regard to subsequent risks of MS or NMO. Fourth, recurrent ON is associated with an increased likelihood of developing MS or NMO in children and adults [1, 31, 35, 36]. However, we were unable to address this issue because previous diagnosis code was often retained in subsequent visits in our electronic health information systems, making differentiation between inactive and relapsing ON difficult. Fifth, the awareness of NMO as a distinct clinical entity was relatively recent, and NMO could be underdiagnosed in the earlier years of our study period. Therefore, the association of timing of ON diagnosis with subsequent development of NMO in adults (Table 3) was likely artifactual.