In this study, by using the national Swedish MS registry data, that cover 80% of prevalent MS patients we showed that carriage of CSF OCB is associated with a higher risk to conversion to progressive phase of MS and increase risk of reaching EDSS milestones 3 and 4. We observed clinical and demographic differences between OCB-positive and negative patients in agreement with the previously published genetic studies.3–7
In 2013, a meta-analysis regarding OCB role in MS and CIS prevalence and prognosis, including 12,253 MS patients from 71 studies, showed that OCB-positive MS patients had a higher risk to reach disability outcomes with an odds ratio of 1.96.11 Evidence of intrathecal production of immunoglobulins, mostly IgG, has been an important component of MS diagnostic workout. Although OCB is present in 95% of MS patients (2) and being highly specific for MS, there was varying importance of CSF OCB role for MS diagnosis during historical evolvement of MS diagnostic criteria.12–15 Revisions of McDonalds criteria at 2017, recommended OCB presence as a criterion to fulfil the dissemination in time in CIS patients with a fulfilled criterion of dissemination in space.15 Adoption of modern analytical techniques including iso-electric focusing and immunoblotting has greatly increased the proportion of OCB positivity in MS, leaving only around 10% of the patients consistently being negative in European MS populations. The findings of genetic and imaging differences between the groups 3–7 have prompted a need for renewed assessment of potential clinical differences, as such a distinction would be of importance for how to understand OCB negative MS – as a subgroup of MS or potentially as an entity of its own.
Our study shows that MS subgroups, separated by OCB carriership in CSF, develops similar disability progression patterns in time albeit with varying rates of progression as evident on Kaplan-Meier curves. Hence, it is most likely that these two MS subgroups, defined by OCB carriership in CSF, are very similar and do not create separate disease entities. Our previous publication on familial risk of OCB-positive and OCB-negative groups also indicated that MS lacking OCB is etiologically closely related to the dominant subgroup of OCB positives.16
Disease modifying feature of OCBs maybe most prominent in early stages of MS were inflammatory burden is higher compared with later stages. It is known that inflammatory events like relapses with unfavorable characteristics and number of gadolinium enhancing lesions early in disease are associated with adverse long term outcomes 17 and many studies reported that relapse rate decline with disease duration.18
This comprehensive study includes the largest number of OCB negative patients, 828 (11.3%) in total of 7322 MS patients allowing us to calculate a more precise estimation of the prevalence of OCB negative patients in Sweden. Our estimates here is two times the prevalence previously reported by our group previously (5.5%)3 and to be considered as representative for Swedish MS population and comparable to OCB-negative MS prevalence reported in Scandinavia (12%).5 A study on OCB status and association to specific genetic risk alleles in a Scandinavian cohort 5 also reported a higher prevalence of male gender and older age of onset in OCB negative group.
OCBs are produced by plasma cells which are terminally differentiated B cells. In addition to the presence of OCBs and higher IgG index, the involvement of B cell in MS immunopathology and progression is also supported by the identification of B cell follicles in the meninges of SPMS patients.19,20 These ectopic B cell follicles can be the site of differentiation of the OCB producing plasma cells.19 IMTs affect OCB presence in treated MS patients. No evidence of effect of rituximab that primarily target B cells on OCB presence in CSF has been reported,21 however, conversion to OCB negative after exposure to natalizumab has been reported in a small subset of patients.22,23 Histopathological studies had revealed different frequencies of CSF OCB production depending on histopathological MS lesion type: patients with pattern I lesion type harbor OCBs in 88% of cases and in patients with pattern II and III lesions OCB was present only in 22%. In the latter group two patients were only transiently OCB-positive.24 Despite that, OCBs are considered to be a diagnostic mainstay feature in MS.2,25
The presence of OCBs is a clear indication of the inflammatory process in the CNS 26 which is believed even though sometimes debated to be followed by neurodegeneration 27 that is reflected clinically in disability progression. However their specificity and role in the inflammatory process is still under investigation.26 In a group of CIS and early MS patients, CSF cell counts were observed to be high in OCB positive patients and correlated with percentage of intrathecal IgG production, in addition the latter correlated strongly with percentage of plasma cells in the CSF.28 Moreover, the levels of serum neurofilament light chain, a well-established marker for neurodegeneration,29 is higher in OCB positive patients and correlates with CSF IgG levels,30 indicating higher extension neuro-axonal damage and loss as well as chronic degeneration in OCB positive patients. This is in line with the increased brain atrophy in OCB positive patients but still only confirms the end but not the means or the how.
OCB could be suggested as a potential clinical covariate in randomized clinical trials (RCT). Our current study endpoints were not designed to answer this question, however. In RCT, short term disability progress outcomes are used, such as “confirmed disability progression at 3 months” and “confirmed disability progression” at 6 months.31,32 International RCT with high number of included RRMS patients ( n > 4000) and low EDSS, long time follow up period (3 years) could be characteristics of studies were number of OCB-negative patients would be substantial and time sufficient to evident the OCB effect on disability progression.
Limitation of this study include high number of patient without recorded OCB status. Hence, Kaplan-Meyer estimates might somewhat be affected by exclusion of old patients that reached milestones but were lacking OCB data. Another limitation of this study is lack of data with regard to factors known to have disease modifying effects such as comorbidities, vitamin D levels, smoking 33–36 or intrinsic laboratory features (presence of IgM bands in CSF37 and also clinical characteristics),38 that could potentially alter final results.