Association of Intrathecal Immunoglobulin G Synthesis With Disability Worsening in Multiple Sclerosis

Gasperi, Christiane; Salmen, Anke; George, Antony; Bayas, Antonios; Heesen, Christoph; Kümpfel, Tania; Linker, Ralf A.; Paul, Friedemann; Stangel, Martin; Tackenberg, Björn; Bergh, Florian Then; Warnke, Clemens; Weber, Frank; Wiendl, Heinz; Wildemann, Brigitte; Zettl, Uwe K.; Ziemann, Ulf; Zipp, Frauke; Tumani, Hayrettin; Gold, Ralf; Hemmer, Bernhard

doi:10.1001/jamaneurol.2019.0905

Cited by 59 publications

(57 citation statements)

References 35 publications

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“…By contrast, OCB positivity failed to predict early disease activity in our study. This finding favoring the prognostic value of quantitative IgG synthesis over OCB was also indicated by several large studies before (10,(36)(37)(38)(39). A recent prospective study with 1,376 German patients found that patients with an elevated IgG index were twice more likely to develop disability worsening 4 years after onset, whereas the presence of OCB failed to show a higher risk of EDSS worsening (10).…”

Section: Discussionmentioning

confidence: 75%

“…Given its low cost and easy accessibility, IgG index is still considered a potential candidate for MS diagnosis despite a relatively low sensitivity (50-75% among MS patients) (3). Studies on its specificity, however, generated mixing results (7)(8)(9)(10). Furthermore, the prognostic value of IgG index or OCB remains undetermined based on existing evidence (10)(11)(12)(13).…”

Section: Introductionmentioning

confidence: 99%

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IgG Index Revisited: Diagnostic Utility and Prognostic Value in Multiple Sclerosis

et al. 2020

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Objective: Early and accurate diagnosis of multiple sclerosis (MS) remains a clinical challenge. The main objective is to evaluate the diagnostic and prognostic value of the routinely performed immunoglobulin G (IgG) index for MS patients in the Asian population. Methods: A retrospective study was conducted among a cohort of clinically isolated syndrome (CIS) patients in China with known oligoclonal band (OCB) status and IgG index at baseline. We first evaluated the predictive value of IgG index for OCB status. Secondly, the diagnostic utility and prognostic value of IgG index alone were tested. Lastly, we incorporated IgG index into the 2017 McDonald criteria by replacing OCB with either "IgG index or OCB" (modified criteria 1), "IgG index and OCB" (modified criteria 2), or "IgG index" (modified criteria 3). The diagnostic utility of different criteria was calculated and compared. Results: In a CIS cohort in China (n = 105), IgG index > 0.7 forecasted OCB positivity (X 2 = 22.90, P < 0.001). An elevated IgG index was highly prognostic of more clinical relapses [1-year adjusted odds ratio [OR] = 1.32, P = 0.015; 2-years adjusted OR = 1.69, P = 0.013] and Expanded Disability Status Scale worsening (1-year adjusted OR = 1.76, P = 0.040; 2-years adjusted OR = 1.85, P = 0.032). Under the 2017 McDonald criteria (Positive Likelihood Ratio = 1.54, Negative Likelihood Ratio = 0.56), an IgG index > 0.7 in CIS patients increased the likelihood of developing MS within 2 years, either when OCB status was unknown (Positive Likelihood Ratio = 2.11) or with OCB positivity (Positive Likelihood Ratio = 2.11) at baseline; An IgG index ≤ 0.7, along with a negative OCB, helped rule out the MS diagnosis (Negative Likelihood Ratio = 0.53). Conclusions: IgG index > 0.7 predicts OCB positivity at the initial attack of MS and is prognostic of early disease activity. IgG index serves as an easily-obtainable and accurate OCB surrogate for MS diagnosis in the Asian population.

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Section: Discussionmentioning

confidence: 75%

Section: Introductionmentioning

confidence: 99%

IgG Index Revisited: Diagnostic Utility and Prognostic Value in Multiple Sclerosis

et al. 2020

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“…Shift in the balance between Tregs and proinflammatory T-cells [44][45][46][47] Lower percentage of CD4 + Foxp3 Tregs, memory CD4 and CD8 cells and CD56 high NK Cells 44,46,47 Increased Th17 cell responses 48 Low TCR diversity 49…”

Section: Immunological Features In the Bloodmentioning

confidence: 99%

“…Detection of CSF IgM OCB 50,51 Elevated IgG Index 48 Elevated levels of NfL in CSF or serum [52][53][54][55] CSF CXCL13 56,57 1000 patients with clinically isolated syndromes (CIS) characteristic of MS showed that a high brain T2 lesion load at baseline was the most robust predictive factor for future disability accrual. 68 Tintore et al 13 used a Barcelona-based inception cohort and, like Malpas et al, 14 defined aggressive MS as reaching an EDSS ⩾6.0 within 10 years of disease onset.…”

Section: E Biomarker Correlatesmentioning

confidence: 99%

Aggressive multiple sclerosis (1): Towards a definition of the phenotype

et al. 2020

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While the major phenotypes of multiple sclerosis (MS) and relapsing–remitting, primary and secondary progressive MS have been well characterized, a subgroup of patients with an active, aggressive disease course and rapid disability accumulation remains difficult to define and there is no consensus about their management and treatment. The current lack of an accepted definition and treatment guidelines for aggressive MS triggered a 2018 focused workshop of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) on aggressive MS. The aim of the workshop was to discuss approaches on how to describe and define the disease phenotype and its treatments. Unfortunately, it was not possible to come to consensus on a definition because of unavailable data correlating severe disease with imaging and molecular biomarkers. However, the workshop highlighted the need for future research needed to define this disease subtype while also focusing on its treatment and management. Here, we review previous attempts to define aggressive MS and present characteristics that might, with additional research, eventually help characterize it. A companion paper summarizes data regarding treatment and management.

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“…B cells play an important role in the pathophysiology of multiple sclerosis (MS). B cells are detected in MS lesions and cerebrospinal fluid (CSF), and the persistence of intrathecal oligoclonal immunoglobulin G (IgG) bands is a fundamental hallmark of disease and associated with worsening disability [5,16]. Phase 3 clinical trials have demonstrated that B cell-depleting therapies are effective in reducing clinical and MRI activity in relapsing and progressive forms of disease [9,10,24].…”

Section: Introductionmentioning

confidence: 99%

Fingolimod alters intrathecal B cell maturation in multiple sclerosis patients

Kowarik

Astling

Lepennetier

et al. 2020

Preprint

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Background: B cells are postulated to play multiple roles in the pathogenesis of multiple sclerosis (MS) including pathogenic antibody production, antigen-presentation and pro-inflammatory cytokine secretion. Natalizumab and fingolimod are effective MS therapies that disrupt lymphocyte migration but exert differential effects on B cell maturation and trafficking. Herein, we investigated their effects on peripheral blood and cerebrospinal fluid (CSF) B cell repertoires.Methods: Paired CSF and peripheral blood (PB) lymphocytes were collected from MS patients at baseline and after 6 months of treatment with fingolimod (n = 4) or natalizumab (n = 4). B cell subsets including naïve, CD27+ memory, CD27-IgD- double-negative B cells and plasmablasts were collected by FACS and their respective heavy-chain variable region (VH) repertoires assessed by next generation deep sequencing (Illumina MiSeq).Results: Treatment with fingolimod lead to a distinct contraction of the PB B cell pool whereas natalizumab resulted in an expansion of circulating PB B cells. In contrast, CSF B cell numbers remained stable under treatment with fingolimod but decreased following natalizumab therapy. Clonal overlap between CSF and peripheral blood B cells was reduced following natalizumab treatment (-24% reduction of clonal groups) but remained stable with fingolimod therapy. Lineage analyses of CSF B cell repertoires at baseline and following therapy revealed large, clonally expanded B cell clusters in natalizumab-treated MS patients but no intrathecal clonal expansion following fingolimod therapy. Conclusions: Our findings suggest that natalizumab treatment diminishes the exchange of peripheral and intrathecal B cells but does not impact intrathecal clonal expansion. In contrast, fingolimod treatment fails to alter B cell exchange across the blood-brain-barrier but affects intrathecal clonal expansion. Sphingosine-1 phosphate receptor inhibition may impact MS disease progression by inhibiting intrathecal germinal center activity.

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Association of Intrathecal Immunoglobulin G Synthesis With Disability Worsening in Multiple Sclerosis

Cited by 59 publications

References 35 publications

IgG Index Revisited: Diagnostic Utility and Prognostic Value in Multiple Sclerosis

IgG Index Revisited: Diagnostic Utility and Prognostic Value in Multiple Sclerosis

Aggressive multiple sclerosis (1): Towards a definition of the phenotype

Fingolimod alters intrathecal B cell maturation in multiple sclerosis patients

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