Trial of intrathecal rituximab in progressive multiple sclerosis patients with evidence of leptomeningeal contrast enhancement

doi:10.1016/j.msard.2019.02.013

Multiple Sclerosis and Related Disorders

Volume 30, May 2019, Pages 136-140

https://doi.org/10.1016/j.msard.2019.02.013 Get rights and content

Highlights

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Enrolled progressive MS patients with leptomeningeal contrast enhancement (LME).
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Two doses of intrathecal rituximab (25 mg) were tolerated without serious adverse events.
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Intrathecal rituximab treatment did not affect LME over follow-up period of 6 months.
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Intrathecal rituximab treatment transiently reduced CSF B cells and altered certain chemokine levels.

Abstract

Background

Leptomeningeal inflammation is associated with increased cortical damage and worse clinical outcomes in MS. It may be detected on contrast-enhanced T2-FLAIR imaging as focal leptomeningeal contrast-enhancement (LME).

Objective

To assess the safety of intrathecal (IT) rituximab in progressive MS (PMS) and to assess its effects on LME and CSF biomarkers.

Methods

PMS patients had a screening MRI to detect LME. Participants satisfying eligibility criteria underwent two IT administrations of 25 mg rituximab 2 weeks apart. Follow-up lumbar puncture and MRI were performed at 8 and 24 weeks after the first treatment.

Results

Of 36 patients screened 15 had LME, 11 consented, and 8 received study treatment. Mean age was 56.7 years and number of LME lesions ranged from 1 to 3. No serious adverse effects occurred. We noted profound reductions in peripheral B cells from baseline to week 2 and 8 with some return at week 24. We also observed transient reductions in CSF B cells and CXCL-13 levels with an increase in BAFF levels. However, the number of LME did not change following treatment.

Conclusions

IT rituximab was well tolerated in PMS patients and had transient effects on CSF biomarkers but did not change LME.

Introduction

Leptomeningeal inflammation was described in patients with secondary progressive multiple sclerosis (SPMS) in 2004 and has subsequently been identified at all stages of the disease (Howell et al., 2011, Lucchinetti et al., 2011, Magliozzi et al., 2007, Serafini et al., 2004). While initial reports described lymphoid follicles in the meninges, subsequent manuscripts suggest a spectrum of changes ranging from unorganized inflammation to tertiary lymphoid tissue (Wicken et al., 2018). Meningeal inflammation has been associated with cortical demyelination and neuro-axonal damage (Choi et al., 2012, Howell et al., 2011, Magliozzi et al., 2010). B cells from MS patients produce molecules that are toxic to oligodendroglia and neurons(Lisak et al., 2017). Since gray matter lesions are linked to disability (Kutzelnigg et al., 2005) and patients with meningeal inflammation have a more severe disease course (Choi et al., 2012), it has been postulated that leptomeningeal inflammation may contribute to disease progression in MS.

Recent work has demonstrated that specific MRI sequences may identify areas of meningeal inflammation (Absinta et al., 2015), which demonstrate leptomeningeal enhancement (LME) on contrast-enhanced T2-FLAIR imaging, which could provide a potential biomarker to assess the effects of interventions on meningeal inflammation. Immune cells in areas of meningeal inflammation include B cells, plasma cells, follicular helper T cells, follicular dendritic cells, and macrophages. Rituximab is a monoclonal antibody targeting CD20 that has been shown in multiple trials to be effective in reducing MS disease activity. Intravenous administration results in very low CSF concentration of rituximab, which may not be sufficient to impact meningeal B cells (Czyzewski et al., 2013). Since B cells are an important component of meningeal inflammation and monoclonal antibodies targeting anti-CD20 are effective therapies in MS, (Hauser et al., 2017, Montalban et al., 2017) we hypothesized that direct intrathecal (IT) administration of rituximab may provide a more effective method of resolving meningeal inflammation (Bonnan et al., 2014).

The goal of this trial was to assess the safety of IT rituximab in progressive MS patients with LME and to assess the effects on both LME and CSF biomarkers.

Section snippets

Participants and standard protocol approvals, registrations and patient consents

This single-center, open-label trial enrolled adults with a confirmed diagnosis of progressive MS and evidence of LME on contrast-enhanced T2-FLAIR imaging (complete eligibility criteria in Table 1) between August 2014 and May 2017. Study procedures were approved by the Johns Hopkins Institutional Review Board. The trial was registered on clinicaltrials.gov (NCT02253264).

Study drug

We selected the dose of 25 mg of rituximab, since it was the highest dose previously well-tolerated in studies in CNS

Study participants

Of the 36 participants screened for the trial, 15 (42%) demonstrated the presence of LME (Fig. 1B). Eleven consented to participate in the trial, and eight fulfilled eligibility criteria and received the intervention. Mean age was 56.7 years, most participants had SPMS (n = 7) and median baseline EDSS was 6.0. Demographic and disease characteristics of the study participants are in Table 2.

Adverse events

None of the 8 participants experienced a serious adverse event related to IT rituximab. The most common

Discussion

In this open-label trial of IT rituximab treatment in progressive MS patients with imaging evidence of meningeal inflammation, we noted no significant adverse effects attributable to the intervention. Intrathecal administration of rituximab resulted in significant and sustained reduction in circulating B cells and a transient drop in CSF B cells, but this did not translate to a change in the number or appearance of LME on imaging.

Few studies have utilized an intrathecal approach to administer

Conflict of interest

Dr. Bhargava has nothing to disclose.

Ms. Wicken has nothing to disclose.

Mr. Smith has nothing to disclose.

Dr. Strowd has nothing to disclose.

Dr. Cortese has nothing to disclose.

Dr. Reich reports personal fees and non-financial support from At the Limits, personal fees from Leventhal and Puga, LLC, outside the submitted work; In addition, Dr. Reich has a patent System and method of automatically detecting tissue abnormalities (US Patent 9607392) issued, and a patent Method of analyzing

Acknowledgments

We would like to thank Dr. John Laterra, Dr. Michael Levy and Dr. Matthias Holdhoff for serving on the Data Safety Monitoring Board.

This study was supported by a pilot award from the Race to Erase MS and a grant from the International Progressive MS Alliance to PAC. P.B. was supported by a Career Transition Award from the National MS Society, the John F Kurtzke Clinician Scientist development award from the American Academy of Neurology and a Young Investigator Award from the Race to Erase MS.

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A pilot trial of ocrelizumab for modulation of meningeal enhancement in multiple sclerosis
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Autopsy data suggests that meningeal inflammation in multiple sclerosis (MS) is driven by CD20+ B-cells. Ocrelizumab is an anti-CD20 monoclonal antibody, and thus could potentially ameliorate meningeal inflammation in MS. Leptomeningeal enhancement (LME) on MRI is suggested as a surrogate biomarker of meningeal inflammation in MS, and thus may be a way of monitoring for this treatment effect.
To determine if ocrelizumab impacts meningeal enhancement (ME) on 7T MRI in MS.
Twenty-two patients with MS started on ocrelizumab by their treating physician were enrolled into this single-center, open-label, prospective trial. Participants underwent 7T MRI of the brain prior to first infusion, with screening for the presence of LME. Fourteen patients (48 ± 11 years; 11 women) had LME on the baseline scan and were invited to return for an additional 7T MRI after 1 year of treatment. Fourteen MS patients (49 ± 10 years; 11 women) on non-CD20 treatment from a separate observational cohort of annual 7T MRIs were used for comparison – matched for LME at baseline, age, and sex. Post-contrast FLAIR and subtraction images were reviewed for LME and paravascular and dural enhancement (PDE).
All subjects in the ocrelizumab and comparison groups had LME and PDE on their baseline scan. At the beginning of the study the mean number of foci of LME and PDE in the study group were 2.3 ± 1.7 and 6.6 ± 3.9 respectively. Mean LME and PDE count for the comparison group were 1.7 ± 1.5 and 7.8 ± 5.5. Mean volume of LME in the study group was 50.5 mm³ ± 65.0 mm³ and that of the PDE was 866 mm³ ± 937.9. Mean volume of LME and PDE for comparison group were 28.4 mm³ ± 36.0 and 885 mm³ ± 947.7 respectively.
At follow-up, the number of patients with LME decreased to 8 (57 %) in both groups, whereas the proportion of patients with PDE was unchanged. Minimal mean change in the number of LME after 1 year were seen in both the study group (0.07 ± 2.9, p = 0.97) and comparison group (-0.71 ± 1.5, p = 0.08). Minimal mean change was seen in the volume of LME in both the study group (-21.91 mm³ ± 77.66, p = 0.27) and comparison group (3.4 mm³ ± 32.11, p = 0.77).
There was minimal change in the mean number of foci of PDE after 1 year in both the study group (-0.71 ± 2.36, p = 0.32) and in the comparison group (-0.17 ± 3.89, p = 0.15). Mean change in volume of PDE was measurable, but not significant in both the study group (-397.1 mm³ ±959.6, p = 0.80) and in the comparison group (-417.0 mm³ ± 922.7) (p = 0.80).
Comparisons between the changes in foci count and volume for both LME and PDE in the study versus comparison groups showed no significant differences.
In this small pilot trial, ocrelizumab did not significantly reduce the number or volume of foci of LME or PDE in MS patients.
A systematic review of the safety and efficacy of monoclonal antibodies for progressive multiple sclerosis
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Progressive multiple sclerosis (PMS) is a debilitating condition characterized by progressively worsening symptoms. Monoclonal antibodies are novel therapies for MS, but their safety and efficacy in the progressive form have not been comprehensively studied. In this systematic review, we aimed to evaluate the available evidence regarding monoclonal antibody treatment for PMS.
After registration of the study protocol in PROSPERO, we systematically searched three major databases for clinical trials involving monoclonal antibodies administration for PMS treatment. All the retrieved results were imported into the EndNote reference manager. After removing the duplicates, two independent researchers did the study selection and data extraction. The risk of bias was assessed using the Joanna Briggs Institute (JBI) checklist.
Of the 1846 studies in the preliminary search, 13 clinical trials investigating monoclonal antibodies (Ocrelizumab, Natalizumab, Rituximab, and Alemtuzumab) in PMS patients were included. Ocrelizumab was significantly effective in reducing clinical disease progression measures in primary PMS patients. The results for Rituximab were not completely reassuring and only showed significant changes for some endpoints on MRI and clinical measures. Natalizumab decreased the relapse rate and improved MRI features for secondary PMS patients, but not clinical endpoints. The studies on Alemtuzumab treatment revealed conflicting outcomes, with improvements observed in MRI endpoints but clinical worsening in patients. Additionally, among the studied adverse events, upper respiratory infections, urinary tract infections, and nasopharyngitis were frequently reported.
Based on our findings, Ocrelizumab is the most efficient monoclonal antibody for primary PMS, although it is associated with a higher risk of infection. While other monoclonal antibodies did not show significant promise in treating PMS, more research is necessary.
Effect of ocrelizumab on leptomeningeal inflammation and humoral response to Epstein-Barr virus in multiple sclerosis. A pilot study
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Therefore, given that the LM CE is associated with key clinical and imaging features of MS, there is an increasing interest for the application of this imaging modality in monitoring treatment effectiveness in clinical trials (Ineichen et al., 2022). Although the use of LM CE in MS clinical trials is only in its infancy, initial reports examining use of intrathecal administration of rituximab (Bhargava et al., 2019; Bonnan et al., 2021) or currently available disease-modifying treatments (DMTs) (Zivadinov et al., 2019; Jonas et al., 2018; Hildesheim et al., 2021) did not show a beneficial treatment effect. Epstein-Barr virus (EBV) is the most plausible cause of MS (Bjornevik et al., 2022) and its activation may precede demyelinating and axonal pathology in MS (Guan et al., 2019).
Ocrelizumab is an effective treatment for relapsing and primary-progressive multiple sclerosis (MS). However, the effect of ocrelizumab on leptomeningeal (LM) inflammation is unknown.
To investigate whether ocrelizumab reduces LM inflammation by reducing the exposure to Epstein-Barr virus (EBV)-infected B cells in relapsing-remitting (RR) MS.
This was a Phase IV, prospective, open-label, single-center, observational, longitudinal pilot study of RRMS patients who started treatment with ocrelizumab (NCT03025269). Clinical, MRI and EBV-antibodies outcomes at baseline, 12- and 24-month of the study were evaluated. The MRI outcomes included T2, T1 and T1-contrast enhancing (CE) lesion counts and volumes, LM CE count, and percentage brain volume changes.
27 RRMS patients started ocrelizumab and 24 remained on the treatment for whole duration of the study. Most patients remained stable (74.1%) or improved (18.5%) in their disability status. At baseline, 42.3% of patients showed LM CE lesions. The majority of patients remained stable in their LM CE status over the follow-up (72.7%). A significant decrease in percentage volume loss of cortex (p=0.009), GM (p=0.01) and thalamus (p=0.038) was detected, while T1-LV increased (p=0.02). A significant decrease of EBNA-1 IgG (p=0.013) was evidenced. An infusion-related allergic reaction led to discontinuation of the medication in one patient at first dose.
Treatment with ocrelizumab was safe and clinically effective. Brain volume loss and accumulation of T1-LV occurred. While ocrelizumab decreased humoral response to EBV possibly by reducing B cells, it did not reduce LM inflammation.
Leptomeningeal enhancement in multiple sclerosis and other neurological diseases: A systematic review and Meta-Analysis
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Another study assessing the efficacy of dimethyl fumarate or teriflunomide on LME reported no differences in LME resolution between treatment groups (8 of 12 patients showed stable LME, and 2 patients developed new LME) (Zivadinov et al., 2019). One study assessing intrathecal rituximab treatment in 15 progressive MS patients observed stable LME foci in all patients over the 24-week follow-up period (Bhargava et al., 2019). In contrast to these studies with relatively small sample size and consequently lower statistical power, one study including 241 MS patients observed resolution of LME in 2 patients after high-dose steroid treatment within 6 months follow-up (Titelbaum et al., 2020).
The lack of systematic evidence on leptomeningeal enhancement (LME) on MRI in neurological diseases, including multiple sclerosis (MS), hampers its interpretation in clinical routine and research settings.
To perform a systematic review and meta-analysis of MRI LME in MS and other neurological diseases.
In a comprehensive literature search in Medline, Scopus, and Embase, out of 2292 publications, 459 records assessing LME in neurological diseases were eligible for qualitative synthesis. Of these, 135 were included in a random-effects model meta-analysis with subgroup analyses for MS.
Of eligible publications, 161 investigated LME in neoplastic neurological (n = 2392), 91 in neuroinfectious (n = 1890), and 75 in primary neuroinflammatory diseases (n = 4038). The LME-proportions for these disease classes were 0.47 [95%-CI: 0.37–0.57], 0.59 [95%-CI: 0.47–0.69], and 0.26 [95%-CI: 0.20–0.35], respectively. In a subgroup analysis comprising 1605 MS cases, LME proportion was 0.30 [95%-CI 0.21–0.42] with lower proportions in relapsing-remitting (0.19 [95%-CI 0.13–0.27]) compared to progressive MS (0.39 [95%-CI 0.30–0.49], p = 0.002) and higher proportions in studies imaging at 7 T (0.79 [95%-CI 0.64–0.89]) compared to lower field strengths (0.21 [95%-CI 0.15–0.29], p < 0.001). LME in MS was associated with longer disease duration (mean difference 2.2 years [95%-CI 0.2–4.2], p = 0.03), higher Expanded Disability Status Scale (mean difference 0.6 points [95%-CI 0.2–1.0], p = 0.006), higher T1 (mean difference 1.6 ml [95%-CI 0.1–3.0], p = 0.04) and T2 lesion load (mean difference 5.9 ml [95%-CI 3.2–8.6], p < 0.001), and lower cortical volume (mean difference −21.3 ml [95%-CI −34.7–-7.9], p = 0.002).
Our study provides high-grade evidence for the substantial presence of LME in MS and a comprehensive panel of other neurological diseases. Our data could facilitate differential diagnosis of LME in clinical settings. Additionally, our meta-analysis corroborates that LME is associated with key clinical and imaging features of MS.
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Although rituximab is not licensed for use in MS, it is currently used off-label in different countries.. It has been reported from a small case series in patients with MS that rituximab treatment results in significant and sustained reduction of circulating B cells and in a transient drop of CSF B cells (Cross et al., 2006; Martin Mdel et al., 2009; Stuve et al., 2005), but this did not translate to a change in the number or appearance of leptomeningeal contrast-enhancement on imaging or sCD21 used as surrogate marker for intrathecal B cells (Bhargava et al., 2019). Rituximab has been reported to be detectable in the CSF of patients with MS, albeit at concentrations which are 1000-fold lower that serum concentrations (Petereit and Rubbert-Roth, 2009).
With the recent approval of cladribine tablets, siponimod and ozanimod, there has been a renewed interest into the extent to which these current generation disease-modifying therapies (DMTs) are able to cross into the central nervous system (CNS), and how this penetration of the blood-brain barrier (BBB) may influence their ability to treat multiple sclerosis (MS).
The integrity of the CNS is maintained by the BBB, blood-cerebrospinal fluid barrier, and the arachnoid barrier, which all play an important role in preserving the immunological environment and homeostasis within the CNS. The integrity of the BBB decreases during the course of MS, with a putative temporal relationship to disease worsening. Furthermore, it is currently considered that progression of the disease is mediated mainly by resident cells of the CNS.
The existing literature provides evidence to show that some of the current generation DMTs for MS are able to penetrate the CNS and potentially exert direct effects on CNS-resident cells, in particular the CNS-penetrating prodrugs cladribine and fingolimod, and other sphingosine-1 phosphate receptor modulators; siponimod and ozanimod. Other current generation DMTs appear to be restricted to the periphery due to their high molecular weight or physicochemical properties.
As more effective brain penetrant therapies are developed for the treatment of MS, there is a need to understand whether the potential for direct effects within the CNS are of significance, and whether this brings additional benefits over and above treatment effects mediated in the periphery. In turn, this will require an improved understanding of the structure and function of the BBB, the role it plays in MS and subsequent treatments.
This narrative review summarizes the data supporting the biological plausibility of a potential benefit from therapeutic molecules entering the CNS, and discusses the potential significance in the current and future treatment of MS.
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Studies in adults with MS have shown that even low doses (3.5–25 mg) of intrathecal rituximab leads to peripheral B-cell depletion and central pro-inflammatory cytokine reduction within as little as 2 weeks while higher doses result in sustained reduction for up to 3–6 months.( Svenningsson et al., 2015; Bhargava et al., 2019) Case reports have also demonstrated variable success with IT rituximab in adults with IgG4-related hypertrophic pachy-meningitis (Della-Torre et al., 2018) and anti-NMDA receptor encephalitis (Casares et al., 2019). However, the safety, feasibility, and efficacy of this treatment has not been evaluated in the pediatric population.
Historically, treatment options for refractory neuroimmunologic disorders have been limited. Use of intrathecal rituximab has been described in a few case reports but experience in pediatric patients is limited. Here, we report our experience with intrathecal rituximab in 5 pediatric patients with refractory neuroimmunologic conditions. Patients were identified based on treatment-refractory symptoms despite first and second-line therapies and treated according to a standardized protocol. Although individual outcomes varied, intrathecal rituximab showed a favorable safety profile and was well-tolerated. Three out of five patients showed evidence of a positive clinical response assessed by modified Rankin score or Mitchell-Pike Opsoclonus-Myoclonus score. Findings from this retrospective observational study suggest that intrathecal rituximab is a safe and potentially effective therapy in carefully selected patients with refractory neuroimmunologic disorders despite appropriate first and second-line therapies.

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Clinical trialTrial of intrathecal rituximab in progressive multiple sclerosis patients with evidence of leptomeningeal contrast enhancement

Highlights

Abstract

Background

Objective

Methods

Results

Conclusions

Introduction

Section snippets

Participants and standard protocol approvals, registrations and patient consents

Study drug

Study participants

Adverse events

Discussion

Conflict of interest

Acknowledgments

Blood

J. Neuroimmunol.

J. Neuroimmunol.

Blood

Mult. Scler. Relat. Disord.

Mult. Scler. Relat. Disord.

Gadolinium-based MRI characterization of leptomeningeal inflammation in multiple sclerosis

Neurology.

The place of isotope encephalography by the lumbar route in neurological diagnosis

Proc. R. Soc. Med.

Intrathecal treatment trial of rituximab in progressive MS

Neurology

Intrathecal rituximab therapy in multiple sclerosis: Review of evidence supporting the need for future trials

Curr. Drug Targets