ACTRIMS 2018: Rituximab does not affect MRI detected meningeal lesions

Intrathecal rituximab is worth exploring as a treatment option? Can it eliminate the B-cells driving progressive disease?

Phase 1 Trial of Intrathecal Rituximab in Progressive MS Patients with Evidence of Leptomeningeal Contrast Enhancement


Leptomeningeal inflammation is associated with increased cortical demyelination, neuronal damage and worse clinical outcomes, suggesting it may play a role in MS disease progression. Contrast-enhanced FLAIR imaging can detect areas of leptomeningeal contrast-enhancement (LME) corresponding to meningeal inflammation. Since B cells contribute to meningeal inflammation in MS, we hypothesized that targeting them using intrathecal (IT) rituximab could potentially impact LME.


To assess the safety of IT rituximab in progressive MS (PMS). Also, to assess effects of IT rituximab on the persistence of LME detected by MRI, and on cerebrospinal fluid (CSF) biomarkers.

PMS patients had a screening MRI to detect areas of LME. Those with LME who satisfied other eligibility criteria underwent repeat scanning to confirm presence of LME, followed by two IT administrations of 25 mg rituximab 2 weeks apart. Follow up lumbar puncture and MRI were performed at 8 and 24 weeks following the first treatment. We performed clinical evaluations and safety labs at baseline and at weeks 2, 8, 24 and 48. We measured levels of CXCL13, CCL19, CCL21, BAFF, sCD14 in the CSF collected before and after IT rituximab. We then assessed changes in LME lesions and CSF biomarker levels over 24 weeks.

We screened 36 PMS patients and identified 15 with LME. Eleven consented, and 8 fulfilled eligibility criteria and received study treatment. Median age was 55.5 years (IQR: 9.0), 5 were female, and number of LME lesions ranged from 1 - 3. No serious adverse effects (AE) occurred. Two participants had worsening of their EDSS over 48 weeks of follow up.

We noted a profound reduction in peripheral blood B cells from baseline (median: 18.55%, IQR:7.2) to week 2 (0.1%, IQR: 1.2) and 8 (0.1%, IQR: 0.8) with some return at 24 weeks (3.6%, IQR: 9.0). However, we noted no change in the number of LME following IT rituximab over the 24-week MRI follow up. We observed transient reductions in CSF B cells (p=0.018) and CXCL-13 levels (p=0.045) with an increase in BAFF levels (p=0.17) with treatment.

LME incidence in our PMS cohort was similar to previous reports. IT rituximab was well tolerated in PMS patients and resulted in profound peripheral B cell depletion. IT rituximab had transient effects on CSF biomarkers of inflammation but did not change LME detected on imaging. IT rituximab was insufficient to completely resolve meningeal inflammation in this small PMS cohort.

Presenting Author
Pavan Bhargava
Johns Hopkins School of Medicine
Additional Authors
Cassie Wicken
Johns HopkinsUniversity
Matthew Smith
Johns Hopkins University
Anupama Kumar
Johns Hopkins University
Irene Cortese
Neuroimmunology Clinic, NINDS, NIH
Daniel S Reich
Translational Neuroradiology Section, NINDS, NIH
Peter A Calabresi
Johns Hopkins University
Ellen M Mowry
Johns Hopkins University

ACTRIMS is one of the many "TRIMS", in this case the "Americas Committee for Treatment and Research in Multiple Sclerosis". They have an annual meeting, every other year this is combined with the European CTRIMS (ECTRIMS).

Nikos Evangelou is an Associate Professor of Neurology at Nottingham University. He is the joint chief investigator of the DELIVER-MS trial. 

Dr Evangelou says: The above study is small but very important. The idea has been for a long time that if we suppress meningeal inflammation, we might reduce the development of cortical lesions and, as a result, clinical disability.  The study assumes that we can detect inflammation in the covering of the brain (meninges) using contrast-enhanced MRI, and indeed there are a couple of studies that support this idea (though it is far from clear-cut). Unfortunately,  injecting rituximab, a B cell depleting drug, directly into in the spinal fluid (via a lumbar puncture) did not change the number of meningeal lesions detected. Is this because the signal changes interpreted as "meningeal lesions" are not what they seem to be? Or does the antibody (which rituximab is) not reach these lesions? Or is rituximab cleared up too quickly from the spinal fluid? More questions than answers...