Leptomeningeal inflammation and Intrathecal Rituximab in Progressive MSDr. Peter A Calabresi, MD, Johns Hopkins University, Baltimore, MD
While many treatment options exist for the relapsing form of MS, there are no effective therapies for progressive MS. Pathological studies have shown the presence of leptomeningeal inflammation (LMI) in people with MS and it is more prevalent in primary and secondary progressive MS. LMI is linked to increased gray matter demyelination and increased sub-pial lesion load, suggesting a possible role for LMI in disease progression. Identifying this process in vivo has been a challenge, but recent studies have shown that time-delayed post-contrast FLAIR sequences can demonstrate leptomeningeal lesions that correspond to areas of inflammation with lymphocyte aggregates seen on autopsy. These lesions appear to remain stable over time and are seen more frequently in people with progressive MS.
Our data suggest that in the late stages of the relapsing remitting experimental autoimmune encephalitis (EAE) model in SJL mice, contrast-enhancing lesions emerge in the meninges overlying the cerebral cortex. These lesions persist over time and consist of B and T lymphocytes, suggesting a process that may be similar to LMI seen in people with MS, which could facilitate screening of therapies designed to target this type of inflammation.
Since anti-CD20 is already FDA approved and has been given intrathecally (IT) to people with MS, we have commenced a clinical trial of IT Rituximab in people with progressive MS who have two baseline MRIs demonstrating leptomeningeal enhancement (LME). Since LME is a persistent process for years, unlike white matter enhancing lesions, any reduction of LME on MRI would be meaningful. The design of the clinical trial and enrollment to date will be discussed.
But as a trial starts another is stopped prematurely because it isn’t going to work
Intrathecal Rituximab in progressive MS stopped for insufficient inhibition of CNS inflammation: a randomized, double-blind, placebo-controlled studyDr. Mika Komori, MD, PhD, Dr. YenChih Lin, PhD, Dr. Irene Cortese, MD, Mr. Andrew Blake, Ms. Joan Ohayon, CNRP, Ms. Jamie Cherup, RN MSN CRNP, Dr. Dragan Maric, PhD, Dr. Peter Kosa, PhD, Dr. Tianxia Wu, PhD and Dr. Bibiana Bielekova, MD, National Institutes of Health, Bethesda, MD
Background: The lack of efficacy of immunomodulatory treatments in progressive multiple sclerosis (MS) may be caused by the unreachable compartmentalized inflammation in the central nervous system (CNS).
Objectives: The double blind combination of Rituximab by IntraVenous and IntraThecal injection versus placebo in patients with Low-Inflammatory Secondary progressive MS (RIVITALISE; NCT01212094) trial was designed to answer: 1. Whether an induction dose of intravenous and intrathecal rituximab efficiently depletes CNS B cells? and 2. If so, whether this leads to global inhibition of CNS inflammation and slowing of CNS tissue destruction?
Methods: Patients aged 18-65 years were randomly assigned (2:1; randomization sequence table balanced for age) to rituximab (n=18) or placebo (n=9). Protocol-stipulated interim analysis of serum and cerebrospinal fluid (CSF) biomarkers in patients who completed the induction dose of study drug quantified the efficacy of B cell depletion.
Results: The selected rituximab regimen failed to reach criteria for continuation of the trial. Changes in B cell-related CSF biomarkers (soluble CD21 [sCD21] and B-cell activating factor [BAFF]) occurred only in the active-treatment arm. While the mobile pool of CSF B cells was depleted by a median of -79.71% (p= 0.0176), B cells in CNS tissue were depleted inadequately (~-10-20%, p<0·0001). Consequently, the T cell specific CSF biomarker sCD27 also decreased only slightly (-10.97 %, p=0.0005), while a marker of axonal damage, neurofilament light chain did not change. Insufficient saturation of CD20, lack of lytic complement and paucity of cytotoxic CD56dim NK cells contribute to decreased efficacy of rituximab in the CNS.
Conclusion: Biomarker studies reliably quantified complementary pharmacodynamic effects of rituximab in the CNS, exposed causes for poor efficacy and determined that the RIVITALISE trial would be underpowered to reliably measure efficacy on clinical outcomes.
Again 3-4 underpowered studies verses a joined-up definative answer…same old same old:-(
If you are going for this approach would it not be best to target the Plamsa cells which do not express CD20, ensuring that the antibody is complement fixating and that complement s around and not killing by Antibody-dependent cellular cytotoxicity that need other cells to do the killing