Clinical NeuroimmunologyRituximab reduces B cells and T cells in cerebrospinal fluid of multiple sclerosis patients
Introduction
Evidence implicates B cells and antibodies (Abs) in the pathogenesis of MS (Cross et al., 2001). The most consistent laboratory abnormality found in MS patients is increased intrathecal production of oligoclonal immunoglobulin (Ig), present in > 90% of persons with definite MS (Walsh et al., 1985, Trotter and Rust, 1989). These Igs include IgG, IgA, IgM and IgD (Walsh and Tourtelotte, 1986). Several studies have correlated high levels of CSF Ig, including both IgG and IgM, with worse prognosis (Olsson and Link, 1973, Villar et al., 2002, Izquierdo et al., 2002). MS patients lacking CSF oligoclonal bands (OCBs) have a more benign course (Zeman et al., 1996), whereas higher numbers of OCBs are associated with a poor prognosis (Avasarala et al., 2001). These studies provide correlative data, but may reflect an altered humoral immune system rather than abnormalities fundamental to pathogenesis.
To better define the role of B cells in MS, we undertook an open-label Phase II clinical trial of B cell depletion in relapsing-remitting MS (RRMS) patients with suboptimal response to standard therapies. Serial measurements of serum and cerebrospinal fluid (CSF) Abs to the myelin proteins, myelin oligodendrocyte glycoprotein (MOG) and myelin basic protein (MBP) and serial measures of B and T cells in CSF were performed.
Section snippets
Study design
This Phase II trial was designed to study the use of rituximab as an add-on therapy in RRMS patients continuing to have MS activity, both clinically and by MRI, despite therapy with an FDA-approved medication. The study was approved by the Washington University Human Studies Committee (IRB). All subjects provided full informed consent prior to enrollment. The primary endpoint, still blinded, is to determine if the number of gadolinium enhancing lesions on brain MRI is reduced after
Patients receiving rituximab
As of January 2006, 16 patients (10F, 6M) had been fully treated with rituximab, after screening of 36 (Table 1). Of these, 4 were on intra-muscular beta-interferon 1a, 2 were on subcutaneous beta-interferon 1a, 7 were taking subcutaneous beta-interferon 1b, and 3 were taking glatiramer acetate. One of the subjects (021) refused LP after an initial attempt failed, but remained in the study and was treated with study drug.
Blood
Circulating B cells were depleted to zero in all subjects that received
Discussion
The role of B cells and Abs in MS pathogenesis is unknown. Several published studies have suggested that increased immunoglobulins in CSF portend a worse course. The presence and number of OCBs, the level of CSF free kappa light chains, and an elevated IgG index all have been correlated with a worse prognosis (Rudick et al., 1995). Published data indicate that patients with serum IgM Abs to MBP and MOG may have a more aggressive type of MS (Berger et al., 2003). However, these data do not prove
Acknowledgments
Supported by the National Multiple Sclerosis Society USA RG 3292; NIH K24RR017100-02; the Washington University General Clinical Research Center MO1 RR00036; Genentech/IDEC. Dr. Cross was supported in part by the Manny and Rosalyn Rosenthal–Dr. John L. Trotter Chair in Neuroimmunology. We thank Robert Mikesell for excellent technical assistance, Drs. Becky Jo Parks and Robert T. Naismith for referral of patients and our patients for their participation. The paper is dedicated to the memory of
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