Rituximab In MS Abstracts

We evaluated the safety, tolerability, pharmacodynamics, and activity of B-Cell depletion with Rituximab in patients with Relapsing/Remitting Multiple Sclerosis, receiving two courses of Rituximab 6 months apart, and followed for a total of 72 weeks.

No serious adverse events were noted; events were limited to mild-to-moderate infusion-associated events, which tended to decrease with subsequent infusions. Infections were also mild or moderate, and none led to withdrawal.

Fewer new Gadolinium-enhancing or T₂ lesions were seen starting from week 4 and through week 72.

An apparent reduction in relapses was also observed over the 72 weeks compared with the year before therapy.

Background
There is increasing evidence that B-Lymphocytes are involved in the pathogenesis of Multiple Sclerosis, and they may be a therapeutic target.

Rituximab, a MonoClonal AntiBody, selectively targets and depletes CD20⁺ B-Lymphocytes.

Methods
In a phase 2, double-blind, 48-week trial involving 104 patients with Relapsing/Remitting Multiple Sclerosis, we assigned 69 patients to receive 1000 mg of intravenous Rituximab and 35 patients to receive placebo on days 1 and 15.

The primary end point was the total count of Gadolinium-enhancing Lesions detected on Magnetic Resonance Imaging scans of the Brain at weeks 12, 16, 20, and 24.

Clinical outcomes included safety, the proportion of patients who had relapses, and the annualized rate of relapse.

Results
As compared with patients who received placebo, patients who received Rituximab had reduced counts of total Gadolinium-enhancing lesions at weeks 12, 16, 20, and 24 (P < 0.001)

And, of total new Gadolinium-enhancing lesions over the same period (P < 0.001); these results were sustained for 48 weeks (P < 0.001).

As compared with patients in the placebo group, the proportion of patients in the Rituximab group with relapses was significantly reduced at week 24 (14.5% vs. 34.3%, P=0.02) and week 48 (20.3% vs. 40.0%, P=0.04).

More patients in the Rituximab group than in the placebo group had adverse events within 24 hours after the first infusion, most of which were mild-to-moderate events; after the second infusion, the numbers of events were similar in the two groups.

Conclusions
A single course of Rituximab reduced inflammatory Brain lesions and clinical relapses for 48 weeks.

This trial was not designed to assess long-term safety or to detect uncommon adverse events. The data provide evidence of B-Cell involvement in the pathophysiology of Relapsing/Remitting Multiple Sclerosis.

Copyright 2008 Massachusetts Medical Society.

Increasing awareness of the importance of aberrant B-Cell regulation in Autoimmunity has driven the clinical development of novel B-Cell-directed biologic therapies with the potential to treat a range of Autoimmune Disorders.

The first of these drugs-Rituximab, a chimeric MonoClonal AntiBody against the B-Cell-specific surface marker CD20-was recently approved for treating Rheumatoid Arthritis in patients with an inadequate response to other biologic therapies.

The aim of this review is to discuss the potential use of Rituximab in the management of Other Autoimmune Disorders.

Results from early phase clinical trials indicate that Rituximab may provide clinical benefit in Systemic Lupus Erythematosus, Sjögren's Syndrome, Vasculitis, and ThrombocytoPenic Purpura.

Numerous case reports and several small pilot studies have also been published reporting the use of Rituximab in conditions such as Myositis, AntiPhospholipid Syndrome, Still's Disease, and Multiple Sclerosis.

In general, the results from these preliminary studies encourage further testing of Rituximab therapy in formalized clinical trials.

Based on results published to date, it is concluded that Rituximab, together with other B-Cell-directed therapies currently under clinical development, is likely to provide an important new treatment option for a number of these Difficult-To-Treat Autoimmune Disorders.

Objective
To describe the unique case of a patient with Multiple Sclerosis (MS) and Anti-Myelin-Associated Glycoprotein (MAG) polyneuropathy who developed MS relapses after treatment with Rituximab.

Design & Setting
Case report. University of Genova, Department of NeuroSciences, Ophthalmology, and Genetics, Genova, Italy.

Patient A 59-year-old man with an 18-year history of MS presented with an unusually rapid progression of Paraparesis with HypoPallesthesia and Areflexia in 4 limbs.

NeuroPhysiological and Serological studies led to the diagnosis of Anti-MAG PolyNeuropathy.

CerebroSpinal Fluid analysis disclosed the loss of OligoClonal IgG Bands that were previously detected at MS onset. Intervention Rituximab was administered at a dosage of 375 mg/m(2)/wk for 4 weeks.

Result
The patient developed 2 CorticoSteroid-responsive MS relapses with improvement of the PolyNeuropathy.

Conclusion
Rituximab can be effective in Anti-MAG PolyNeuropathy but can possibly lead to unexpected consequences in individuals with MS.

Effects of B-Cell depletion by Rituximab, a MonoClonal AntiBody to CD20, were studied in patients with Relapsing MS that had not responded optimally to standard ImmunoModulatory Therapies.

Flow cytometry demonstrated reduced CerebroSpinal Fluid (CSF) B-Cells and T-Cells in most patients at 6 months post-treatment.

ELISAs demonstrated modest reductions in Serum AntiBodies to Myelin Oligodendrocyte Glycoprotein and Myelin Basic Protein in some subjects.

Interferon-beta Neutralizing AntiBodies were reduced in three subjects, but developed anew after treatment in three others, suggesting caution in considering Rituximab as a means to eliminate NABs.

In summary, Rituximab depleted B-Cells from CSF at 24 weeks after initial treatment, and this B-Cell depletion was associated with a reduction in CSF T-Cells as well.

Purpose
Rituximab, a humanized MonoClonal AntiBody directed to the CD20 Antigen present on B-Lymphocytes, could potentially abrogate the Humoral Immune Response to murine MonoClonal AntiBodies or ImmunoToxins by depleting AntiBody-producing B-Cells.

Experimental Design
A Phase II study of LMB-1, an ImmunoToxin targeting the Lewis Y tumor Antigen, in combination with Rituximab was conducted to test the hypothesis that Rituximab could abolish or diminish the development of human AntiBodies to LMB-1.

Five patients were treated in this study and received 375 mg/m(2) Rituximab on days 1 and 7 followed by 45 micro g/kg/day LMB-1 on days 10, 12, and 14. The development of human AntiBodies against LMB-1 was detected using a Serum neutralization and ELISA.

Results
All five of the patients had a total suppression of circulating CD20/CD19 B-Cell population before the administration of the first dose of the ImmunoToxin.

Before Rituximab treatment, the mean percentage of CD20/CD19-positive B-Cells in the five treated patients was 19.8% (range, 4.5-29.8%) of the total peripheral Lymphocytes.

After two doses of Rituximab, CD20/CD19-positive B-Lymphocytes constituted < /=0.1% of the total peripheral Lymphocytes.

Despite absent circulating AntiBody-producing B-Cells, before and during LMB-1 treatment, all of the patients developed neutralizing AntiBodies to the ImmunoToxin by day 21 of drug administration, which prevented retreatment.

Conclusions
Even though Rituximab caused complete depletion of circulating CD20/CD19-positive B-Cells, it had no effect in suppressing the human AntiBody response to LMB-1 and may be of limited utility in suppressing human AntiBody responses to other immunogenic proteins.

In a pilot study four patients with Systemic Lupus Erythematosus (SLE) and Autoimmune ThrombocytoPenia (ITP) were treated with Rituximab, a B-Cell depicting chimeric human/mouse Anti-CD20 AntiBody.

Treatment could be performed without serious side effects and resulted in a depletion of B-Cells from the peripheral blood for at least 4 months.

Examination of one patient three months after treatment revealed a complete depletion of B-Cells in the bone marrow and in the Spleen as well.

The time point when peripheral B-Cells returned into the normal range varied between 8 months and over one year and could be observed also in the Spleen.

The follow up over more than 12 months revealed no significant treatment-associated side effects.

Total ImmunoGlobulin and specific AntiBody levels did not change except for one SLE-patient receiving additional ImmunoSuppressive treatment including Cyclophosphamide because of progressive disease.

Clinical effectiveness cannot be judged by the small number of patients.

However, one SLE patient with refractory severe ThrombocytoPenia had a very Favourable response with stable platelet numbers over 100.000/microl now for more than 6 months and disappearance of Anti-DNA AntiBodies.

The treatment failure in another SLE patient could be due to the persistence of CD20-negative plasmablasts in peripheral blood which are not targeted by Anti-CD20 treatment.

Further studies are needed to assess the clinical benefit of B-Cell depletion in the treatment of autoimmune diseases.

Rituximab (IDEC-C2B8, Mabthera, Rituxan), a chimeric MonoClonal AntiBody against the B-Cell specific CD20-Antigen, has been demonstrated to be effective in the treatment of non-Hodgkin's B-Cell Lymphoma (B-NHL).

Previous in vitro studies have shown that direct Complement-Dependent Cytotoxicity (CDC), ADCC and Apoptosis are important in the Rituximab-induced killing of Lymphoma cells.

It is, however, unknown whether Rituximab penetrates the Blood-Brain Barrier.

Therefore, we studied Rituximab levels and Complement (C) activation in blood and CerebroSpinal Fluid (CSF) following intravenous Rituximab therapy in a patient with Relapsing Non-Hodgkin's Lymphoma with Central Nervous System (CNS) involvement.

Longitudinal samples from blood and CSF were taken at 13 time-points during the treatment period.

The results show that the C cascade becomes activated in blood during the first mAb infusion (C3a-desArg concentration rose from 55 to 138 microg/ml during the first 2 hours).

After the first infusion the proportions of Lymphocytes positive for the CD19- and CD20-Antigens in the peripheral blood were reduced from 41% and 35%, respectively, to a level of 2% (for both).

In CSF the Rituximab concentration increased after successive infusions, but remained below 0.55 microg/ml (compared to a Cmax of 400 microg/ml in peripheral blood).

Although a minor and delayed C activation response was seen in the CSF the treatment did not clear CD20-positive cells away from the CNS.

Thus, it appears that an intact Blood-Brain Barrier restricts the entry of Rituximab into the CNS. Possible options to circumvent this would be dose escalation or Intrathecal Rituximab treatment.