Rituximab (Rituxan) Archive
Rituximab Efficiently Depletes Increased CD20-Expressing T Cells in Multiple Sclerosis Patients.
Palanichamy A, Jahn S, Nickles D, Derstine M, Abounasr A, Hauser SL, Baranzini SE, Leppert D, von Büdingen HC.
In multiple sclerosis (MS), B cell-depleting therapy using monoclonal anti-CD20 Abs, including rituximab (RTX) and ocrelizumab, effectively reduces disease activity.
Based on indirect evidence, it is generally believed that elimination of the Ag-presenting capabilities and Ag nonspecific immune functions of B cells underlie the therapeutic efficacy.
However, a small subset of T lymphocytes (T cells) was shown to also express CD20, but controversy prevails surrounding the true existence of this T cell subpopulation. Using single-cell imaging flow cytometry and expression profiling of sorted lymphocyte subsets, we unequivocally demonstrate the existence of CD3+CD20dim T cells.
We show that in MS patients, increased levels of CD3+CD20dim T cells are effectively depleted by RTX. The pathological relevance of this T cell subset in MS remains to be determined.
However, given their potential proinflammatory functionality, depletion of CD20-expressing T cells may also contribute to the therapeutic effect of RTX and other mAbs targeting CD20.
Sources: J Immunol. 2014 Jun 13. pii: 1400118. [Epub ahead of print] & Pubmed PMID: 24928997 (16/06/14)
There are currently no effective treatments for people with secondary-progressive MS who do not experience relapses or who do not have “active” lesions on MRI, however researchers at the National Institutes of Health in Bethesda, Maryland are evaluating the safety and effectiveness of Rituximab (trade names Rituxan and MabThera) – a new experimental drug for treating MS. In this study, Rituximab be delivered intravenously and directly into the cerebrospinal fluid by lumbar puncture of about 80 people with secondary-progressive Multiple Sclerosis. The study is funded by the National Institute of Neurological Disorders and Stroke.
Technically, Rituximab is a genetically engineered chimeric murine/human monoclonal antibody directed against the CD20 antigen found on the surface of normal and malignant B lymphocytes. The antibody is an IgG1 kappa immunoglobulin containing murine light- and heavy-chain variable region sequences and human constant region sequences. Rituximab is composed of two heavy chains of 451 amino acids and two light chains of 213 amino acids.
Since MS is an inflammatory disorder that progressively weakens and destroys the pathways of the nervous system. There are currently no effective treatments for people with secondary-progressive MS who do not experience relapses or who do not have “active” lesions identified via MRI.
Under normal conditions, the blood brain barrier separates the brain and spinal cord from the bloodstream and limits what can gain access to the nervous system. In active stages of MS, inflammation in the brain and spinal cord leads to breakdown of this barrier. This breakdown allows MS medications to reach the brain and spinal cord without being screened out. In people with secondary-progressive MS who do not have “active” disease, the blood-brain barrier is intact. Drugs that could stop the inflammation simply cannot reach the areas of the brain and spinal cord where they are needed.
The NIH researchers want to understand whether Rituximab, which is already used to treat rheumatoid arthritis (another autoimmune disease) and some types of cancer, is able to slow down or stop progression of secondary-progressive MS. In people with earlier, active disease, this drug can stop inflammation in the brain. However, intravenous Rituximab did not help people with primary-progressive MS (typical, as forenoted), possibly because the drug could not get through the intact blood-brain barrier. In this current trial, to ensure that the Rituximab will reach the brain and spinal cord in people with secondary-progressive MS, participants will receive it intravenously and by injection through a lumbar puncture into the cerebrospinal fluid (“spinal tap”).
Participants in the NIH study will be between 18 and 65 years of age, diagnosed with secondary-progressive MS, and able to walk for 25 feet with assistance. The study will last three years and will be divided into two parts. The first part is a 1-year baseline period during which participants will not be treated. The second part is a 2-year treatment period during which there will be a total of 3 infusions with either Rituximab or placebo. Participants will have periodic follow-up clinic visits that will include brain magnetic resonance imaging (MRI) scans, blood tests, and other evaluations. There will be approximately 7 outpatient clinic visits. Outpatient clinic visits will last 2-5 hours. The three infusion visits will each require a 2-3 day admission to the NIH Clinical Center.
The study’s primary outcome objective is to determine whether Rituximab can decrease brain atrophy – loss of brain tissue volume – significantly more than a placebo. There is no cost to take part in this study. Reimbursement for travel, lodging, and food will be offered. People participating in the study will not receive payment.
Source: BioNews Texas (27/01/14)
Third PML case reported with Rituximab(11/07/10)
A case of progressive multifocal leukoencephalopathy (PML) has been reported in a rheumatoid arthritis patient taking rituximab (Rituxan) who had not previously received anti- tumor necrosis factor therapy, according to the FDA and the drug’s manufacturer.
The case is the third seen with rituximab in rheumatoid arthritis, according to a “Dear Healthcare Professional” letter issued by Genentech. The previous two were seen in patients who had received anti-TNF drugs earlier.
PML causes inflammation in the brain, which has been fatal in about half of patients. It is caused by reactivation of latent JC virus infection, presumably a result of immune suppression.
Other biologic drugs targeting immune system components have been linked to PML, as well, including natalizumab (Tysabri) and efalizumab (Raptiva).
Both those drugs were removed from the U.S. market after cases of PML appeared, although natalizumab was later reintroduced with a strict risk evaluation and mitigation strategy. (See Raptiva Yanked from U.S. Market and Tysabri (natalizumab) Allowed Back to Market with Restrictions)
“Physicians should consider PML in any patient being treated with Rituxan who presents with new onset neurologic manifestations,” Genentech’s letter said. “Consultation with a neurologist, brain MRI, and lumbar puncture should be considered as clinically indicated.”
The most recent case involved a 73-year-old woman who had received two doses of rituximab in February 2009. Symptoms developed four to six months later, Genentech said.
The woman had also taken leflunomide, hydroxychloroquine, and prednisone — but not anti-TNF drugs such as infliximab (Remicade) or Etanercept (Enbrel).
The letter did not indicate whether she had survived.
Genentech said about 100,000 rheumatoid arthritis patients have received rituximab, apparently putting the risk much lower than with natalizumab.
The risk of PML with natalizumab has been estimated at about one case per 1,000 patients receiving the drug for two years.
Source: Discuss Pharmacy Copyright 2010 Discuss Pharmacy (11/07/10)
OBJECTIVE: B cells and the humoral immune system have been implicated in the pathogenesis of multiple sclerosis (MS). This study sought to evaluate the efficacy, safety, and tolerability of add-on therapy with rituximab, a monoclonal antibody that depletes circulating B cells, in subjects with relapsing MS with breakthrough disease defined by clinical and MRI activity (Class III evidence).
METHODS: Thirty subjects with a relapse within the past 18 months despite use of an injectable disease-modifying agent, and with at least 1 gadolinium-enhancing (GdE) lesion on any of 3 pretreatment MRIs, received rituximab administered at 375 mg/m(2) weekly x 4 doses. Three monthly posttreatment brain MRI scans were obtained beginning 12 weeks after the first infusion. Multiple Sclerosis Functional Composite (MSFC) and Expanded Disability Status Scale (EDSS) were obtained at baseline and throughout the post-treatment follow-up.
RESULTS: GdE lesions were reduced after treatment with rituximab, with 74% of posttreatment MRI scans being free of GdE activity compared with 26% free of GdE activity at baseline (p < 0.0001). Median GdE lesions were reduced from 1.0 to 0, and mean number was reduced from 2.81 per month to 0.33 after treatment (88% reduction). MSFC improved as well (p = 0.02). EDSS remained stable.
CONCLUSION: Rituximab add-on therapy was effective based upon blinded radiologic endpoints in this phase II study. In combination with standard injectable therapies, rituximab was well-tolerated with no serious adverse events. B-cell-modulating therapy remains a potential option for treatment of patients with relapsing MS with an inadequate response to standard injectable therapies.
CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that add-on rituximab reduces gadolinium-enhancing brain lesions in multiple sclerosis.
Source: Neurology. 2010 Jun 8;74(23):1860-7. & Pubmed PMID: 20530322 (08/06/10)
AAN - Rituximab may be an effective treatment for secondary progressive Multiple Sclerosis(19/04/10)
Targeting B cells implicated in progressive multiple sclerosis with rituximab (Rituxan) therapy might help patients diagnosed with the disease, according to data from a small study reported here.
"This study shows that rituximab could be an effective treatment in a subgroup of patients with secondary progressive multiple sclerosis," Carolina Ionete, MD, of the University of Massachusetts Medical School in Worcester, wrote in a poster presentation abstract for the annual meeting of the American Academy of Neurology.
However, Ionete said that before clinicians begin using the monoclonal antibody in patients with multiple sclerosis, a larger scale study will be required.
Her study scrutinized outcomes in 10 patients who had documented diagnoses of secondary progressive multiple sclerosis without relapses.
Rituximab targets CD20, a protein expressed on most B cells -- believed to be part of the cascade of molecular events involved in the inappropriate autoimmune functioning that is the hallmark of multiple sclerosis.
Ionete and colleagues determined to evaluate the clinical response to rituximab in the treatment of secondary progressive multiple sclerosis in a retrospective study that used chart reviews to identify patients who received rituximab for treatment of secondary progressive multiple sclerosis at the UMass medical center.
All of the patients were treated with intravenous rituximab 1 gram, repeated in two weeks.
Five patients received a second cycle of rituximab at six months, and five patients did not receive the second cycle. Of the latter group, two had adverse reactions, two did not respond to treatment, and one has still had less than one year of follow-up.
Ionete reviewed the patients' neurological examination, Expanded Disability Status Scale (EDSS), 25-foot walk, and modified nine-hole peg test which was performed at baseline, and then at three months, six months and 12 months.
Magnetic resonance imaging scans which recorded new or enlarged T2 lesions and new T1 gadolinium enhancing lesions were collected at baseline and at 12 months.
The patients who received the second cycle of rituximab at six months showed mean extended disability status scale improvement. Their mean baseline scores were 5.4 on the EDSS, and those scores improved to 4.4 at 12 months (P=0.0032).
Ionete also observed improvement in times for the 25-foot walk at month 12 in all five patients who received the second cycle at six months. Four out of five patients showed improvement in the modified nine-hole peg test. The mean time to perform the test at baseline was 17.14 sec, which decreased to 13.94 sec at 12 months.
The researchers did not see changes in the magnetic resonance imaging activity over the 12 month period in any of the patients.
Ionete disclosed financial relationships with Bayer Healthcare, Teva Neuroscience, EMD Serono and Biogen Idec.
Other authors disclosed financial relationships with other industry entities including Berlex and Genentech.
Primary source: American Academy of Neurology
Source reference: Ionete C, et al "Rituximab in secondary progressive multiple sclerosis -- one year follow up" AAN 2010; Abstract P02.147.
Source: Medpage Today © 2004-2010 MedPage Today, LLC(19/04/10)