Rituximab and arthritis

by Nathan Wei, MD, FACP, FACR

Nathan Wei is a nationally known board-certified rheumatologist and author of the Second Opinion Arthritis Treatment Kit. It's available exclusively at this website... not available in stores.

Click here: Second Opinion Arthritis Treatment Kit

From the makers of Rituxan

Rituximab (Rituxan) 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 (based on cDNA analysis) and has an approximate molecular weight of 145 kD. Rituximab has a binding affinity for the CD20 antigen of approximately 8.0 nM.

The chimeric anti-CD20 antibody is produced by mammalian cell (Chinese Hamster Ovary) suspension culture in a nutrient medium containing the antibiotic gentamicin. Gentamicin is not detectable in the final product. The anti-CD20 antibody is purified by affinity and ion exchange chromatography. The purification process includes specific viral inactivation and removal procedures. Rituximab drug product is manufactured from bulk drug substance manufactured by Genentech, Inc. (US License No. 1048).

Rituxan is a sterile, clear, colorless, preservative free liquid concentrate for intravenous (IV) administration. Rituxan is supplied at a concentration of 10 mg/mL in either 100 mg (10 mL) or 500 mg (50 mL) single use vials. The product is formulated for IV administration in 9.0 mg/mL sodium chloride, 7.35 mg/mL sodium citrate dihydrate, 0.7 mg/mL polysorbate 80, and Sterile Water for Injection. The pH is adjusted to 6.5.

Rituximab binds specifically to the antigen CD20 (human B lymphocyte restricted differentiation antigen, Bp35), a hydrophobic transmembrane protein with a molecular weight of approximately 35 kD located on pre B and mature B lymphocytes. The antigen is also expressed on > 90% of B cell non Hodgkin's lymphomas (NHL), but is not found on hematopoietic stem cells, pro B cells, normal plasma cells or other normal tissues. CD20 regulates an early step(s) in the activation process for cell cycle initiation and differentiation, and possibly functions as a calcium ion channel. CD20 is not shed from the cell surface and does not internalize upon antibody binding. Free CD20 antigen is not found in the circulation.

Promising results from the latest research involving rituximab have been published in The New England Journal of Medicine. The international study is led by Jonathan C.W. Edwards, M.D., renowned for his work on the B-cell depletion therapy, at the University College London.

Rituximab, also known as Rituxan, works by targeting B-cells. The optimism surrounding this treatment is based on its ability to precisely target a specific type of immune cell, perhaps paving the way for other "smart" treatments for arthritis and related diseases, as well as other diseases.

Arthritis medications, until now, have treated only the symptoms or modified the disease process with a more broad, less specific approach. The lack of specificity can result in killing healthy cells along with diseased cells.

Rheumatoid arthritis is an autoimmune disease in which antibodies are mistakenly turned against the body's own joint linings, causing the joints to become swollen, inflamed, and painful. The inflammatory process leads to the destruction and deformity of affected joints. B-cells manufacture the antibodies which go haywire in autoimmune disease.

The randomized, double-blind, controlled study involved 161 patients with active rheumatoid arthritis, despite prior treatment with methotrexate. The study participants were randomly assigned one of the following four treatments:

-Oral methotrexate (up to 10 mg per week) - serving as the control group
-Rituximab (1000 mg on days 1 and 15)
-Rituximab plus cyclophosphamide (750 mg on days 3 and 17)
-Rituximab plus methotrexate

The responses, defined by the criteria of the American College of Rheumatology and the European League against Rheumatism, ACR and EULAR respectively, were analyzed at week 24 and 48. At week 24, the percentage of patients achieving a 50 percent improvement in symptoms according to ACR criteria (known as ACR50 response) was:

-43% of patients taking rituximab-methotrexate combination
-41% of patients taking rituximab-cyclophosphamide combination
-33% of patients taking rituximab alone
-13% of patients taking methotrexate alone

In all groups treated with rituximab an even higher percentage achieved 20 percent improvement of symptoms. At week 24, analysis revealed that all ACR responses (20, 50, 70) were maintained in the rituximab-methotrexate group.

Reportedly the majority of adverse events occurred with the first rituximab infusion. At 24 weeks, serious infections occurred in 2.5 percent of the control group and in 3.3 percent of the rituximab groups. One study participant on rituximab died of pneumonia though it was not concluded that the drug was responsible. Chest infection was noted as a possible danger.

It was concluded that in patients with active rheumatoid arthritis despite treatment with methotrexate, a single course of two infusions of rituximab, alone or in combination with methotrexate or cyclophosphamide, provided significant improvement in symptoms at both 24 and 48 weeks. It also was concluded and reported that more testing must be done before widespread use of rituximab for rheumatoid arthritis is approved. Other drugs which target B-cells are also being developed and are in clinical trials.

Rituximab (Rituxan) was approved by the FDA for use in rheumatoid arthritis in February 2006.

NEJM (Volume 350:2572-2581, Number 25)
Associated Press, Drug Appears Effective Against Arthritis

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