Rituximab - Arthritides - Monoclonal Antibodies in Anti inflammatory Therapy

Rituximab

Rituximab in combination with methotrexate is indicated for the treatment of adult patients with moderate to severe rheumatoid arthritis who have had an inadequate response to one or more TNF antagonist therapies. Rituximab is a chimeric murine/human monoclonal antibody directed against the CD20 anti-gen found on the surface of B-lymphocytes. The antibody is an IgG₁ immunoglobulin containing murine light- and heavy-chain variable region se-quences and human constant region sequences . Rituximab is given as two 1000 mg IV infusions separated by 2 weeks in combination with methotrexate. Glucocorticoids administered as methyl-prednisolone 100 mg IV or its equivalent 30 minutes prior to each infusion are recommended to reduce the incidence and severity of infusion reactions. After administration of the two 1000 mg doses of rituximab, the mean C_max was 370 mg/mL. Mean volume of distribution was 4.3 L, mean systemic clearance was 0.01 L/h and mean terminal elimination half-life after the second dose was 19 days. Female patients with RA had a 37% lower clearance of rituximab than male patients, but this does not require dose adjustment.

Treatment of RA patients with rituximab results in nearly complete depletion of circulating B-cells within 2 weeks after receiving the first dose (Marin and Chan, 2006; Silverman, 2006). In clinical trials, the duration of B-cell depletion lasted for at least 6 months in the majority of patients with a gradual recovery thereafter. In a subset of patients (4%), B-cell depletion lasted for significantly longer. During treatment with rituximab, IgM, IgG, and IgA levels were reduced with the largest change in IgM. Mean immunoglobu-lin levels remained in the normal range with between 1% and 7% of subjects having individual values that fell below the lower limit of normal.

As with other RA treatments, rituximab treat-ment resulted in decreases in C-reactive protein, rheumatoid factor, and IL6. Additionally, reductions in serum amyloid protein (SAA), S100 A8/S100 A9 heterodimer complex (S100 A8/9) and anti-citrulli-nated peptide (anti-CCP). Efficacy of rituximab plus methotrexate at week 24 post first dose was signifi-cantly improved over placebo plus methotrexate, with 51% vs. 18% ACR20, 27% vs. 5% ACR50 and 12% vs. 1% ACR70. Development of anti-rituximab antibodies occurred in 5% of subjects (package insert for Rituxan, 2006). Use of corticosteroids to reduce the occurrence and severity of infusion reactions is recommended.