In general, rituximab is well tolerated in both patients with malignancies and those with autoimmune bullous disorders. Except for two reports of serious infections including septic arthritis, Pneumocystis carinii pneumonia and pneumonia after treatment of pemphigus patients with rituximab, the most common adverse events are infusion-related events occurring during or shortly after the first infusion. Larger studies with lymphoma patients demonstrated that about 95% of the infusion-related symptoms such as chills, fever, headache, rhinitis, pruritus or vasodilatation were mild to moderate. Most of these symptoms could be avoided by pre-treatment with antihistamines, antipyretics and steroids. Another report showed that a severe cytokine release syndrome more frequently occurred in lymphoma patients with a higher tumor burden in their peripheral blood which might be correlated with increased serum levels of tumor necrosis factor-alpha (TNF-a) and interleukin 6 (IL-6) after infusion of ritu-ximab. At present, severe cytokine release syndromes have not yet been reported in patients with bullous autoimmune disorders. Hematological toxicity has been reported in about 10% of patients including a temporary reduction of platelets or neutrophils. Despite the depletion of B cells for several months the risk for infectious diseases does not seem to be significantly higher in patients treated with rituximab. A recent study in RA patients demonstrated a significant decrease of serum rheumatoid factor (IgM, IgG and IgA isotypes) over several months, whereas total immuno-globulin levels decreased by only 25 % for IgG and IgA and by 43 % for IgM and the titers for pneumococcal polysaccharide-reactive antibodies remained unchanged. Another recent report showed unaffected levels of anti-tetanus toxoid antibodies in patients treated with rituximab. These observations help to explain why, despite complete depletion of B cells for several months, the risk for secondary infections does not seem to be significantly higher in patients treated with rituximab. As rituximab is a chimeric antibody with reduced immunogenicity, the presence of human anti-chimeric antibodies (HACA) is a rare event which has been reported in less than 1 % of treated patients with NHL. In patients with HACA impairing the function of rituximab, a newly designed humanized monoclonal anti-CD20 antibody (hCD20) might be effective.
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