Mechanism of Action: Tocilizumab, a newer biologic humanized antibody, binds to soluble and membrane-bound IL-6 receptors, and inhibits the IL-6-mediated signaling via these receptors. IL-6 is a proinflammatory cytokine produced by different cell types including T cells, B cells, monocytes, fibroblasts, and synovial and endothelial cells. IL-6 is involved in a variety of physiologic processes such as T-cell activation, hepatic acute-phase protein synthesis, and stimulation of the inflammatory processes involved in diseases such as RA and systemic sclerosis (SSc). In a phase 4 superiority study, tocilizumab monotherapy was superior to adalimumab monotherapy for reduction of signs and symptoms of rheumatoid arthritis in patients with incomplete response to MTX.
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Pharmacokinetics: The half-life of tocilizumab is dose-dependent, approximately 11 days for the 4-mg/kg dose and 13 days for the 8-mg/kg dose. IL-6 can suppress several CYP450 isoenzymes; thus, inhibiting IL-6 may restore CYP450 activities to higher levels. This may be clinically relevant for drugs that are CYP450 substrates and have a narrow therapeutic window (eg, cyclosporine or warfarin), and dosage adjustment of these medications may be needed.
Tocilizumab can be used in combination with nonbiologic DMARDs or as monotherapy. In the United States the recommended starting dose for RA is 4 mg/kg intravenously every 4 weeks followed by an increase to 8 mg/kg (not exceeding 800 mg/infusion) dependent on clinical response.
In Europe, the starting dose of tocilizumab is 8 mg/kg up to 800 mg. Tocilizumab dosage in SJIA or PJIA follows an algorithm that accounts for body weight. Additionally, dosage modifications are recommended on the basis of certain laboratory changes such as elevated liver enzymes, neutropenia, and thrombocytopenia.
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Indications: Tocilizumab is a bDMARD indicated for adult patients with moderately to severely active RA who have had an inadequate response to one or more DMARDs. It is also indicated in patients who are older than 2 years with active SJIA or active PJIA. A recent study showed that it is slightly more effective than adalimumab. There is an ongoing phase 3 study to test its use in SSc.
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Adverse Effects: Serious infections including tuberculosis, fungal, viral, and other opportunistic infections have occurred. Screening for tuberculosis should be done prior to beginning tocilizumab. The most common adverse reactions are upper respiratory tract infections, headache, hypertension, and elevated liver enzymes.
Neutropenia and reduction in platelet counts occur occasionally, and lipids (eg, cholesterol, triglycerides, LDL, and HDL) should be monitored. GI perforation has been reported when using tocilizumab in patients with diverticulitis and in those using corticosteroids, although it is not clear that this adverse effect is more common than with TNF-α–blocking agents. Demyelinating disorders including multiple sclerosis are rarely associated with tocilizumab use. Fewer than 1% of the patients taking tocilizumab develop anaphylactic reaction. Anti-tocilizumab antibodies develop in 2% of the patients, and these can be associated with hypersensitivity reactions requiring discontinuation.
Cytokines play a central role in the immune response (see Chapter 55) and in RA. Although a wide range of cytokines are expressed in the joints of RA patients, TNF-α appears to be particularly important in the inflammatory process.