TNF-α affects cellular function via activation of specific membrane-bound TNF receptors (TNFR1, TNFR2). Five “legacy” bDMARDs interfering with TNF-α have been approved for the treatment of RA and other rheumatic diseases (Figure 36–4). Biosimilar biologics (bsDMARDs) with lower costs are available in some countries and are being tested in other countries. Thus far, the efficacy, toxicity, and immunogenicity of the biosimilars are equivalent to the legacy compounds. These drugs have many adverse effects in common (see below).
1. Mechanism of Action: Adalimumab is a fully human IgG1 anti-TNF monoclonal antibody. This compound complexes with soluble TNF-α and prevents its interaction with p55 and p75 cell surface receptors. This results in down-regulation of macrophage and T-cell function.
FC region of human IgG1
FC region of human IgG1CH3
Extracellular domain VL of human p75 receptor
CH2 FC region of human IgG1 CH3
FIGURE 36–4 Structures of TNF-α antagonists used in rheumatoid arthritis. CH, constant heavy chain; CL, constant light chain; Fc, complex immunoglobulin region; VH, variable heavy chain; VL, variable light chain. Red regions, human derived; blue regions, mouse derived; green regions, polyethylene glycol (PEG).
2. Pharmacokinetics: Adalimumab is given subcutaneously and has a half-life of 10–20 days. Its clearance is decreased by more than 40% in the presence of methotrexate, and the formation of human anti-monoclonal antibody is decreased when methotrexate is given at the same time. The usual dose in RA is 40 mg every other week, but dosing is frequently increased to 40 mg weekly. In psoriasis, 80 mg is given at week 0, 40 mg at week 1, and then 40 mg every other week thereafter. The initial dose in inflammatory bowel disease is higher; patients receive 160 mg at week 0, and 80 mg 2 weeks later, followed by a 40-mg maintenance dose every other week. Patients with ulcerative colitis should continue maintenance treatment beyond 8 weeks if they show evidence of remission by that time. Adalimumab dose depends on the body weight in patients with JIA: 20 mg every other week for patients weighing 15–30 kg, and 40 mg every other week in patients weighing 30 kg or more.
3. Indications: The compound is approved for RA, AS, PsA, JIA, plaque psoriasis, Crohn’s disease, and ulcerative colitis. It decreases the rate of formation of new erosions. It is effective both as monotherapy and in combination with methotrexate and other nonbiologic csDMARDs. Based only on case reports and case series, adalimumab has also been found to be effective in the treatment of Behçet’s disease, sarcoidosis, and notably, noninfectious uveitis.
1. Mechanism of Action: Certolizumab is a recombinant, humanized antibody Fab fragment conjugated to a polyethylene glycol (PEG) with specificity for human TNF-α. Certolizumab neutralizes membrane-bound and soluble TNF-α in a dose-dependent manner. Additionally, certolizumab does not contain an Fc region, found on a complete antibody, and does not fix complement or cause antibody-dependent cell-mediated cytotoxicity in vitro.
2.