TNF-α-Blocking Agents

TNF-α-BLOCKING AGENTS

Cytokines play a central role in the immune response  and in rheumatoid arthritis. Although a wide range of cytokines are expressed in the joints of rheumatoid arthritis patients, TNF-α appears to be particularly important in the inflammatory process.

TNF-α affects cellular function via activation of specific membrane-bound TNF receptors (TNFR₁, TNFR₂). Five biologic DMARDs interfering with TNF-α have been approved for the treatment of rheumatoid arthritis and other rheumatic diseases (Figure 36–4).

Adalimumab

A. Mechanism of Action

Adalimumab is a fully human IgG₁ anti-TNF monoclonal anti-body. 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.

B. 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 rheumatoid arthritis is 40 mg every other week; increased responses may be evident with the higher weekly dosing regimen. In psoriasis, 80 mg is given at week 0, 40 mg at week 1, and then 40 mg every other week thereafter.

C. Indications

The compound is approved for rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, juvenile idiopathic arthritis, plaque psoriasis, and Crohn’s disease. It decreases the rate of formation of new erosions. It is effective both as monotherapy and in combina-tion with methotrexate and other DMARDs.

D. Adverse Effects

In common with the other TNF-α-blocking agents, the risk of bacterial infections and macrophage-dependent infection (including tuberculosis and other opportunistic infections) is increased, although it remains very low. Patients should be screened for latent or active tuberculosis before starting adalimumab or other TNF-α-blocking agents. There is no evidence of an increased incidence of solid malignancies. It is not clear if the incidence of lymphomas is increased by adalimumab. A low incidence of newly formed dsDNA antibodies and antinuclear antibodies (ANAs) has been documented when using adalimumab, but clinical lupus is extremely rare. Rare cases of leukopenia and vasculitis associated with adalimumab have been documented.

Certolizumab

A. Mechanism of Action

Certolizumab is a recombinant, humanized antibody Fab frag-ment 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 F_c region, found on a complete antibody, and does not fix complement or cause antibody-dependent cell-mediated cytotoxicity in vitro.

B. Pharmacokinetics

Certolizumab is given subcutaneously and has a half-life of 14 days. The clearance is decreased with decreasing body weight. Methotrexate does not alter the pharmacokinetics of certolizumab. However, methotrexate does decrease the appearance of anti-certolizumab antibodies. The usual dose for rheumatoid arthritis is 400 mg ini-tially and at weeks 2 and 4, followed by 200 mg every other week.

C. Indications

Certolizumab is indicated for the treatment of adults with moder-ately to severely active rheumatoid arthritis. It can be used as mono-therapy or in combination with nonbiologic DMARDs. Additionally, certolizumab is approved to reduce signs and symptoms and main-tain clinical response in adult patients with Crohn’s disease.

D. Adverse Effects

Consistent with other TNF-α blockers, the risk of serious infec-tions, including tuberculosis, fungal, and other opportunistic pathogens, is increased and patients should be monitored closely. Prior to initiation of treatment, testing for latent tuberculosis should be performed. The association of lymphoma and other tumors with TNF-α blockers as a class, of which certolizumab is a member, is not fully understood.

Etanercept

A. Mechanism of Action

Etanercept is a recombinant fusion protein consisting of two sol-uble TNF p75 receptor moieties linked to the F_c portion of human IgG₁ (Figure 36–4); it binds TNF-α molecules and also inhibits lymphotoxin-α.

B. Pharmacokinetics

Etanercept is given subcutaneously in a dosage of 25 mg twice weekly or 50 mg weekly. In psoriasis, 50 mg is given twice weekly for 12 weeks followed by 50 mg weekly. The drug is slowly absorbed, with peak concentration 72 hours after drug administration. Etanercept has a mean serum elimination half-life of 4.5 days. Fifty milligrams given once weekly gives the same area under the curve and minimum serum concentrations as 25 mg twice weekly.

C. Indications

Etanercept is approved for the treatment of rheumatoid arthritis, juvenile chronic arthritis, psoriasis, psoriatic arthritis, and ankylo-sing spondylitis. It can be used as monotherapy, although over 70% of patients taking etanercept are also using methotrexate. Etanercept decreases the rate of formation of new erosions relative to methotrexate alone. It is also being used in other rheumatic syndromes such as scleroderma, Wegener’s granulomatosis, giant cell arteritis, and sarcoidosis.

D. Adverse Effects

The incidence of bacterial infections is slightly increased, especially soft tissue infections and septic arthritis. Activation of latent tuber-culosis is lower with etanercept than with other TNF-blocking agents. Nevertheless, patients should be screened for latent or active tuberculosis before starting this medication. Similarly, opportunistic infections can rarely occur when using etanercept. The incidence of solid malignancies is not increased, but as with other TNF-blocking agents, one must be aware of possible lymphomas (although their incidence may not be increased compared with other DMARDs or active rheumatoid arthritis itself ). While positive ANAs and dsDNAs may be found in patients receiving this drug, these find-ings do not contraindicate continued use if clinical lupus symptoms do not occur. Injection site reactions occur in 20–40% of patients, although they rarely result in discontinuation of therapy. Anti-etanercept antibodies are present in up to 16% of treated patients, but they do not interfere with efficacy or predict toxicity.

Golimumab

A. Mechanism of Action

Golimumab is a human monoclonal antibody with a high affinity for soluble and membrane-bound TNF-α. Golimumab effectively neutralizes the inflammatory effects produced by TNF-α seen in diseases such as rheumatoid arthritis.

B. Pharmacokinetics

Golimumab is administered subcutaneously and has a half-life of approximately 14 days. Concomitant use with methotrexate showed increased serum levels of golimumab as well as a decrease in anti-golimumab antibodies. The recommended dose is 50 mg given every 4 weeks.

C. Indications

Golimumab, given with methotrexate, is indicated for the treat-ment of moderately to severely active rheumatoid arthritis in adult patients. It is also indicated for the treatment of psoriatic arthritis and ankylosing spondylitis.

D. Adverse Events

TNF-α blockers, including golimumab, increase the risk of seri-ous infections, including tuberculosis, fungal, and other opportu-nistic pathogens. Prior to initiation of treatment, testing for latent tuberculosis should be performed. As with other TNF-α-blocking agents, there is a potential association with lymphoma; there is no association with other solid tumors (except possibly non-melan-otic skin cancers).

Infliximab

A. Mechanism of Action

Infliximab (Figure 36–4) is a chimeric (25% mouse, 75% human) IgG₁ monoclonal antibody that binds with high affinity to soluble and possibly membrane-bound TNF-α. Its mechanism of action probably is the same as that of adalimumab.

B. Pharmacokinetics

Infliximab is given as an intravenous infusion with “induction” at 0, 2, and 6 weeks and maintenance every 8 weeks thereafter. Dosing is 3–10 mg/kg, although the usual dose is 3–5 mg/kg every 8 weeks. There is a relationship between serum concentra-tion and effect, although individual clearances vary markedly. The terminal half-life is 9–12 days without accumulation after repeated dosing at the recommended interval of 8 weeks. After intermittent therapy, infliximab elicits human antichimeric antibodies in up to 62% of patients. Concurrent therapy with methotrexate markedly decreases the prevalence of human antichimeric antibodies.

C. Indications

Infliximab is approved for use in rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, and Crohn’s disease. It is being used in other diseases, including psoriasis, ulcerative colitis, juvenile chronic arthritis, Wegener’s granulomatosis, giant cell arteritis, and sarcoidosis. In rheumatoid arthritis, a regimen of infliximab plus methotrexate decreases the rate of formation of new erosions more than methotrexate alone over 12–24 months. Although it is recom-mended that methotrexate be used in conjunction with infliximab, a number of other DMARDs, including antimalarials, azathioprine, leflunomide, and cyclosporine, can be used as background therapy for this drug. Infliximab is also used as monotherapy, although this is neither approved by regulatory agencies nor advisable.

D. Adverse Effects

Like other TNF-α-blocking agents, infliximab is associated with an increased incidence of bacterial infections, including upper respiratory tract infections. As a potent macrophage inhibitor, infliximab can be associated with activation of latent tuberculosis, and patients should be screened for latent or active tuberculosis before starting therapy. Other infections have been documented, though rarely. There is no evidence of an increased incidence of solid malignancies and it is not clear whether the incidence of lymphoma is increased with infliximab. Because rare demyelinat-ing syndromes have been reported, patients with multiple sclerosis or neuro-uveitis should not use infliximab. Rare cases of leukope-nia, hepatitis, activation of hepatitis B, and vasculitis have been documented. The incidence of positive ANA and dsDNA anti-bodies is increased, although clinical lupus erythematosus remains an extremely rare occurrence and the presence of ANA and dsDNA does not contraindicate the use of infliximab. Infusion site reactions correlate with anti-infliximab antibodies. These reactions occur in approximately 3–11% of patients, and the com-bined use of antihistamines and H₂-blocking agents apparently prevents some of these reactions.