Page 1237 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHaPTEr 89 Biological Modifiers of Inflammatory Diseases 1199

TABLE 89.2 recombinant Inhibitors of Pro-Inflammatory Cytokines
Molecule Construct Half-Life Dosing (Maintenance)
Etanercept sTNFR:Fc 3–4 days 50 mg subcutaneously (SC) once a week or 25 mg SC 2x/week
Infliximab aTNF-α (chimeric IgG1κ) 7–12 days 3–10 mg/kg intravenously (IV) q4–8 weeks
Adalimumab aTNF-α (human IgG1κ) 10–20 days 10–40 mg SC q1–2 weeks
Certolizumab aTNF-α (humanized Fab’)-PEG 14 days 200-400 mg SC q2–4 weeks
Golimumab aTNF-α (human IgG1κ) 14 days 50-100 mg SC every 4 weeks 2 mg/kg IV every 8 weeks
Anakinra sIL-1Ra 4–6 hours 1–8 mg/kg SC daily (max 200 mg/day)
Rilonacept IL-1R1:Fc(IgG1):IL-1RAcP 8–9 days 2.2 mg/kg (max 160 mg) SC per week
Canakinumab aIL-1β (human IgG1κ) 26 days 2–8 mg/kg SC (max 600 mg) SC every 8 weeks
Tocilizumab aIL-6R (humanized IgG1κ) 13 days 4-12 mg/kg (max 800 mg) IV every 2–4 weeks 160 mg SC every 1–2 weeks
Ustekinumab aIL-12/23 p40 (human IgG1κ) 15–32 days 0.75 mg/kg (pediatric) or 45–90 mg SC every 12 weeks
Secukinumab aIL-17A (human IgG1κ) 22–31 days 150-300 mg SC every 4 weeks
Ixekizumab aIL-17A (humanized IgG4κ) 13 days 80 mg SC every 2–4 weeks

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consideration of potential clinical relevance in patients at risk and are approved for treatment of these disorders. Pyoderma
for SLE or related autoimmune syndromes (see below). syndromes and the oral and genital lesions of Behçet disease are
Infliximab, adalimumab, and golimumab are monoclonal reported to respond favorably to TNF-α inhibition therapy. 17,18
antibody (mAb) reagents with comparable avidity for both soluble Although very well tolerated as a class, TNF-α inhibitors may
and cell-bound TNF-α but differ with regard to the derivation impair innate host defenses, resulting in delay of resolution of
of the antigen-binding sequence and half-life. Infliximab is a intercurrent infections. TNF-α inhibitors are associated with
chimeric antibody with a murine-derived variable-region TNF- reactivation of tuberculosis and fungal infections, including
binding domain. Adalimumab and golimumab are both human histoplasmosis and coccidioidomycosis, and viral infections such
sequence–derived mAb reagents. Certolizumab pegol is a construct as hepatitis B. 19,20 In all circumstances of intercurrent infection,
consisting of recombinant human sequence–derived F(ab)’ the standard recommendation is for treatment with TNF-α
anti–TNF-α covalently liked to 40-kilodalton (kDa) polyethylene inhibitors to be withheld until the infection has resolved. No
glycol. The pegylated construct enhances the half-life of the complications have been reported regarding their use in patients
reagent, and absence of the Fc- and complement-binding domains with intercurrent hepatitis C infection or in patients with human
renders certolizumab less likely to engender local injection site immunodeficiency virus (HIV) infection that is well controlled
reactions and precludes placental crossing of certolizumab into with highly active antiretroviral therapy (HAART).
the fetal circulation when administered to pregnant women. In the context of its role in promoting cell apoptosis, TNF-α
In cytokine profile studies of joint tissues and synovial fluids constitutes a component of the host defense against tumor cell
derived from patients with RA, TNF-α is consistently among survival and growth. As such, the incidence and prevalence of
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the highest expressed inflammatory cytokines. All five TNF-α cancer in populations treated with TNF-α inhibitors has been
inhibitors have been shown to decrease the signs and symptoms emphasized in pharmacovigilance programs surrounding the
of disease activity and to inhibit the progression of structural use of this class of therapeutic agents. Lymphoma has been
damage in RA, with greatest benefits and probability of disease reported in patients treated with TNF-α inhibitors, with most
remission seen among patients with early RA. Inhibition of reported cases occurring in the context of treatment for RA.
radiographic progression of disease, as measured by joint space However, the relative risk for lymphoma in patients with RA in
narrowing and osseous erosions at joint margins, can be dissoci- the pre–biologicals era approximates 3.0, and the prevalence of
ated from clinical efficacy as measured by composite scoring lymphoma in patients with RA exposed to TNF-α inhibitors
measures, such as the American College of Rheumatology has not been shown to exceed the otherwise expected prevalence
20%/50%/70% improvement criteria or the Disease Activity Score among patients with RA. Among patients with RA, IBD, or
(DAS)-28. 12 psoriasis, the risk of cancer has not been shown to be increased
21
TNF-α levels are also notably increased in biopsy samples of in the context of treatment with TNF-α inhibitors. Although
skin and synovial tissues from patients with psoriasis and psoriatic it is often recommended that TNF-α inhibitor therapy be dis-
arthritis, and the TNF-α inhibitors have been shown to be highly continued in the setting of a newly diagnosed cancer and that
effective in suppressing manifestations of plaque psoriasis as initiation of such therapy be avoided in patients with known
well as articular disease in psoriatic arthritis. 13,14 Improvements malignancy, there are no clinical data to confirm whether
in joint symptoms (axial and peripheral) and uveitis manifesta- continued treatment with TNF-α inhibitors impairs therapeutic
tions are observed in patients with other spondyloarthropathies, response to cancer therapy.
including ankylosing spondylitis, during treatment with TNF-α The role of TNF-α inhibition in facilitating apoptosis is also
inhibitors; however, use of these agents has not been shown to of relevance with regard to the development or potentiation of
delay fusion of axial joints in patients with spondylitis. Insights autoimmunity. Although rare, the development of psoriasiform
from rodent models and the known inhibitory effect of TNF-α skin eruptions, demyelinating syndromes, and drug-induced
on Smad pathway–mediated bone formation by osteoblasts suggest SLE are well documented occurrences in patients treated with
that TNF inhibition may, in fact, promote ossification at sights TNF-α inhibitors. 22-24 All of the anti–TNF-α reagents may
of inflammation and increased bone turnover. 15 attenuate TNF-α–mediated apoptosis of autoreactive T cells.
mAb inhibitors of TNF-α as well as certolizumab (but not Infliximab, adalimumab, and golimumab may induce the release
etanercept) have been shown beneficial in the management of of apoptotic products in the context of antibody-dependent
intestinal inflammation in patients with Crohn disease or UC cellular cytotoxicity (ADCC) of cells bearing surface TNF-α,