DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

1018 cyclosporine and prednisone. In one randomized trial, basiliximab
was found to be safe and effective when used in a maintenance regimen
consisting of cyclosporine, MMF, and prednisone (Lawen
et al., 2000).
There presently is no marker or test to monitor the effectiveness
of anti–IL-2R therapy. Saturation of an α chain on circulating
lymphocytes during anti–IL-2R mAb therapy does not predict rejection.
The duration of IL-2R blockade by basiliximab was similar in
patients with or without acute rejection episodes (34 ± 14 days versus
37 ± 14 days, mean ± SD) (Kovarik et al., 1999). In another
daclizumab trial, patients with acute rejection were found to have
circulating and intragraft lymphocytes with saturated IL-2R
(Vincenti et al., 2001). A possible explanation is that those patients
who reject despite anti–IL-2R blockade do so through a mechanism
that bypasses the IL-2 pathway due to cytokine–cytokine receptor
redundancy (i.e., IL-7, IL-15).
Toxicity. No cytokine-release syndrome has been observed with
these antibodies, but anaphylactic reactions can occur. Although lymphoproliferative
disorders and opportunistic infections may occur, as
with the depleting antilymphocyte agents, the incidence ascribed to
anti-CD25 treatment appears remarkably low. No significant drug
interactions with anti–IL-2-receptor antibodies have been described
(Hong and Kahan, 1999).
SECTION IV
INFLAMMATION, IMMUNOMODULATION, AND HEMATOPOIESIS
Alemtuzumab. Alemtuzumab (CAMPATH) is a humanized
mAb that has been approved for use in chronic
lymphocytic leukemia. The antibody targets CD52, a
glycoprotein expressed on lymphocytes, monocytes,
macrophages, and natural killer cells; thus, the drug
causes extensive lympholysis by inducing apoptosis of
targeted cells. It has achieved some use in renal transplantation
because it produces prolonged T- and B-cell
depletion and allows drug minimization. Large controlled
studies of efficacy or safety are not available.
Although short-term results are promising, further
clinical experience is needed before alemtuzumab
is accepted into the clinical armamentarium for
transplantation.
Anti-TNF Reagents. TNF has been implicated in the
pathogenesis of several immune-mediated intestinal,
skin, and joint diseases. For example, patients with
rheumatoid arthritis have elevated levels of TNF-α in
their joints, while patients with Crohn’s disease have
elevated levels of TNF-α in their stools. As a result, a
number of anti-TNF agents have been developed for the
treatment of these disorders.
Infliximab (REMICADE) is a chimeric anti–TNF-α
monoclonal antibody containing a human constant
region and a murine variable region. It binds with high
affinity to TNF-α and prevents the cytokine from binding
to its receptors.
In one trial, infliximab plus methotrexate improved the signs
and symptoms of rheumatoid arthritis more than methotrexate alone.
Patients with active Crohn’s disease who had not responded to other
immunosuppressive therapies also improved when treated with
infliximab, including those with Crohn’s-related fistulae. Infliximab
is approved in the U.S. for treating the symptoms of rheumatoid
arthritis and is typically used in combination with methotrexate in
patients who do not respond to methotrexate alone. Infliximab also
is approved for treatment of symptoms of moderate to severe Crohn’s
disease in patients who have failed to respond to conventional therapy
and in treatment to reduce the number of draining fistulae in
Crohn’s disease patients (Chapter 47). Other FDA-approved indications
include ankylosing spondylitis, plaque psoriasis, psoriatic
arthritis, and ulcerative colitis. About one of six patients receiving
infliximab experiences an infusion reaction characterized by fever,
urticaria, hypotension, and dyspnea within 1-2 hours after antibody
administration. The development of antinuclear antibodies, and
rarely a lupus-like syndrome, has been reported after treatment with
infliximab.
Although not a monoclonal antibody, etanercept
(ENBREL) is mechanistically related to infliximab
because it also targets TNF-α. Etanercept contains the
ligand-binding portion of a human TNF-α receptor
fused to the Fc portion of human IgG 1
, and binds to
TNF-α and prevents it from interacting with its receptors.
It is approved in the U.S. for treatment of the
symptoms of rheumatoid arthritis in patients who have
not responded to other treatments, as well as for treatment
of ankylosing spondylitis, plaque psoriasis, polyarticular
juvenile idiopathic arthritis, and psoriatic
arthritis. Etanercept can be used in combination with
methotrexate in patients who have not responded adequately
to methotrexate alone. Injection-site reactions
(i.e., erythema, itching, pain, or swelling) have occurred
in more than one-third of etanercept-treated patients.
Adalimumab (HUMIRA) is another anti-TNF product
for intravenous use. This recombinant human IgG 1
monoclonal antibody was created by phage display
technology and is approved for use in rheumatoid
arthritis, ankylosing spondylitis, Crohn’s disease, juvenile
idiopathic arthritis, plaque psoriasis, and psoriatic
arthritis.
Toxicity. All anti-TNF agents (i.e., infliximab, etanercept, adalimumab)
increase the risk for serious infections, lymphomas, and
other malignancies. For example, fatal hepatosplenic T-cell lymphomas
have been reported in adolescent and young adult patients
with Crohn’s disease treated with infliximab in conjunction with azathioprine
or 6-mercaptopurine.
IL-1 Inhibition
Plasma IL-1 levels are increased in patients with
active inflammation (Moltó and Olivé, 2009; see also
Chapter 34). In addition to the naturally occurring IL-1
receptor antagonist (IL-1RA), several IL-1 receptor