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

improve significantly (generally within 7 days) in response to intravenous
cyclosporine (2-4 mg/kg per day), sometimes avoiding
emergent colectomy. Careful monitoring of cyclosporine levels is
necessary to maintain a therapeutic level in whole blood between
300 and 400 ng/mL.
Oral cyclosporine is less effective as maintenance therapy in
Crohn’s disease, perhaps because of its limited intestinal absorption.
In this setting, long- term therapy with NEORAL or GENGRAF (formulations
of cyclosporine with increased oral bioavailability) may be
more effective, but this has not been studied fully. The calcineurin
inhibitors can be used to treat fistulous complications of Crohn’s disease.
A significant rapid response to intravenous cyclosporine has
been observed; however, frequent relapses accompany oral
cyclosporine therapy, and other medical strategies are required to
maintain fistula closure. Thus, the calcineurin inhibitors generally
are used to treat specific problems over a short term while providing
a bridge to longer- term therapy (Sandborn, 1995).
Other immunomodulators that are being evaluated in IBD
include the calcineurin inhibitor tacrolimus (FK 506, PROGRAF),
mycophenolate mofetil and mycophenolate (CELLCEPT, MYFORTIC),
inhibitors of inosine monophosphate dehydrogenase to which lymphocytes
are especially susceptible (Chapter 35).
BIOLOGICAL THERAPIES
Infliximab (REMICADE, cA2) is a chimeric immunoglobulin
(25% mouse, 75% human) that binds to and neutralizes
TNFα. Although many, both pro- and anti- inflammatory
cytokines, are generated in the inflamed gut in IBD
(Figure 47–1), there is some rationale for targeting
TNF-α because it is one of the principal cytokines mediating
the T H
1 immune response characteristic of Crohn’s
disease (Targan et al., 1997).
Although infliximab was designed specifically to target
TNFα, it may have more complex actions. Infliximab binds
membrane- bound TNFα and may cause lysis of these cells by
antibody- dependent or cell- mediated cytotoxicity. Thus, infliximab
may deplete specific populations of subepithelial inflammatory cells.
These effects, together with its mean terminal plasma t 1/2
of 8-10 days,
may explain the prolonged clinical effects of infliximab.
Infliximab (5 mg/kg infused intravenously at intervals of several
weeks to months) decreases the frequency of acute flares in
approximately two- thirds of patients with moderate to severe Crohn’s
disease and also facilitates the closing of enterocutaneous fistulas
associated with Crohn’s disease (Present et al., 1999). Its longer- term
role in Crohn’s disease is evolving, but emerging evidence supports
its efficacy in maintaining remission (Rutgeerts et al., 2004) and
in preventing recurrence of fistulas (Sands et al., 2004). The combination
of infliximab and azathioprine is more effective than infliximab
alone in induction of remission and mucosal healing in
steroid- resistant patients (Rutgeerts et al., 2009). In contrast, there
appears to be no synergistic benefit of the combination of methotrexate
and infliximab. Infliximab has also proven to be an effective treatment
for refractory ulcerative colitis (Rutgeerts et al., 2009).
The use of infliximab as a biological response modifier raises
several important considerations. Both acute (fever, chills, urticaria,
or even anaphylaxis) and subacute (serum sickness–like) reactions
may develop after infliximab infusion, but a frank lupus- like syndrome
occurs only rarely. Antibodies to infliximab can decrease its clinical
efficacy. Each year, at least 10% of patients on infliximab have to
stop therapy because of loss of response or intolerance (Rutgeerts
et al., 2009). Strategies to minimize the development of these antibodies
(e.g., treatment with glucocorticoids or other immunosuppressives)
may be critical to preserving infliximab efficacy for either
recurrent or chronic therapy (Farrell et al., 2003). Other proposed
strategies to overcome the problem of “antibody resistance” include
increasing the dose of infliximab or decreasing the interval between
infusions.
Infliximab therapy is associated with increased incidence of
respiratory infections; of particular concern is potential reactivation
of tuberculosis or other granulomatous infections with subsequent
dissemination. The FDA recommends that candidates for infliximab
therapy be tested for latent tuberculosis with purified protein derivative,
and patients who test positive should be treated prophylactically
with isoniazid. However, anergy with a false- negative skin test has
been noted in some patients with Crohn’s disease, and some experts
routinely perform chest radiographs to look for active or latent pulmonary
disease. Infliximab also is contraindicated in patients with
severe congestive heart failure (New York Heart Association classes
III and IV) and should be used cautiously in class I or II patients. As
with the immunosuppressives, there is concern about the possible
increased incidence of non- Hodgkin’s lymphoma, but a causal role
has not been established. Finally, the significant cost of biological
therapies such as infliximab is an important consideration.
Adalimumab (HUMIRA) is a humanized recombinant human
IgG 1
monoclonal antibody against TNFα. It is effective in inducing
remission in mild to moderate, severe, and fistulizing Crohn’s disease
(Rutgeerts et al., 2009). Unfortunately, adalimumab cannot be
used to rescue patients who have lost responsiveness to another anti-
TNFα antibody, such as infliximab. Certolizumab pegol (CIMZIA) is
a pegylated humanized fragment antigen binding (Fab) that binds
TNFα. It is approved in the U.S. for the treatment of Crohn’s disease.
It appears to have comparable efficacy to that of adalimumab and
infliximab for the treatment of Crohn’s disease, although direct comparative
studies have not been performed (Rutgeerts et al., 2009).
With both adalimumab and certolizumab pegol, immunogenicity
appears to be less of a problem than that associated with infliximab.
Another anti- TNF α agent, Etanercept (ENBREL), is a fusion
protein of the ligand- binding portion of the TNF α receptor and the
Fc portion of human IgG 1
. This construct binds to TNFα and blocks
its biologic effects but is ineffective in Crohn’s disease.
Natalizumab (TYSABRI) is a humanized monoclonal antibody
against α4-integrin (also known as VLA-4). Binding of the antibody
to this adhesion molecule will reduce extravasation of certain leukocytes
(e.g., lymphocytes), preventing them from migrating to sites of
inflammation where they may exacerbate tissue injury. In 2008,
natalizumab was approved in the U.S. for induction and maintenance
of remission of moderate to severe Crohn’s disease. Natalizumab
had previously been withdrawn from the market and carries a black
box warning because it appears to interact with other immunemodulating
drugs to increase the risk of progressive multifocal
leukoencephalopathy (PML). Thus, natalizumab is contraindicated
for use with other immunomodulators. Because of the capacity of corticosteroids
to produce immunosuppression, patients taking natalizumab
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CHAPTER 47
PHARMACOTHERAPY OF INFLAMMATORY BOWEL DISEASE