IBD Watch®
Timely Information for Practicing Physicians
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Current Controversies in
Biologic Therapy of CD: Debating the Application
of Emerging Clinical Data to Daily Treatment Decisions Special Issue Based on a
CME Satellite Symposium Held on October 14, 2007 in Philadelphia, Pennsylvania Remo Panaccione, MD: A Case for Using Biologic Agents Routinely as
Monotherapy for CD Patients. In
2007, there are two main issues to consider when using biologics and
immunosuppressants: safety and efficacy. A recent publication in the European
Journal of Gastroenterology showed that one of the main concerns of patients
with CD is medication side effects; with the use of combination therapy (a
biologic agent plus an immunosuppressive) there is evidence of increased
toxicity. Recent data from the Mayo Clinic showed an increased risk of
opportunistic infections associated with the use of immunosuppressive
medications, while data presented at the 2007 Digestive Disease Week Annual
Meeting showed that the combined use of immunosuppressive drugs (eg, 6-MP/azathioprine
[AZA] and steroids) significantly increases the risk of opportunistic
infections. To date, there have been ten confirmed cases of hepatosplenic T-cell
lymphoma associated with the use of infliximab in combination with 6-MP or AZA;
thus, physicians must exercise appropriate caution when contemplating
combination therapies. ¨
Although properly designed randomized controlled trials evaluating the potential
for increased efficacy with combination therapy are being conducted, the results
are several years away. Subanalyses of existing data across several biologic
development programs suggest that there is no clear efficacy benefit of
combination therapy over biologic monotherapy. In the largest cohort studied to
date (80 patients), there was no clear difference in efficacy over 2 years
between patients receiving continuous infliximab monotherapy and patients
receiving combination therapy with infliximab and an immunosuppressant. Data
from the Crohn’s Trial of the Fully Human Antibody Adalimumab for Remission
Maintenance (CHARM) showed no difference in efficacy between patients receiving
adalimumab plus an immunomodulator and patients receiving adalimumab monotherapy
at weeks 26 and 56. ¨
Thus, in 2007, the evidence suggests that biologics can be used as monotherapy
without sacrificing efficacy with an overall better safety profile than
combination therapy. Brian Feagan, MD: A Case for Using Combination Biologic and
Immunosuppressive Therapy in CD Patients. Recent randomized controlled trials performed in patients with rheumatoid
arthritis (RA) may help us deal with the current treatment challenges in
patients with CD. MTX is the cornerstone of treatment for RA and is a
well-tolerated disease-modifying antirheumatic drug. However, MTX monotherapy
allows the progression of bone erosions that ultimately result in disability.
The introduction of anti-TNF agents has been a critical advance in the
management of RA, and recent trials of combination therapy with adalimumab,
infliximab, and etanercept have demonstrated a striking synergy between MTX and
these agents, such that therapy with either MTX alone or an anti-TNF agent alone
is clearly inferior to combination therapy. Thus, an alternative exists to the
traditional step-up approach to CD treatment. ¨
Two studies support the efficacy of combination therapy in patients with CD.
Lemann et al evaluated the combination of AZA and infliximab in corticosteroid-dependent
patients. Participants were randomly assigned to receive infliximab or placebo
in addition to AZA. A significantly higher percentage of patients assigned to
the infliximab/AZA group were in remission at weeks 12, 24, and 52 compared with
the patients who received placebo/AZA. In a second study, patients with early CD
were randomly assigned a top-down approach, featuring the early use of combined
immunosuppression with AZA and infliximab, or the traditional step-up approach.
The results showed that the top-down treatment strategy was superior to
conventional management for the induction of remission without corticosteroids
at weeks 26 and 52. Furthermore, patients assigned to early combined
immunosuppression were more likely to show complete ulcer healing at the end of
2 years. ¨
Critics of combined therapy for CD have indicated that safety considerations
preclude the use of multiple agents. However, in RA trials it has not been
possible to show additive or synergistic toxicity attributable to combination
therapy (typically MTX plus an anti-TNF agent). Further, in patients with CD,
data from the Therapy, Evaluation, and Assessment Tool (TREAT) registry do not
support this belief either. Finally, an added advantage of combination therapy
is that it is highly effective in preventing antibodies to foreign proteins,
which remains an important issue for all biologic agents. Brian Feagan, MD: A Case for Switching Biologic Therapy in CD Patients
Who Develop Attenuated Response or Become Intolerant to a Biologic Agent. Only
one third of patients with CD will experience significant improvement with
initial biologic therapy, and a substantial proportion will lose response over
time for a variety of reasons, including immunogenicity of the anti-TNF agent.
Thus, clinicians must be prepared to treat patients who experience primary or
secondary failure with an anti-TNF agent. Very little data exist to guide
decision-making in CD, although a large number of observational and case-control
studies have been performed in patients with RA. However, these studies are
inherently biased toward using a second member of the same drug class; very
little experience exists with switching to a second drug with a different
mechanism of action. In the specific context of CD, this is problematic because
the only out-of-class agent likely to be available in the near term is
natalizumab. ¨
With regard to secondary failures, observational data from RA trials support the
concept of switching within the anti-TNF class. However, existing studies may
overestimate the efficacy of the practice. The Gauging Adalimumab Efficacy in
Infliximab Nonresponders (GAIN) trial was a large-scale, two-armed, multicenter,
randomized trial in patients with a secondary failure to infliximab due to loss
of efficacy or intolerance, which was designed to answer this question in
patients with CD. Patients received induction therapy with adalimumab or
placebo. The primary end point was clinical remission (CD Activity Index score
<150 points) at week 4. Twenty-one percent of patients treated with
adalimumab entered remission within 4 weeks of treatment compared with 7% of
patients receiving placebo (P
<0.001). Further, rather than optimizing the dose of an anti-TNF agent to
overcome the attenuated response, there may be a cost advantage to switching to
another anti-TNF agent. Thus, evidence supports switching within a drug class in
patients experiencing a secondary failure to infliximab. It is not clear whether
switching secondary failures from adalimumab to infliximab would be effective or
whether switching anti-TNF agent failures to natalizumab would be more effective
than switching within the class. Uma Mahadevan-Velayos, MD: A Case for the Step-up Approach to Treating
CD. Most patients
with CD will never require steroids or biologic therapy. Budesonide is an
effective induction agent for mild to moderate right-sided CD. 6-MP is an
effective steroid-sparing agent and an effective agent for the maintenance of
remission for up to 5 years. Azathioprine is effective for inducing and
maintaining remission in patients with steroid-dependent CD, and it has been
demonstrated to result in significant mucosal healing; its toxicity has been
documented in more than five decades of use in patients with CD. While the
top-down approach has recently been advocated, data indicate no difference in
remission rates at 2 years among patients treated with top-down versus step-up
therapy. In addition, cost of therapy is higher with the use of biologic agents,
even taking into account a reduction in rates of hospitalization and surgery.
Thus, while biologic agents are effective and important agents in the management
of CD, conventional agents such as AZA should be used first in the appropriate
patients as they are effective, less costly, and have an acceptable safety
profile. In patients who are intolerant of, or unresponsive to, AZA, biologics
should be introduced quickly to avoid disease complications. Remo Panaccione, MD: A Case for the Top-down Approach to Treating CD. Under
the step-up treatment paradigm, agents with low efficacy, such as
aminosalicylates, are used for prolonged periods while uncontrolled inflammation
results in tissue damage. Patients who fail aminosalicylates are then treated
with corticosteroids while immunosuppressant therapy is reserved for the
patients with steroid-refractory or steroid-dependent disease. Many patients may
continue to receive therapies to which they are not responding for a prolonged
duration because clinicians may be reluctant to step up to therapy that is
perceived as more toxic. It is evident that individual clinicians will allow
patients to remain on suboptimal therapy for variable durations before deciding
to switch or escalate therapy. ¨
The more recently described top-down approach is based upon the idea that early
use of the most effective treatments available will alter the natural history of
the disease, resulting in a reduced dependence on glucocorticoids and reduced
requirements for hospitalization and surgery. There are now several lines of
evidence to suggest that this approach is beneficial. If the effectiveness of a
top-down approach is established, the real challenge will be to develop a means
of identifying patients who are at the greatest risk for poor outcomes in the
absence of aggressive therapy and to target the top-down strategies toward those
patient populations. There is already evidence that certain phenotypic features
of CD and some genetic and serologic markers will help in predicting which
patients have this type of aggressive disease course. In the future, such
markers will likely be used to stratify patients to assist in making treatment
decisions.
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