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MEDICAL FRONTIERS - 18th United European Gastroenterology Week

Barcelona, Spain / October 23-27, 2010

With 10 years’ experience with tumour necrosis factor alpha (TNF-a) inhibitors or anti-TNFs and greater knowledge of Crohn’s disease (CD), clinicians are now moving towards more focused management with initiation of the right treatment at the right time for the right patient.

Patient Selection

Prof. Daniel Hommes, Professor of Gastroenterology, Leiden University Medical Center, The Netherlands, stated, “In our clinical practice today, we are indeed able to select the right patient and decide upon the right time to install the different therapeutics that are available, because today we are able to discriminate high-risk from low-risk patients. Patient selection and timing are key components in changing the course of disease. We can look into disease history, disease course and quality of life to define the parameters that help us predict the near future for our patients. We are now also able to look at the very extensive safety profiles of the different immunosuppressants and anti-TNFs to select the right therapeutic strategies. We can obtain an endoscopic assessment of disease activity and even intensify drug therapy if needed. We have learned to individualize patient care.”

According to Prof. Paul J. Rutgeerts, Professor of Medicine, University of Leuven, Belgium, successful anti-TNF therapy begins with proper selection of candidates for treatment. “Proper and timely patient selection is essential in treatment of the disease with anti-TNF therapy.”

The anti-TNF with the most experience and data in CD treatment is infliximab. It has shown efficacy in inducing clinical remission and complete mucosal healing in patients with moderate to severe CD. It is indicated for induction and maintenance of remission of active luminal disease where a high level of C-reactive protein should be validated before starting therapy.

Prof. Rutgeerts also told delegates that it has demonstrated “efficacy in steroid-dependent CD, fistulizing disease and in systemic manifestations of irritable bowel disease.”

Reviewing Safety Concerns

The long-term safety of anti-TNF therapy, including the risk of serious infection and potential cancer risk, has been an area of ongoing investigation and debate. “We are well into a decade of CD treatment with TNF antagonists, over the course of which there have been many misperceptions regarding immunogenicity, long-term safety and dosing with infliximab and other anti-TNF agents,” stated Dr. Brian Feagan, Director, Robarts Research Institute, London, Ontario.

All monoclonal antibodies are immunogenic, Dr. Feagan stated. Studies of patients receiving infliximab or adalimumab have indicated development of anti-drug antibodies that can lead to adverse events as well as lower drug concentrations and, in turn, loss of efficacy.

However, concomitant immunosuppressive therapy may reduce the prevalence of antibodies and may increase efficacy. In SONIC (Study of Biologic-Immunomodulator-Naive patients in Crohn’s Disease), antibodies to infliximab were detected in 14.6% of patients receiving infliximab alone and in 1% of those receiving the combination infliximab/azathioprine (N Engl J Med 2010;362(15):1383-95). Median serum infliximab levels in patients in the combination-therapy arm of the study were approximately double those in the infliximab alone arm. Dr. Feagan reported that in the COMMIT (Combination of Maintenance Methotrexate-Infliximab) trial conducted at the Robarts Institute, the addition of methotrexate to the infliximab regimen also reduced antibody formation.

The possibility of serious infection with anti-TNF agents has been an area of concern. A Mayo Clinic case-control study (Gastroenterology 2008;134(4):929-36) concluded that combination therapy is associated with a greater risk of serious infection than monotherapy. Similarly, a pooled safety analysis by Sandborn et al. presented here at the UEGW showed that CD patients at risk of experiencing treatment-emergent serious infections increased with the combination immunomodulators and adalimumab and were at highest risk when corticosteroids were added.

However, as Dr. Feagan commented, “With regard to serious opportunistic infection… I have a lot of patients who are transiently on triple therapy and that has not been my experience.”

In the TREAT (Crohn’s Therapy Resource, Evaluation and Assessment Tool) registry, 3401 patients received infliximab and 2872 received other therapies. An analysis of TREAT determined that while the infection rate appeared higher with infliximab-treated patients, when data were adjusted for increased severity of disease and concomitant use of immunomodulators and prednisone, the difference was not significant. The landmark SONIC trial also showed no difference in the rate of serious infection between the monotherapy and combination treatment arms.

The severity of CD is an independent predictor of serious infections, Dr. Feagan observed. “It is the debilitated patients with multiple medical problems who get serious infections. If you can get more of those patients well by administering combination therapy, which is more effective, you are going to take them out of harm’s way and reduce the risk. To prevent infection, immunize and don’t administer these drugs to patients who have pelvic sepsis,” he stressed.

Whether there is an increased risk of lymphoma associated with anti-TNF therapy in CD remains an unresolved question. Although some studies have made the link, attempts to determine the signal associated with infliximab have been confounded by the stronger signal associated with azathioprine. Some data from infliximab studies in patients with rheumatoid arthritis have also shown a weak association, but there are negative studies as well. “It is reassuring that we are 10 years out and still remain uncertain if there is a true association,” Dr. Feagan told delegates.

To Switch or Not to Switch

Incomplete primary response or secondary loss of response may occur with any anti-TNF therapy, noted Dr. Feagan. As a result, antibody formation or other processes may be contributing factors. Low anti-TNF serum concentrations may be managed by increasing dose, reducing the interval between infusions or switching to another agent.

With newer anti-TNFs available, experience with these agents is increasing. One such agent, adalimumab, demonstrated efficacy in achieving mucosal healing in the EXTEND (Extend the Safety and Efficacy of Adalimumab Through Endoscopic Healing) trial. When patients either lose response or develop an intolerance to infliximab, switching may be an option as shown in the GAIN (Gauging Adalimumab Effectiveness in Infliximab Nonresponders) trial where 52% of patients responded after being switched to adalimumab (Figure 1).

Figure 1.

However, prospectively switching agents when patients respond to treatment is not a warranted strategy. As demonstrated in the SWITCH (Switch from infliximab to adalimumab in CD patients in remission) study, Prof. Pierre Michetti, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland, reported that of patients switched to adalimumab, 47% required dose escalation or had to terminate therapy; the proportion was 16% in those treated with inflixima
2).

Figure 2.

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Importantly, Prof. Michetti observed, “Not all anti-TNF agents are equally effective. Clinical data suggest that a class effect should not be assumed, but that we should really [make the selection] effect by effect, indication by indication, and maybe even side effect by side effect.”

Prof. Michetti noted that for CD therapy, data on mucosal healing are more robust for infliximab than they are for other agents tested. He added, “[It is] the most robust in CD in terms of efficacy and safety and should be the first-choice anti-TNF agent, and I would say also in combination therapy, according to the most recent data.”

Optimizing Therapy

Although confronted with loss of response, evidence from SWITCH has shown that it should be better to optimize the present agent with dose escalation before opting to switch therapy. According to Prof. Rutgeerts, the majority of patients experiencing a loss of response will experience renewed benefit from increased dosing of their initial therapy. This course of action is worth considering before a switch. “Overall it is not a good idea to immediately switch therapy when you lose response; first, optimize your therapy,” he suggested.

“Data in patients who initially responded to 5 mg/kg infliximab but lost response showed that they can regain response with dose escalation or decreasing the interval between infusions to recapture the efficacy of the drug, and both interventions appear to be equally effective,” Prof. Rutgeerts told delegates.

Some patients may express the desire for a therapy that might be easier to administer, but he noted, “It is also not a good idea to switch therapies only for the sake of [the patient’s desire for] convenience, because that risks losing control of the disease.”

Dose Escalation and De-Escalation

Once response has been regained following an upward adjustment to the anti-TNF medication dose, it is often possible for the patient to return to the original dose or treatment schedule.

For example, according to a national cohort study evaluating adalimumab in 720 patients with CD, dose escalation was needed in 34% of patients at a median of 7 months of treatment with successful escalation reported in 62%. De-escalation was attempted in 52% and successful in 62%.

Similarly, in a sample of 273 patients in whom infliximab dosing was increased via treatment interval shortening, Prof. Rutgeerts reported that 29% were able to return to the pre-adjustment dose. Among those who had experienced 1 or 2 dose increases, 70% were able to return to the original dose. In individuals in whom both strategies were used, 62% were able to return to their original regimen once response was re-established.

Another large health claims database evaluated response to dose escalation with adalimumab and infliximab. Of the 3866 infliximab-treated patients identified, 28% had dose escalation; of those, 99% were first-time infliximab users. For adalimumab, of 935 cases identified, 24% had a dose escalation. Among them, 65% were
users, the other 35% had switched from infliximab.

Figure 3.

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Notably, the mean time to dose escalation after induction was 10.4 months with infliximab and 3 months for adalimumab first-time users and 1.8 months for those switched to adalimumab from infliximab (Figure 3). Mean time to discontinuation of treatment was shorter for adalimumab at 3.7 months for first-time users and 4.7 months for those who had switched from infliximab vs. 12.6 months with infliximab. A similar rate of patients who dose-escalated remained on therapy after 12 months.

These results emphasize the need to optimize therapy with dose escalation before attempting to switch therapy. As Prof. Rutgeerts and his colleagues suggested, “If you have mucosal healing, of course you continue therapy; if you do not… you might want to dose-escalate those patients to optimize your therapy.”

Summary

Keeping in mind that the benefits of mucosal healing are reduction in hospitalizations and surgery, sustained steroid-free treatment remission, and prevention of endoscopic recurrence in the post-operative population, optimizing a particular therapy becomes essential for long-term management. Data showed that optimizing therapy with dose escalation or decreasing treatment intervals in order to recapture response should be considered before attempting to switch therapy.