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PRIORITY PRESS - 2010 Advances in Inflammatory Bowel Diseases

Hollywood, Florida / December 9-12, 2010

Although there is no cure for Crohn’s disease (CD) or ulcerative colitis (UC), the advent of small-molecule immunosuppressive agents such as the thiopurines 6-mercaptopurine (MP)/azathioprine, and biologic agents such as the tumour necrosis factor-alpha (TNF) inhibitors infliximab and adalimumab, have revolutionized the clinical approach to these intractable inflammatory bowel diseases (IBD). Yet over time, even the most efficacious therapy can lose its therapeutic potency due to a variety of known and unknown factors, and it is incumbent upon physicians who treat patients with these chronic, lifelong conditions to understand risk factors associated with various types of therapy, stated Dr. William J. Sandborn, Chief, Division of Gastroenterology, and Professor of Clinical Medicine, University of California, San Diego.

“This is a very common scenario we’re all facing in clinical practice every day and every week: the loss of response to anti-TNF agents and frankly to immunomodulators,” he told delegates.

Monitoring for 6-MP/Azathioprine Resistance

The strategy for managing loss of response may differ according to whether the loss is secondary to subtherapeutic concentrations of drugs, to immunogenicity from exposure to biologic agents or to drug intolerance. Options for managing loss of response include dose escalation for subtherapeutic concentrations or switching within a drug class (i.e. from one immunomodulator to another or from one anti-TNF agent to another). If a patient is intolerant to a therapy, the clinician may try switching to another agent within that class, or consider stopping and switching to another class of drug, Dr. Sandborn suggested.

He cited a 2002 study that demonstrated that serial monitoring of the 6-MP metabolite 6-thioguanine nucleotide could identify patients with IBD who are naturally resistant to 6-MP/azathioprine therapy and might therefore benefit from a therapeutic category switch (Dubinsky et al. Gastroenterology 2002;122(4):904-15).

Although some investigators have suggested that 6-MP/azathioprine resistance can be overcome with the co-administration of allopurinol, which inhibits the xanthine oxidase enzyme responsible for the breakdown of MP, Dr. Sandborn professed a disinclination for this strategy: “I have a lot of experience with azathioprine pharmacology... I don’t think the safety is established,” he remarked.

Measuring HACA Concentrations

Dr. Sandborn discussed a study looking into the clinical utility of measuring infliximab and human anti-chimeric antibody (HACA) concentrations in patients with IBD. He reported that he and colleagues found the measurement was helpful in identifying patients with a loss of response to the drug, but less helpful for identifying those who had infusion reactions or who were reintroduced to infliximab after a drug holiday.

“If you had detectable HACA or anti-infliximab antibodies, and you just increased the infliximab dose, at least in our experience, the likelihood of response in an immunized patient was low, about 17%. On the other hand, if you switched to another anti-TNF like adalimumab or certolizumab, many of the patients would have a clinical response,” he remarked. Conversely, he added, if patients are not immunized to infliximab, with no detectable HACA but appear to be non-responsive to the drug, they may respond with dose escalation or shortening the treatment interval.

Dr. Sandborn and colleagues have developed a treatment algorithm for patients with IBD. If the patient has a subtherapeutic infliximab concentration, defined as <12 µg/mL at 4 weeks or an undetectable trough level, the dose or frequency of infliximab can be increased; if disease persists, then a switch to a different anti-TNF agent may be warranted. If a switch has already been tried and the disease is persistent, then a drug with a different mechanism of action may be required.

Other possible causes of loss of response may include inflammation; disease complications such as strictures, fistulae or abscesses; complications of surgical resection such as bile salt diarrhea, steatorrhea or small bowel bacterial overgrowth; infection with Clostridium difficile or cytomegalovirus; or depression.

Demographic and Disease Factors

In addition to HACA levels, certain demographic and disease characteristics may predict patient loss of response to infliximab, suggested Dr. Ira Shafran and Patricia Burgunder, ARNP, Shafran Gastroenterology Center, Winter Park, Florida.

They reviewed 12 years of clinical experience with infliximab in CD in their centre and found that smoking, fibrostenotic disease, disease confined to the small bowel and treatment at an institution that performed infliximab infusions were predictive of initial non-response to infliximab. They also found that women who smoke and have disease localization in both the small bowel and the colon appear to be more likely to lose response to the drug during maintenance therapy.

The same investigators presented data from a retrospective chart review of adalimumab efficacy for the improvement of CD symptoms in patients who were unresponsive or intolerant to infliximab, based on 6 years of experience with adalimumab. They found that “adalimumab effectively induced and maintained remission of CD symptoms in patients who were intolerant of or unresponsive to infliximab.”

Their findings, they noted, supported those of an earlier double-blind, placebo-controlled study of 325 patients (Sandborn et al. Ann Intern Med 2007;146(12):829-38). As with infliximab, patients more likely to be non-responsive to adalimumab were smokers and those with fibrostenotic disease, as well as narcotic users and those who were steroid-dependent at baseline.

Dose Escalation: How Much Is Enough?

The frequency of dose escalation for efficacy among Canadian patients with CD initiating therapy with an anti-TNF agent was the subject of a study led by investigators from Montreal and the Centre Hospitalier universitaire de Québec, Quebec City. Researcher Alexandra Goyette and colleagues sifted through data on 1880 patients starting on infliximab and 896 starting on adalimumab. The patients were followed for a mean duration of 345 days for those on adalimumab and 379 days for those on infliximab.

For every patient, the investigators calculated weekly dosing for each dosing episode (the time between 2 prescriptions) of maintenance therapy with each drug. They evaluated dose escalation from 3 different angles: index vs. last, comparing the first and last maintenance doses; average dose; and trend over time. Regardless of method of measurement, adalimumab-treated patients required significantly less dose escalation than did infliximab-treated patients. The respective differences were 11.0% for adalimumab vs. 18.4% for infliximab by the index vs. last method (P<0.0001); 10.9% vs. 62.7% by the average dose measure (P<0.0001); and 13.7% vs. 25.7% by the time trend method.

“This exploratory analysis provides insight on the importance of definition of drug utilization measures in databases,” the investigators wrote in a poster presentation. “High dose escalation proportion has a significant impact on drug costs. A lesser need for dose escalation may imply more sustained efficacy.”

If first and second anti-TNF agents fail, should clinicians abandon the strategy? Maybe not, Dr. Sandborn said. He cited a recent European study which showed that among patients with CD who received either adalimumab or certolizumab pegol as a third-line agent, 61% of patients had responses and 18% had remissions at 6 weeks; at 20 weeks, 51% of patients maintained responses and 19% had remissions (Allez et al. Aliment Pharmacol Ther 2010;31(1):92-101).

Summary

While the current goals of therapy for IBD are to relieve symptoms and, ideally, to induce remission, the ultimate goal will be to change the course of the natural history of the disease, concluded Dr. Stephen B. Hanauer, Section Chief, Gastroenterology, Hepatology and Nutrition, and Joseph B. Kirsner Professor of Medicine and Clinical Pharmacology, University of Chicago, Illinois. “Our new therapeutic goals for the future—and these are continuing to be revised—are going to be prevention, stabilization or resolution of structural damage. From the patients’ standpoint, we cannot forget the symptoms and complete and persistent control of the inflammation.”