Reports

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

PRIORITY PRESS - 2010 Advances in Inflammatory Bowel Diseases

Hollywood, Florida / December 9-12, 2010

Crohn’s disease (CD) and ulcerative colitis (UC) are difficult, often refractory disorders that cause both pain and suffering for patients. Over the last few decades, however, the advent of new, more effective treatments for these inflammatory bowel diseases (IBDs) has revolutionized patient care. In particular, biologic agents that target the cytokine tumour-necrosis factor alfa (anti-TNF agents) have helped many patients achieve durable remissions where other therapies have failed. But as presenters here at the conference stressed, anti-TNF agents are not magic bullets, and both patients and physicians must have realistic expectations about their benefits, and an understanding of how they are best used.

Modifiable Risk Factors

Increasingly, clinical researchers are attempting to identify patient-specific factors that may affect response to specific therapies, with the goal of optimizing treatment for each patient. For example, Dr. Ira Shafran and Patricia Burgunder, ARNP, Shafran Gastroenterology Center, Winter Park, Florida, have identified both modifiable and disease-specific risk factors associated with patient response to infliximab for treatment of CD. They reviewed 12 years of clinical experience with the anti-TNF agent 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 colon appear to be more likely to lose response to the drug during maintenance therapy, suggesting that smoking cessation efforts could help such patients achieve more durable remissions.

IL-17 Predicts Remission in UC

Other investigators are working to identify factors that can predict favourable outcomes following infliximab induction therapy for treatment of UC. Dr. Trine Olsen, Laboratory of Gastroenterology, Institute of Clinical Medicine, University of Tromsø, Norway, and colleagues evaluated 62 patients with moderate to severe UC who received infliximab 5 mg/kg at treatment outset and at weeks 2 and 6. The investigators assessed UC disease activity index (UCDAI) scores, including endoscopic subscores, both before and after therapy.

They found that in a multivariate logistic regression model, neither age, gender nor levels of transforming growth factor beta (TGF-ß), interleukin (IL)-6 or IL-23 were predictive of mucosal healing or clinical remission. In contrast, they identified an independent association between pre-treatment levels of IL-17 and clinical remission, with an odds ratio (OR) of 2.5 (P=0.01).

“Among the various candidate genes evaluated, pre-treatment IL-17 mRNA in colorectal mucosa was the only significant independent factor predicting remission (OR 2.45, P<0.01),” they wrote in a poster presentation.

Mucosal Healing Pattern

Canadian investigators reported that infliximab induces mucosal healing in patients with acute UC and that it appears to do so in a distinct proximal-to-distal pattern.

Dr. Cynthia H. Seow, Assistant Professor, Department of Medicine and Community Health Sciences, University of Calgary, Alberta, along with colleagues in Calgary and at the University of Toronto Mount Sinai Hospital, Ontario, studied 105 patients with acute UC and a baseline Mayo score of 26. The patients received a 3-dose induction course of infliximab and responders were continued on schedule maintenance infusions. The patients underwent colonoscopy at baseline and at a follow-up evaluation at least 6 weeks after starting therapy, or before a colectomy. The authors calculated Mayo endoscopic disease activity scores for the rectum, sigmoid, descending colon, transverse colon, ascending colon and cecum. Two independent physicians viewed the image and assigned a Mayo endoscopic activity score. They defined endoscopic improvement as a reduction of at least 1 point from baseline to follow-up. Normal mucosa was defined as the disappearance of all mucosal lesions.

They found that 49% of patients had endoscopic improvement and 13% had complete mucosal healing. In the remaining 38% of patients, the mucosa appeared unchanged. Of the latter patients, 65% went on to colectomy compared with only 28% of those with improvement or complete healing. Among the responders, 63% had a pattern of healing from proximal to distal portions while 37% had comparable improvements in all anatomic segments.

Their findings suggest that “endoscopic evaluation with flexible sigmoidoscopy may not adequately reflect the impact of infliximab in mucosal healing. The addition of topical therapy may provide clinical benefit to patients who would otherwise be considered infliximab failures,” they reported here.

Intestinal Behçet’s Disease

Intestinal Behçet’s disease—characterized by intestinal inflammation, ulceration and often severe gastrointestinal symptoms—is often treated with corticosteroids. But as Japanese investigators reported here in a poster presentation, infliximab was effective in more than 80% of patients for whom corticosteroids failed.

Dr. Hiroshi Fujita, Kagoshima University Graduate School of Medical and Dental Sciences, and colleagues reported on 23 patients with intestinal Behçet’s disease: “Although corticosteroid [therapy] is widely used to treat intestinal Behçet’s disease, it was effective in only half of the patients in the study. In contrast, infliximab was effective in 83% of the patients who failed corticosteroid therapy. Infliximab could be a useful therapeutic option for achieving rapid improvement and maintenance of remission in patients with intractable intestinal Behçet’s disease. Accumulating data on a larger population of patients [is] required to validate the efficacy of infliximab therapy.”

High TNF-a Foretells Relapse

The same investigators observed mucosal TNF-a levels in patients with CD to determine whether they would have a predictive value for identifying patients with long-term remission after cessation of therapy. They found that 21 of 39 patients had a remission, 14 after induction and 7 after 16 to 32 weeks of therapy. Of these 21, 14 relapsed, at a median time to relapse after discontinuation of therapy of 32 weeks for those patients with mucosal TNF-a levels <12000 copies/µg. But among patients with mucosal TNF-a above 12,000 copies/µg, median time to relapse was 12 weeks. Abnormally elevated levels of the cytokine “may have an impact on time to relapse, and may be one of several criteria in the evaluation of when to discontinue treatment with adalimumab,” they noted.

Persistence Pays Off

Altering the natural history of IBD is the ultimate goal of therapy, stated Dr. Stephen B. Hanauer, Joseph B. Kirsner Professor of Medicine and Clinical Pharmacology and Chief, Section of Gastroenterology and Nutrition, University of Chicago Medical Center, Illinois. This will include prevention of structural damage or repair when it occurs, in addition to the current goals of relief of symptoms and prolonged remission.

One step toward that ultimate goal appears to be the use of maintenance therapy, according to researcher Chureen Carter, PharmD, Horsham, Pennsylvania, and colleagues. They performed a retrospective claims analysis of data on 448 patients who were on continual infliximab maintenance for at least a year. They observed the effect of persistence with anti-TNF therapy on CD-related hospitalizations, length of stay and inpatient costs.

In all, 344 patients (76.8%) were identified as being persistent with infliximab (defined as a medication possession ratio of 80% or greater) and 104 (23.2%) were non-persistent. The authors found that significantly fewer persistent patients had a CD-related hospitalization at 9.0% compared with 16.3% for non-persistent patients (P=0.034). In addition, among those patients who did require hospitalization, mean and median inpatient costs were significantly lower for persistent patients at $13,704 (US) and $9938 vs. $40,822 and $28,864 for non-persistent patients (P=0.002). Persistent patients also had significantly shorter hospital stays at a mean 5.48, median 5 days, compared with 13.12 mean and 8 median days for non-persistent patients (P=0.010)

“Therapeutic persistence with maintenance infliximab over 12 months was associated with a lower rate of CD-related hospitalizations. Once hospitalized, persistent treatment resulted in lower CD-related inpatient costs and shorter hospital length of stay. Clinicians should monitor their patients with CD to ensure appropriate infliximab treatment paradigms,” the investigators reported in a poster presentation.

Summary

There is currently no cure for IBDs, but researchers and clinicians have made great strides in recent decades toward controlling these often debilitating chronic conditions. Continuing research efforts will focus not just on controlling disease, but ideally on altering its natural history.