Evidence mounts for gut worm therapy

Two sets of findings presented at the 2004 Digestive Disease Week meeting lend strength to the belief that helminthic therapy may be a highly effective treatment for inflammatory bowel disease (IBD) in a double-blind, randomized, placebo-controlled study that included 54 patients with ulcerative colitis (UC), approximately 50 percent of the patients responded to Trichurisuis ova therapy.

In addition, in an open-label study of 29 patients with refractory Crohn’s disease (CD), 79.3 percent of the subjects responded to treatment, and 72.4 percent achieved clinical remission.

Despite these findings, Associate Professor of Medicine, University of Chicago Pritzker School of Medicine, and Co-director, Clinical IBD Services, Division of Gastroenterology and Nutrition, University of Chicago Hospitals, told that helminthic therapy requires more vigorous study and scrutiny before it can be deemed effective in treating IBD. The helminthic hypothesis is interesting, and although the results from these studies do not prove it to be correct, they should lead to further investigations with these or similar agents. The study’s primary investigators, Professor of Internal Medicine and Director of the Division of Gastroenterolog-Hepatology at the University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, and a member of the University of Iowa IBD research team, have previously studied the efficacy of T. suis in a series of seven patients – four with CD and three with UC. Study findings revealed that six (86 percent) of the seven subjects achieved remission. However, because of the small sample size, the encouraging findings were no more than an indication for further research on helminthic therapy for IBD. The group’s rationale for using helminthes to treat IBD is based on a line of reasoning known as he "hygiene hypothesis". The theory argues that improved hygiene in Western countries has led to the elimination of various microorganisms, which alters an individual’s immune response and leads to increased rates of certain diseases, including IBD.

Helminthes are one class of microorganisms that have been eliminated as a result of high standards of hygiene. They began to disappear early in the 20th century corresponding with a rise in the incidence of IBD. Research has shown that helminthes have immunomodulator effects, affecting cells that regulate CD4+T helpter (Th) 1 and Th2 subsets.

Because IBD may result from overactive immune responses to intestinal bacteria, reasoned that administering helminthes to patients with IBD would dampen these abnormal immune responses and thereby relieve their symptoms. Moreover, because helminthes are endemic in other countries, where, by and large, they are not associated with disease, the researchers believed that administering worm therapy would be safe.

To date, their research has supported both hypotheses. In a continuation of their previous work, two doctors and colleagues conducted two separate studies.

The first, an open-label study, included 29 patients with long-standing, refractory CD and a mean CD activity index (CDAI) score of 296.7. Patients received 2,500 T. suis ova orally every three weeks for 24 weeks. For each patient, the investigators conducted a thorough medical history, a physical examination, complete blood count, liver profile tests and stool examinations for ova and parasites every six weeks. Participants who were taking other medications concurrently maintained stable doses throughout the study period. The researchers used an intent-to-treat analysis to interpret the outcomes. The investigators found that after 12 weeks of T. suis therapy, 22 (75.9 percent) of 29 patients exhibited a decrease of between 100 and 150 points on the CDAI. More than half (62.1 percent) of the patients achieve remission, with a decrease on the CDAI of >100 points and a total CDAI score of <150. Improvements were maintained at 24 weeks, with 23 (79.3 percent) of 219 patients responding to therapy and 21 (72.4 percent) achieving remission. The mean CDAI score among responders was 286.3 at study outset, falling to 92 at 12 weeks and remaining stable at 99.9 after 24 weeks.

According to the researchers, no treatment-related adverse events occurred. Furthermore, treatment efficacy was not affected by disease location or duration, use of other IBD medications or smoking status. The open-label design of the study weakened the significance of the findings. They stated that "a placebo effect cannot be ruled out at this time." However, it was noted that placebo remission rates in studies of CD rarely exceed 30 percent and that the >70 percent remission rates in this study suggest that the treatment may be effective. However, clearly more studies are required. The second study that conducted was a double-blind, placebo-controlled, crossover study in which 54 patients with refractory UC were ramdomized to receive either 2,500 T. suis ova or placebo for 12 weeks, with doses administered every two weeks. After 12 weeks, patients receiving T. suis ova were administered placebo, and those receiving placebo were switched to T. suis ova. Patients in the two groups had similar characteristics of baseline and a mean UC disease activity index (UCDAI) score of 8.7 at study outset. Response to therapy in this study was defined as a decrease of >4 points on the UCDAI. As with the CD study, analysis of outcomes was conducted on an intent-to-treat basis. After 12 weeks, the researchers found that 13 (43.3 percent) of 30 T. suis patients met the responder criteria compared with only 4 (16.7 percent) of 24 placebo patients (P=0.04). UCDAI scores feel from a mean of 8.8 to 2.8 by week 12 of the study, indicating a response to therapy. Furthermore, at the end of the second, crossover phase of the study, the proportion of responders was 56.3 percent (9 of 16) among those who switched to T. suis ova, compared with 13.3 percent (2 of 15) of those who were switched to placebo (P=0.02). As in the CD study, no adverse events were reported. The researchers concluded that the combined results of both study phases suggests an overall ova response rate of 47.8 percent, compared with a placebo response rate of 15.4 percent (P=0.002). In light of the encouraging findings from both sets of researcher, doctors and a network of other researchers are planning large multicenter studies at T. suis therapy across the United States and Europe. It seems possible that helminthic therapy could prove effective and will have a good safety profile, but this must be confirmed in the upcoming multicenter trials.