Hookworm Therapy for MS:
First Randomized Trial

June 18, 2020

Treatment with hookworm larvae was well tolerated in patients with multiple sclerosis (MS), and although the primary outcome was not met there was some evidence of a beneficial therapeutic effect in the first randomized clinical trial to evaluate such an approach.  

"It appears that a living organism can precipitate immunoregulatory changes that may affect MS disease activity," the study authors conclude.

"What I think is clear is that there is a therapeutic effect, but this is probably modest compared to the powerful disease-modifying drugs now available for MS," coauthor Cris S. Constantinescu, MD, PhD, University of Nottingham, UK, told Medscape Medical News.

"But I think there would be a niche for this approach — for individuals with mild disease who don't want to take immunomodulating drugs for life and would prefer a more natural approach," he added.

The study was published online June 15 in JAMA Neurology.

Constantinescu explained that helminths have cohabited in the human gut for thousands of years. "We became good friends and provided a mutual benefit to each other. We gave them a suitable host and they created an environment that reduces inflammatory processes."

The "hygiene" hypothesis suggests that by improving our hygiene practices we have removed these organisms or "old friends," which has led to an increase in autoimmune and inflammatory conditions, he noted.

In MS, there is good evidence that regulatory T cells — which normally prevent excessive inflammation — are defective. Hookworm infection has also been shown to restore regulatory T cell activity in experimental models, Constantinescu said.

For the study, 71 patients with relapsing MS without disease-modifying treatment were randomly assigned to receive hookworm therapy or placebo. The treatment was given as 25 Necator americanus larvae applied to the skin in a patch, mimicking natural infection.

MRI scans were performed monthly during months 3 through 9 of treatment, and then 3 months post-treatment.

The primary endpoint — the cumulative number of new/enlarging T2/new enhancing T1 lesions at month 9 — was not significantly different between the two groups, with 154 in the hookworm group vs 164 for the placebo group (mean based imputation).  

"However, looking more closely at the data, more than half the patients given hookworm did not have any new lesions, and the statistical model used loses power under these circumstances," Constantinescu said. "So in way we were the victim of our own success."

Of the patents treated with hookworm, 51% had no detectable MRI activity vs 28% of those who received placebo.

"In a post-hoc analysis focusing on the number of patients with no new lesions, there was a significant difference between the two groups," he added.

"This analysis hints at larger baseline enhancing lesion counts increasing the odds and, independently, hookworm treatment lowering the odds of subsequent detectable MRI activity," the researchers report.

The secondary endpoint, the percentage of regulatory T cells of total CD4+ cells in peripheral blood, significantly increased in the hookworm group and decreased in the placebo arm. "This is consistent with the expected immunological effects of helminths," the researchers say.

There were 5 clinical relapses (14.3%) in the hookworm group vs 11 (30.6%) in those receiving placebo.

There were no differences in adverse events between groups other than more application-site skin discomfort in the hookworm group (82% vs 28% placebo).

"While a major infection with hookworm is not entirely harmless — in Africa people may have infection with 1000 or more larvae and this can lead to growth retardation and cognitive problems — but with just 25 larvae we didn't see any issues," Constantinescu commented.    

"In hygienic conditions hookworm infection cannot be transmitted. The eggs are hatched in the stool and require 2 weeks in muddy earth to develop into larvae. The larvae are then normally absorbed through the skin in the feet by people walking barefoot.

"But in the modern world, if we give 25 larvae, then there will remain 25 larvae in the gut for several years. This is another potential advantage of this approach — it is likely to have a long and sustained effect," he added. 

The researchers gave patients a drug to kill the hookworm at the end of the study but they were not obliged to take it. "We plan to follow patients up, and compare those that took the drug and those that didn't to see if there were long-lasting effects of hookworm infection," Constantinescu said. 

"We also saw significant possible beneficial changes on gut microbiota with hookworm infection, and there were some differences in gut microbiota in those patients who had new lesions and those who didn't," he added. "We would like to study this more closely to see if we can target a more specific population who are responders."

He noted that the researchers did not have trouble recruiting patients for this study. "This particular group were very keen to try it. It does take a particular type of person though — those who prefer a natural treatment to a pharmaceutical approach."

They believe there is enough here to justify carrying on with this research, Constantinescu concluded. "This study has taught us a lot, but we hope to learn more about the biology and immunology of infection with different doses, including giving a second booster dose to enhance the therapeutic response."

"Keep the Worms in the Mud"

In an accompanying editorial, Daniel Ontaneda, MD, PhD, and Jeffrey A. Cohen, MD, Mellen Center for Multiple Sclerosis, Cleveland Clinic, Ohio, say the results of this trial should be interpreted cautiously.

"The effect on the immune profile is interesting; however, this finding cannot be translated to evidence of clinical efficacy," they write.

"Although the treatment with N americanus larvae has been safe, its efficacy appears modest, making it unlikely to be a sufficient stand-alone treatment for MS," the editorialists say. "Use of helminth therapy as an add-on treatment is difficult given the potential increase in infection rates when used with concomitant immunomodulating medications," they add.

"The implications regarding the effect of heightened, and even excessive, hygiene for preventing infection may be important for us to consider as we try to determine how to stop autoimmune diseases like MS. However, in terms of a tool for our therapeutic arsenal, the worms might just have to stay in the mud," they conclude.

This study was supported by the MS Society of the Great Britain and Northern Ireland, the Forman Hardy Charitable Trust via the University of Nottingham, and an unrestricted grant from Bayer-Schering.

Constantinescu has disclosed no relevant financial relationships. Several coauthors reported relationships with industry relevant to the study. The full list can be found with the original article. Ontaneda reported grants from the National Multiple Sclerosis Society, National Institutes of Health, Patient-Centered Outcomes Research Institute, and Genzyme; grants and personal fees from Genentech and Novartis; and personal fees from Merck outside the submitted work. Cohen reported personal fees from Adamas, Convelo, MedDay, Mylan, and Population Council as well as serving as editor of Multiple Sclerosis Journal outside the submitted work.

JAMA Neurol. 2020. Published online June 15. Abstract, Editorial

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