Helminth Therapy in RA

An unorthodox treatment for rheumatoid arthritis is gaining steam in the laboratory.

Helminth therapy - using parasitic worms or their products to treat allergies or autoimmune disease - currently has a distinct underworld flavor. Patients buy eggs over the internet, share tips in online forums, and generally operate outside of the bounds of sober medical advice. But helminths now have the attention of medical researchers around the world who are conducting preliminary research.

With current treatments for rheumatoid arthritis, "most patients need to take more than one drug, and the current medication only eases the symptoms, while the disease remains," said Aline Bozec, a researcher in rheumatology and immunology at Friedrich Alexander University Erlangen-Nurnberg in Germany. "Helminth therapy might be a potential treatment.”

It's a big promise, and one with hurdles to meet before it makes it into the clinic.

In theory, helminth therapy could offer benefits over traditional treatments for rheumatoid arthritis. Today's medications are immunosuppressive, said Yehuda Shoenfeld, M.D., a rheumatologist at Tel Aviv University who studies helminth-derived therapies.

"Sometimes you immunosuppress too much and then patients may suffer from the development of infections," Shoenfeld said. "The helminth is much more clever."

Helminths want two things:  To survive inside their hosts without attracting immune attention, and to keep their hosts alive. They do this by excreting compounds that don't suppress the immune system, but modulate it. Immunomodulation is a much more sensitive tool than immunosuppression, Shoenfeld said.

The idea of using helminths to treat autoimmune disorders arose from the Hygiene Hypothesis, first proposed in 1989, which suggests that as societies reduce their exposure to microbes and parasites, the immune system is increasingly likely to turn on the body's own tissues (or, in the case of allergies, to overreact to the foreign triggers it does encounter). On a cellular level, helminths have been found to down-regulate Th17, to enhance T-regulatory and B-regulatory cell differentiation and to promote a Type 2 cytokine response, creating an anti-inflammatory environment.

"Overall, there is substantial evidence that the increased regulatory activity during helminth infection needs to strike a fine balance between protection against pathology and clearance of the infection," Helena Helmby, Ph.D., a researcher at the London School of Hygiene and Tropical Medicine, wrote in a 2015 review in BMC Immunology.

Helminths look promising in animal models of rheumatoid arthritis. A 2009 study in the International Journal of Parasitology found that infecting mice with collagen-induced arthritis (a model for RA) with the parasite Schistosoma mansoni down-regulated Th1, TNF-alpha and IL-17A while upregulating Th2 and the IL-10. These changes lessened the severity of the arthritis. Similar mouse model results have been seen using the tapeworm Hymenolepsis diminuta, and the blood fluke Schistosoma japonicum.

Bozec and her colleagues tested the roundworm Nippostrongylus brasiliensisin two mouse models, one with serum-induced arthritis and one genetically engineered to overexpress human TNF-alpha. In both cases, they found that roundworm infection spurred the accumulation of Th2 cells and eosinophils in the joints, which in turn inhibited both arthritis and bone loss.

"With different genetically modified mice, we could prove that this protective effect is dependent on IL-4/IL-13-induced STAT6 activation in hematopoietic cells," Bozec said. "Finally, we could also demonstrate the presence of these pathways in human disease by detection of GATA3-positive cells and eosinophils in the joints of rheumatoid arthritis patients."

Given the 'ick' factor of swallowing live parasites - not to mention concerns about side effects of an ongoing parasite infection - many researchers are less interested in using worms and their eggs to treat rheumatoid arthritis than they are in finding out what compounds these worms excrete to modulate the immune system. A 2012 study of mice with collagen-induced arthritis found that a total extract of the liver fluke Fasciola hepatica diminished the severity of arthritis, in part by increasing the population of T-regulatory cells.

The most well-studied helminth compound in rheumatoid arthritis is likely ES-62, which is produced by the nematode Acanthocheilonema viteae. Multiple studies have found that this compound suppresses inflammation and reduces the symptoms of arthritis in mouse models; in particular, a 2008 study published in the journal Annals of the Rheumatic Diseases, found that just one segment of the ES-62 molecule, a phosphorycholine, is responsible for the anti-inflammatory effect.

Shoenfeld and his colleagues have developed a compound mimicking this natural helminth product, tufsin-phosphorycholine (TPC). The group has tested TPC on a mouse model of colitis, systemtic lupus erythematosus and rheumatoid arthritis; all three studies have shown promising results.

"Now we are moving to see how it will affect human beings," Dr. Shoenfeld said. Beyond toxicity studies, the researchers are testing TPC in human tissue affected by rheumatoid arthritis, he said.

"We do hope that it will be found as effective in [these] models and in the future, that it will be an ideal therapy," he said.

So far, there is not any data on helminths or helminth-derived therapies for rheumatoid arthritis from human trials. One prospective, double-blind randomized controlled trial at the Immanuel Krankenhouse in Berlin is studying the effect of Trichuris suis (pig whipworm) eggs in patients with rheumatoid arthritis with an insufficient response to methotrexate. That study is still ongoing. Pig whipworm eggs are a popular choice for helminth therapy because the worms either don't hatch or don't live long in a human host. Patients have to take multiple doses of eggs as the batches died and the effects wear off, but the long-term risks of parasitic infection are lessened.  [[{"type":"media","view_mode":"media_crop","fid":"50015","attributes":{"alt":"©olgaru79/Shutterstock.com","class":"media-image media-image-right","id":"media_crop_1520553233341","media_crop_h":"0","media_crop_image_style":"-1","media_crop_instance":"6081","media_crop_rotate":"0","media_crop_scale_h":"0","media_crop_scale_w":"0","media_crop_w":"0","media_crop_x":"0","media_crop_y":"0","style":"font-size: 13.008px; line-height: 1.538em; float: right;","title":"©olgaru79/Shutterstock.com","typeof":"foaf:Image"}}]]

What will happen as helminth therapy research moves into humans is an open question, however. Some small studies have shown striking results, like a 2007 paper published in the Annals of Neurology that found major improvements in 12 multiple sclerosis patients treated with helminths and followed over four and a half years. Studies in other conditions have seen mixed results; while some placebo-controlled, double-blind research has found improvements in ulcerative colitis and Crohn's, Coronado Biosciences announced in a 2013 news release that its Phase 2 clinical trial testing Trichuris suis eggs in Crohn's patients did not meet its primary endpoint. The company later canceled a European Phase 2 study due to lack of efficacy, the London School of Hygiene and Tropical Medicine's Helmby wrote in BMC Immunology.

"One challenge might be to choose the appropriate parasite, which on the one hand is host-specific and can trigger the desired T-helper type 2 immune response, and on the other hand has no pathogenic potential and can't spread," Bozec said. There are also questions about dosing and how to properly administer the worms, she said. Side effects can include gastrointestinal symptoms or even malnutrition, and there is the potential that helminths might trigger asthma, which starts with the activation of a T-helper type 2 response, Bozec said.

"The challenge specific to rheumatoid arthritis is that all patients have different disease background, and the progression of the disease and former medication might influence the success of the parasite treatment," Bozec said.

While studies are underway, Bozec recommends that doctors temper the enthusiasm of patients who might be tempted to self-treat with parasites bought online.

"It is very important that the parasites they are using are not harmful and can't easily spread," she said. "Using untested parasites is not only dangerous for themselves, but also for nearby society."

References:

Versini M, Bizzaro G, Shoenfeld Y. Helminths and autoimmunity: the good, the bad and the ugly. Israel Medical Association Journal. 2015;14(4):249-250. http://www.ima.org.il/imaj/viewarticle.aspx?year=2015&month=04&page=249.

Helmby H. Human helminth therapy to treat inflammatory disorders- where do we stand? BMC Immunology. 2015;16:12. doi:10.1186/s12865-015-0074-3.

Osada Y, Shimizu S, Kumagai T, Yamada S, Kanazawa T. Schistosoma mansoni infection reduces severity of collagen-induced arthritis via down-regulation of pro-inflammatory mediators. International Journal for Parasitology. 2009;39(4):457-464. doi:10.1016/j.ijpara.2008.08.007.

Shi M, Wang A, Prescott D, et al. Infection with an intestinal helminth parasite reduces Freund's complete adjuvant-induced monoarthritis in mice. Arthritis & Rheumatism. 2011;63(2):434-444. doi:10.1002/art.30098.

Song X, Shen J, Wen H, et al. Impact of Schistosoma japonicum Infection on Collagen-Induced Arthritis in DBA/1 Mice: A Murine Model of Human Rheumatoid Arthritis. Idzko M, ed. PLoS ONE. 2011;6(8):e23453. doi:10.1371/journal.pone.0023453.

Salinas-Carmona MC, Cruz-Galicia GDL, Pérez-Rivera I, et al. Spontaneous arthritis in MRL/ lpr mice is aggravated by Staphylococcus aureus and ameliorated by Nippostrongylus brasiliensis infections. Autoimmunity. 2009;42(1):25-32. doi:10.1080/08916930802228290.

Carranza F, Falcón CR, Nuñez N, et al. Helminth Antigens Enable CpG-Activated Dendritic Cells to Inhibit the Symptoms of Collagen-induced Arthritis through Foxp3+ Regulatory T Cells. Zheng SG, ed. PLoS ONE. 2012;7(7):e40356. doi:10.1371/journal.pone.0040356.

Harnett MM, Kean DE, Boitelle A, et al. The phosphorycholine moiety of the filarial nematode immunomodulator ES-62 is responsible for its anti-inflammatory action in arthritis. Annals of the Rheumatic Diseases. 2007;67(4):518-523. doi:10.1136/ard.2007.073502.

Chen Z, Andreev D, Oeser K, et al. Th2 and eosinophil responses suppress inflammatory arthritis. Nature Communications Nat Comms. 2016;7:11596. doi:10.1038/ncomms11596.

Bashi T, Shovman O, Fridkin M, et al. Novel therapeutic compound tuftsin-phosphorylcholine attenuates collagen-induced arthritis. Clin Exp Immunol Clinical & Experimental Immunology. 2016;184(1):19-28. doi:10.1111/cei.12745.

Correale J, Farez M. Association between parasite infection and immune responses in multiple sclerosis. Annals of Neurology Ann Neurol. 2007;61(2):97-108. doi:10.1002/ana.21067.