Crohn's Disease

Summary — Crohn's disease is a field in which stem cell research has reached a large randomised phase 3 study. In a randomised, double-blind phase 3 study (2016) of patients with complex perianal fistulas associated with Crohn's disease, in which cultured mesenchymal stem cells from donor fat tissue were injected around the fistula, a higher proportion of the cell group than the control group achieved combined remission. On the basis of this result the product was approved in Europe, Japan and elsewhere, and the results of a follow-up phase 3 study have since been announced.

What is Crohn's disease?

Crohn's disease is an inflammatory bowel disease in which chronic inflammation can occur anywhere in the digestive tract from mouth to anus. It mostly affects the end of the small intestine and the colon, and inflammation characteristically extends into the deep layers of the bowel wall. Abdominal pain, diarrhoea, weight loss and fatigue are typical, and symptoms come and go. It usually begins in people in their teens to thirties and is thought to result from a combination of genetic predisposition, gut bacteria, immune responses and environmental factors.

Some people with Crohn's disease develop 'fistulas' around the anus — abnormal tracts connecting the inside of the bowel or anal canal to the skin around the anus. They discharge pus continuously and cause pain and recurrent inflammation, greatly reducing quality of life. 'Complex fistulas', with multiple or branching tracts, are particularly difficult to treat.

Current standard treatment

Crohn's disease itself is treated with anti-inflammatory drugs, steroids, immunomodulators and biologics such as TNF-α inhibitors, and several new classes of biologics and oral targeted drugs have recently been developed. Perianal fistulas are treated with antibiotics and biologics together with surgery, such as placing a drainage thread (seton) to drain pus and keep the tract open. Complex fistulas often fail to close or recur despite these treatments, and repeated surgery can damage the anal sphincter and raise the risk of faecal incontinence. Because of these limits, stem cell therapy was studied as a way to help fistulas close while preserving the sphincter.

Why stem cells are studied

Mesenchymal stem cells modulate immune responses and inflammation. The hypothesis is that, injected directly around a fistula, factors they secrete could calm excessive local inflammation and create an environment in which tissue heals, helping the fistula close. Mesenchymal stem cells from fat tissue can be obtained in relatively large amounts, and donor cells can be expanded in advance into a quality-controlled product.

Reported research findings

Randomised, double-blind phase 3 study (ADMIRE-CD, 2016) — in this study involving many institutions in Europe and Israel, about 200 adults with Crohn's disease and complex perianal fistulas that had not responded adequately to existing treatment were randomised. All first underwent cleaning of the fistula tracts; one group then received allogeneic adipose-derived mesenchymal stem cells injected around the fistula and the other saline. At 24 weeks, the proportion achieving 'combined remission' — closure of all external openings with no fluid collection on MRI — was about half in the cell group, higher than in the control group (about one-third). The study was published in the Lancet.

On this basis, the cell product was approved in the European Union in 2018 and in Japan in 2021 for complex perianal fistulas in Crohn's disease. The manufacturer later announced that a follow-up international phase 3 study, including North America, did not meet its primary outcome. This is an example of how the same treatment can produce different results in different studies, and why it is important to look at data after approval as well.

What has been reported about safety

In the phase 3 study, adverse events occurred at similar rates in the cell and control groups and were mainly events related to the underlying disease, such as perianal abscess or pain. Because the cells are injected locally, systemic effects are considered likely to be smaller than with intravenous administration.

Scope of interpretation

These results concern a specific condition — complex perianal fistulas in Crohn's disease — and a specific method, local injection. They cannot be applied directly to intestinal inflammation in Crohn's disease itself or to intravenous stem cell interventions. Studies of intravenous mesenchymal stem cells for intestinal inflammation in Crohn's disease have also been carried out but remain at an early stage. A review of the clinical use of mesenchymal stromal cells names standardised manufacturing and potency measurement as challenges for the field as a whole.

How results are measured in Crohn's fistula research

The effect of treatment on perianal fistulas is assessed with both clinical examination and imaging. Examination checks whether the external openings have closed and whether discharge appears with gentle finger pressure. Because a fistula may look closed outside while an abscess remains inside, pelvic MRI is used to check whether fistula tracts and fluid collections larger than 2 cm remain. 'Combined remission' in the ADMIRE-CD study meant meeting both criteria.

The Perianal Disease Activity Index (PDAI), measures of overall Crohn's disease activity and quality-of-life questionnaires are also used. Because fistulas often close temporarily and reopen, long-term follow-up confirming that remission lasts a year or more is also an important part of assessment.

The above summarises results reported in published papers and public-agency materials. University and institute names are given to identify research sources, not to introduce or recommend any medical institution. Reported results do not mean the same effect for everyone, and the suitability of any treatment is decided by the medical team.

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