HTA of allogeneic mesenchymal stem cells for Crohn’s disease-associated complex perianal fistulas

Crohn’s disease is a chronic inflammatory condition characterized by transmural inflammation and skin lesions. It can lead to fibrosis and strictures or results in sinus tracts giving rise to micro perforations and fistulas. Fistulas usually occur when a fissure penetrates the gut wall, surrounded by granulation tissue with acute and chronic inflammation.

The authors have focused on allogenic mesenchymal stem cells (MSCs) in patients with complex perianal fistulas caused by CD. Current standard treatments are associated with high recurrence rates. During the actual process, via a fine long needle, allogeneic MSCs are injected locally and distributed into the patient’s tissue adjacent to all fistula tracts and internal openings. Allogeneic MSCs are assumed to prevent repeating surgeries, which can lead to high morbidity, and subsequently to a loss of quality of life (QoL). Additionally, due to their less invasive character, especially for the anal sphincter apparatus, they may prevent the need for a permanent stoma.

The authors’ objective was to reveal if adult human MSCs of allogeneic origin are more effective to increase remission rates and the QoL of CD patients with complex perianal fistulas. Another objective was to reveal if MSCs are safer concerning adverse events in comparison to placebo, fibrin glue or fistula plugs. 

The authors have performed a systematic literature search in four databases (Cochrane, CRD, Embase, Medline). The search included randomized controlled trials (RCTs) and prospective non-RCTs for efficacy and additionally, interventional single-arm studies for safety. The search ranged 2007 - 2017 and accepted publications in English or German language only. Finally, three (3) studies were included for further analysis. A search in three clinical trials registries (ClinicalTrials.gov; WHO-ICTRP; EU Clinical Trials) was conducted in order to identify ongoing and unpublished studies, resulting in 45 potential hits.

In order to address clinical effectiveness, two RCTs comparing allogeneic MSCs to placebo were considered. These studies had a total of 231 patients. Both of these reported improvements in combined remission in the interventional group compared to the placebo group. Neither of the two communicated on fistula-relapse-free-survival. Considering other outcomes, the results across the different scores were very inconclusive, indicating that MSC-therapy is not deemed to improve QoL or reduce the severity of the disease of the patients. The authors remind that the quality of this evidence is meagre.

In order to address safety, one (1) single-arm study with 24 was considered. No cases of mortality were reported. However, several adverse events were identified, anal abscesses being the most common ones. The authors remind that the quality of this evidence is also very poor.

In conclusion, the authors agree that an effective and safe allogeneic MSC-therapy would have a societal impact because the patients concerned are in the productive stage of their lives. But, the current evidence is not sufficient to prove that allogeneic MSCs in patients with complex perianal fistulas caused by CD, who are refractory to standard medical therapy, are more effective or safe compared to the placebo therapy. The fact that the product that could perform this procedure, Cx601 by Darvadstrocel, has not yet received marketing authorization, only supports the conclusion that in the inclusion of MSCs as add-on therapy in refractory CD-patients with complex perianal fistulas in the Austrian catalogue of benefits is not recommended. The authors suggest a new evaluation in 2022.

See the full report in English (with summary in German) here.

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