Misconceptions, hurdles and recommendations regarding the use of mesenchymal stem/stromal cells in perianal Crohn disease

A fistula is defined as an abnormal communication between two epithelium-lined surfaces, and fistula-in-ano consists of an abnormal tract connecting the anal canal or rectum with the perianal skin or vagina [ [1] Goligher J. Fistula-in-ano. in: Goligher J. Surgery of the anus, rectum, and colon. 5th ed. Bailliere Tindall, 1984: 178-220 Google Scholar ]. When developing in Crohn disease, fistulas—considered an independent phenotype and referred to as perianal disease [ [2] Satsangi J, Silverberg MS, Vermeire S, Colombel J-F. The Montreal classification of inflammatory bowel disease: controversies, consensus, and implications. Gut 2006;55:749-53. Google Scholar ]—represent a grievous and disabling condition, resulting in significant human and health care costs because of a high relapse rate despite the use of biologics combined with surgery as standard therapy [ [3] Molendijk I Nuij VJ van der Meulen-de Jong AE. Disappointing durable remission rates in complex Crohn's disease fistula. Inflamm Bowel Dis. 2014; 20: 2022-2028 Crossref PubMed Scopus (88) Google Scholar ]. The advent of novel therapeutic strategies based on minimally invasive surgery and mesenchymal stem/stromal cells (MSCs) offers an unprecedented opportunity. Following the results of a phase 3 trial in which 212 patients were randomly assigned to receive a single local injection of 120 millions of allogeneic adipose tissue-derived MSCs (darvadstrocel, formerly Cx601) or placebo, which showed that MSCs performed better to achieve combined remission (51.5% versus 35.6% at week 24) within a shorter time [ [4] Panés J García-Olmo D Van Assche G Colombel JF Reinisch W Baumgart DC et al. Expanded allogeneic adipose-derived mesenchymal stem cells (Cx601) for complex perianal fistulas in Crohn's disease: a phase 3 randomised, double-blind controlled trial. Lancet. 2016; 388: 1281-1290 Abstract Full Text Full Text PDF PubMed Scopus (650) Google Scholar ], the European Medicines Agency granted marketing authorization (Alofisel; Takeda, Tokyo, Japan) for use in refractory cases [ [5] EMA/1380/2018 EMEA/H/C/004258. https://www.ema.europa.eu/en/documents/overview/alofisel-epar-summary-public_en.pdf. Google Scholar ]. Since that time, several issues have been raised that hamper its use and jeopardize the knowledge regarding its therapeutic value. This prompted the authors to highlight in this editorial the misconceptions and hurdles that, based on the authors' own experience, hinder an appropriate application of this new treatment and to establish a list of recommendations whose implementation may help this therapy find its right positioning in the management of this dismal condition.