Original article
Long-Term Follow-Up of Crohn Disease Fistulas After Local Injections of Bone Marrow–Derived Mesenchymal Stem Cells

https://doi.org/10.1016/j.mayocp.2015.03.023Get rights and content

Abstract

Objective

To assess the long-term outcome of patients treated with serial intrafistular injections of autologous bone marrow–derived mesenchymal stem cells (MSCs) for refractory Crohn fistulas in terms of safety and efficacy.

Patients and Methods

Starting from January 10, 2007, through June 30, 2014, clinical evaluation, calculation of the Crohn disease activity index (CDAI), therapeutic management, and documentation of adverse events in 8 of the 10 patients (5 men; median age, 37 years) who had been injected locally with MSCs were prospectively recorded for 72 months. Cumulative probabilities of fistula recurrence and medical or surgical treatment were estimated using a Kaplan-Meier method, whereas differences among the pre- and post-MSC CDAI values were calculated with the Mann-Whitney U test.

Results

Following disease remission observed after 12 months from MSC treatment (P<.001), the mean CDAI score increased significantly during the subsequent 2 years (P=.007), and was then followed by a gradual decrease, with the patients achieving remission again (P=.02) at the end of the 5-year follow-up. The probability of fistula relapse-free survival was 88% at 1 year, 50% at 2 years, and 37% during the following 4 years, and the cumulative probabilities of surgery- and medical-free survival were 100% and 88% at 1 year, 75% and 25% at 2, 3, and 4 years, and 63% and 25% at 5 and 6 years, respectively. No adverse events were recorded.

Conclusion

Locally injected MSCs constitute a safe therapy that rescues refractory patients and regains responsiveness to drugs previously proved ineffective.

Section snippets

Study Population and Protocol

Starting from January 10, 2007, through June 30, 2014, 10 patients with CD who had undergone serial intrafistular injections of autologous bone marrow–derived MSCs (median, 4; range, 2-5; scheduled at 4-week intervals) as compassionate use for patients with refractory disease or inability to undergo standard therapies12 were prospectively enrolled in this study. The study parameters, including careful clinical and perianal examination, routine laboratory tests, and calculation of the CDAI,14

Long-Term Outcome and Management

A total of 8 (median age, 37 years; range, 21-64 years) of the 10 patients who completed the first 12-month follow-up period after the end of treatment with serial local injections of autologous bone marrow–derived MSCs for refractory fistulizing CD12 were available for the further 5-year assessment. Their demographic and clinical features are presented in the Table. As regards fistula localization, 7 had complex perianal fistulas, whereas the remaining patient (no. 4) had had multiple

Discussion

Over the past decade, great efforts have been made to improve and standardize the complex management of fistulizing CD, which is now based on a balanced use of both medical and surgical approaches.18 In this regard, the availability of new tools such as several biological agents and an array of specific procedures such as mucosal advancement flap, muscle transposition, ligation of the intersphincteric fistula tract, and the use of bioprosthetic plugs or fibrin glue18 have made the treatment of

Conclusion

Our evidence opens up several issues in the use of local injections of MSCs for Crohn fistulas that have important implications for physicians and patients. First, this treatment option seems highly efficacious in refractory conditions in the short term and the medium term (up to 12 months), thus rescuing the patients from severely disabling symptoms. Nevertheless, most of the patients relapse to varying extents at later time points, but regain responsiveness to drugs that had previously proved

Acknowledgment

We are grateful to Ms Sheila McVeigh for her thorough revision of the English text.

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    Grant Support: This study was financed by grants (R.C.) from the IRCCS San Matteo Hospital Foundation (Progetti di Ricerca Corrente), project titled “Studio immunofenotipico e funzionale delle cellule stromali mesenhimali midollari di pazienti affetti da malattie infiammatorie croniche intestinali,” (project no: 08064409) and Ministero dell’Istruzione, dell’Università e della Ricerca (Progetti di Rilevante Interesse Nazionale), project titled “Study of immunomodulatory and immunosuppressive effects of mesenchymal stem cells on T lymphocytes of patients with Crohn’s disease” (prot. 2010K34C45_007).

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