Autologous Stem Cell Transplantation
Since almost 30 years, small case series reported success of autologous stem cell transplantation (ASCT) for CD . Approximately 70% of patients achieved remission or disease activity could be controlled with standard therapy for CD [97, 98]. ASCT has subsequently been tested in the ASTIC trial, in which stem cells were mobilized in all patients with immediate transplantation in one arm and delayed ASCT after ≥1 year in the control group . ASTIC recruited patients with severe CD despite ≥3 therapies including steroids, not amendable to surgery. ASTIC further used a highly stringent composite end point of clinical remission (Crohn’s disease activity index < 150 for ≥3 months) 1 year after ASCT without steroids, immunosuppressants or biologics, and no radiologic or endoscopic evidence of disease activity. The study was negative since the primary end point was met by only 2 out of 23 patients in the treatment group versus 1 out of 22 controls. However, some benefits were suggested regarding secondary end points. Furthermore, long-term data from both treatment arms of this trial showed improvements regarding quality of life and endoscopic activity . Severe side effects, mainly infections, were frequent after therapy, and 1 patient in the ASTIC trial died of sinusoidal obstruction syndrome.
ASCT is a relevant treatment option for the most severe CD cases, refractory to all treatments. However, this option should be reserved for highly experienced centers. Development of safer treatment protocols remains the most important challenge.
Allogeneic Stem Cell Transplantation
Allogeneic stem cell transplantation is an established treatment option for childhood IBD (very early-onset IBD) with most patients suffering from inherited mutations in signaling pathways including IL-10R1 and IL-10R2 [101, 102]. However, even though potentially effective, due to high risks, allogeneic transplantation is rarely considered in adult IBD.
Mesenchymal Stroma Cell Therapy
Treatment with MSCs might be a paradigm shift in the treatment of fistulizing CD. MSCs are adherent cells with a fibroblast-like phenotype with reservoir function as stem cells for adipocytes, osteoblasts and chondrocytes [96, 103, 104]. MSCs constitute up to 1% of the cellular content of the adipose tissue but can also be found in the bone marrow and other tissues. Upon stimulation by pro-inflammatory cytokines, MSCs secrete a variety of immunosuppressive molecules, thus decreasing overall inflammation [105, 106]. In addition, MSCs can promote wound healing and tissue regeneration by secretion of TGF-β and fibroblast growth factor, and MSCs are also able to differentiate into fibroblasts or endothelial cells for formation of granulation tissue [106-108]. Thus, MSCs combine anti-inflammatory and regenerative properties, and both of these properties would be of value for the treatment of fistulizing CD. MSCs do not express MHC II, and only low amounts of MHC I, and do not stimulate T cells, thus enabling escape from immune surveillance and low rejection after transplantation [104, 109].
MSCs have been successfully used for the treatment of active complex perianal fistula in CD patients. In a large study with 212 patients, 120 million adipocyte-derived MSCs were injected into the fistula tract and the primary end point of absence of fistula discharge, and lack of large fluid collection on MRI >2 cm was met in 50% of patients in the treatment group versus 34% with placebo . A recent meta-analysis demonstrated an effect of MSC treatment with an OR for fistula persistence of 0.21 . Overall, treatment of MSCs has found to be generally safe even though long-term data are still lacking. Malignant transformation of stem cells would be a potential concern since protumorigenic effects have been observed in mice [112, 113]. However, to the best of our knowledge, no cases have been reported in humans. MSCs have been approved for the treatment of fistulizing CD in various countries and provide an attractive treatment option for the subgroup of CD patients with treatment-refractory perianal fistula. In contrast, systemic use of MSCs for the treatment of luminal CD is less established, and future studies would be needed [96, 104].
Mesenchymal stem cell therapy is an innovative therapy for CD fistula with surprisingly high success rates in this very hard-to-treat patient population. While MSC therapy is currently established in large centers, costs, logistical challenges, and lack of long-term data so far limit wide-spread application.