Description of the condition
Crohn's disease is a chronic inflammatory disease of the gastrointestinal tract that typically affects young adults between 15 and 35 years of age. The prevalence of Crohn's disease is nearly 320 per 100,000, with the highest prevalence in Europe and North America. The prevalence of Crohn's disease in developing countries might be underestimated due to a lack of rigorous population-screening studies (Molodecky 2012).
Crohn's disease presents mainly with abdominal pain, diarrhoea, fever, malabsorption, and weight loss (Abraham 2009; Ruiz 2015). Crohn's disease causes both mucosal and transmural inflammation that can affect any part of the gastrointestinal tract, but mostly the small bowel (Wiarda 2012). There are three Crohn's disease behaviours (Montreal classification) that can occur at any time during the disease course. These are non-stricturing non-penetrating, stricturing and penetrating disease (Satsangi 2006). Common complications of Crohn's disease include perianal fistulae and abscesses. Some patients may have immune-mediated extra-intestinal (i.e. arthritis, eye, skin, and liver) manifestations (Isene 2015; Peyrin-Biroulet 2017).
Crohn's disease follows a relapsing and remitting course (Nikfar 2013). The therapeutic goal of treatment is to induce and maintain clinical remission. Different interventions have been investigated for inducing remission in active Crohn's disease (Dassopoulos 2013). These interventions include systemic corticosteroids such as hydrocortisone or prednisolone (Benchimol 2008), locally acting corticosteroids such as budesonide (Rezaie 2015), sulphasalazine (Lim 2016), tumour necrosis factor alpha (TNF-α) antagonists such as infliximab (Kawalec 2013), azathioprine (Chande 2016), interleukin inhibitors e.g. ustekinumab (MacDonald 2016), methotrexate (McDonald 2014) and alpha-4 integrin monoclonal antibodies such as vedolizumab (Sandborn 2013).
Immunosuppressive drugs are the standard treatment for Crohn's disease. For those who do not respond, or lose response to this therapy, treatment solutions become a challenge (Cooper 2017). Further, endoscopic recurrence following surgery may occur in up to 70% of cases (Day 2013; Lawrance 2014).
Description of the intervention
Stem cell therapy includes hematopoietic stem cells (HSCs) and mesenchymal stem (stromal) cells (MSCs). Stem cell therapy, whether HSCs or MSCs, can be subdivided into autologous donation (isolated from the patient) or allogenic donation (isolated from a donor, ideally human leukocyte antigen matched) (Dalal 2012; Duran 2016).
HSCs can be isolated from bone marrow, umbilical cord blood, or more commonly peripheral blood. HSCs are progenitors of both myeloid (monocytes, erythrocytes macrophages, neutrophils, and dendritic cells) and lymphoid (T cells, B cells, and natural killer cells) lineages. HSCs can be administered by an intra-arterial or intravenous approach (Duran 2016). MSCs can be successfully isolated for clinical application from bone marrow, umbilical cord blood or adipose tissue. MSCs can be administered by an intra-arterial or intravenous route or by local injection (Duran 2016).
How the intervention might work
The goal in treating CD is to achieve remission and halt any ongoing disease progression (Gomollón 2017). Stem cells have immunoregulatory potential. Therefore, stem cell therapy, either hematopoietic or mesenchymal, may induce remission in active CD (Dalal 2012; Dave 2015; Duran 2016; Ricart 2013).
HSCs extends immune modulation and suppression by maximizing immune suppression to the point of immune ablation. HSCs can migrate to a damaged tissue or differentiate to epithelial or immunomodulatory cells in order to restore normal mucosal tissue (Duran 2016). The role of HSCs in treating inflammatory bowel disease was originally supported by clinical remissions observed in patients undergoing stem cell transplant for haematological disorders. These observations led to trials of HSCs in patients with active Crohn's disease (Burt 2003; Burt 2010; Cassinotti 2008; Clerici 2011; Craig 2003; Kreisel 2003; Oyama 2005). The largest multi-centre randomised clinical trial of autologous HSCs in refractory CD was conducted from 2007 to 2011, with follow-up through 2013 (Hawkey 2015). The infusion of either autologous or allogeneic HSCs is associated with adverse events, with cardiovascular and pulmonary adverse events being the common (Vidula 2015).
MSCs are multipotent cells that have immunomodulating capabilities to down-regulate mucosal immune reactivity and promote tissue healing. MSCs can inhibit T-cell proliferation in vitro, and can inhibit lymphocyte proliferation by activating a programmed cell death pathway. There are only a few studies reporting on the use of autologous (Duijvestein 2010), or allogeneic (Forbes 2014), bone marrow-derived MSCs for luminal Crohn's disease. In fistulising CD, local injection of MSCs may be beneficial for healing of the fistula (Ciccocioppo 2011; de la Portilla 2013; Garcia-Olmo 2005; Garcia-Olmo 2009; García-Arranz 2016; Lee 2013).
Why it is important to do this review
Patients with active CD suffer high morbidity and mortality. Controversy regarding the potential benefits and harms of stem cell transplant for patients with active Crohn's disease still exists (Duran 2016; Gomollón 2017). This systematic review summarizes the current evidence regarding the efficacy and safety of stem cell transplantation in active Crohn's disease.