List of Abbreviations
Adipose-derived stem cells
The Crohn’s Disease Activity Index
Inflammatory bowel disease
Mesenchymal stem cells
The Perianal Disease Activity Index
Tumor necrosis factor
Crohn’s disease (CD) is one of the important disorders that compose the inflammatory bowel disease complex, with a reported incidence of 1.34 to 7.1/100.000 persons in Western countries. This inflammatory disease compromises the whole intestinal tract from mouth to anus, with its main locations in ileum, colon, and rectum. The different phenotypes include inflammatory, stricturing, and penetrating disease. Currently, CD patients are divided in subgroups on the Montreal Classification ( Table 18.1 ) which is modified from the Vienna Classification, based on age at diagnosis, and location and behavior of the disease. If fistulizing perianal disease is present, the suffix “p” is added. Perianal disease is common in CD, which is observed in 13%–40% of patients at the time of diagnosis, and the cumulative risk at 20 years of disease course is estimated between 26% and 28%.
|Vienna a||Montreal b|
|Age at diagnosis||A1 age < 40 years||A1 age < 16 years|
|A2 age > 40 years||A2 age 17–40 years|
|A3 above 40 years|
|Location||L1 ileal||L1 ileal|
|L2 colonic||L2 colonic|
|L3 ileocolonic||L3 ileocolonic|
|L4 upper||L4 isolated upper disease c|
|Behavior||B1 non-stricturing, non-penetrating||B1 non-stricturing, non-penetrating|
|B2 stricturing||B2 stricturing|
|B3 penetrating||B3 penetrating|
|p perianal disease modifier|
a Gasche C, Scholmerich J, Brynskov J, D’Haens G, Hanauer SB, Irvine EJ, Jewell DP, Rachmilewitz D, Sachar DB, Sandborn WJ, Sutherland LR. A simple classification of Crohn’s disease: report of the Working Party for the World Congresses of Gastroenterology, Vienna 1998. Inflamm Bowel Dis 2000; 6 :8–15.
b Silverberg MS, Satsangi J, Ahmad T, Arnott ID, Bernstein CN, Brant SR, Caprilli R, Colombel JF, Gasche C, Geboes K, Jewell DP, Karban A, Loftus EV Jr, Peña AS, Riddell RH, Sachar DB, Schreiber S, Steinhart AH, Targan SR, Vermeire S, Warren BF. Toward an integrated clinical, molecular, and serological classification of inflammatory bowel disease: report of a Working Party of the 2005 Montreal World Congress of Gastroenterology. Can J Gastroenterol September 2005; 19 (Suppl. A):5A–36A.
CD-related perianal fistulae have a different pathogenesis from cryptoglandular fistulae. CD-related perianal fistulae are often associated to active proctitis or active inflammation in the anal canal. Generally, CD perianal disease presents with abscesses and local sepsis, and its anatomy is characterized by multiple complex fistula tracts and sinuses ( Fig. 18.1 ). Patients with perianal CD show an important adverse impact in their quality of life.
Currently, the initial approach for perianal abscess in CD patient is surgical drainage, and the placement of draining setons in the corresponding fistula tracts to prevent recurrent formation of abscesses ( Fig. 18.2 ). However, the carriage of setons itself decreases the quality of life. A recently published metaanalysis reports an initial healing rate of 14%–100% in patients with CD treated with setons, but with a high recurrence rate of up to 83%.
Definite treatment of CD-related fistulae is complex, due to the fact that there are many different surgical techniques available, and there is no single standard treatment that would have shown satisfactory long-term results by itself. The two major problems of surgical treatment are the high rate of recurrence and the potential risk of fecal incontinence due to iatrogenic or disease-related sphincter damage. The most commonly used surgical technique is the endorectal advancement flap ( Fig. 18.3 ), which has shown favorable initial results with healing rates between 64% and 89%, but the observed recurrence rates are still high (around 50%), which is certainly not satisfactory.
One of the reasons for failure of surgical treatment or fistula recurrence is the fistulizing nature of the underlying disease. This means, that meanwhile underlying CD is active, fistula healing will be difficult or even impossible. In consequence, the patient needs to be taken to disease remission before trying to repair the complex fistulae.
Before biological treatment became available, immunomodulation therapy with azathioprine, 6-mercaptopurine (6-MP) or methotrexate was applied and antibiotics had been routinely used to control fistulizing disease. The immunomolator therapy may achieve, moderate success, up to 54% partial healing and 39% complete healing.
Certainly, antibodies against tumor necrosis factor (TNF) have been shown to improve the outcomes of perianal CD. Studies have shown the efficacy of these agents in fistula healing. However, the reported rate of complete fistula closure ranged from 17% to 93%, and the rate of recurrence ranged from 8% to 41%. A combined treatment modality with anti-TNF biological agents and seton placement has shown an added value, with complete rate of healing in up to 65% of cases, but still with a number of recurrence (50% of patients) at a midterm follow-up. The challenge in obtaining long-term healing of fistulizing disease results from an impairment of the wound healing process in the context of underlying CD. Therefore, efforts have been made to identify adjunct treatments which can address this impaired would healing process and eventually improve long-term outcomes.
General Aspects of Stem-Cell Therapy
Regenerating cell therapy based on mesenchymal stem cells (MSCs) is a relatively new field of research and development, which has opened a new branch of treatment options for different diseases, including CD patients with fistulizing disease. Stem cells (SCs) are indifferentiated cells, which are autoregenerating constantly. They are capable of unlimited mitosis even under culture conditions and represent the starting point for the formation of various mature tissues. Depending on local physical and biochemical conditions of the surrounding tissue, stem cells are able to differentiate into different cell lineages ( Table 18.2 ).
|Type of Differentiation||Differentiation Factors|
|Adipogenic||Insulin, 3-isobutyl-1-methylxanthine, dexamethasone, rosiglitazone, indomethacin,|
|Chondrogenic||5-azacytidine BMP-6, 5-azacytidine BMP-7, GFG-2, TGF-β1, TGF-β2, TGF-β3, dexamethasone, IGF-1|
|Osteogenic||1,25(OH) 2 D 3 , β-glycerophosphate, ascorbic acid, BMP-2, dexamethasone, valproic acid|
|Cardiomyogenic differentiation||Trichostatin A,5-azacytidine|
|Hepatic||Hepatocyte growth factor, oncostain dimethyl sulfoxide|
|Neurogenic||EGF, FGF, 25uM fluvastatin, B27/Neurobasal medium (B27/N medium), 5-azacytidine|
|Pancreatic/endocrine||Activin-A exendin-4, pentagastrin, hepatocyte growth factor, nicotinamide, high glucose concentration|