Allogeneic Bone Marrow–Derived Mesenchymal Stromal Cells Promote Healing of Refractory Perianal Fistulas in Patients With Crohn’s Disease

Molendijk, Ilse; Bonsing, Bert A.; Roelofs, Helene; Peeters, Koen; Wasser, Martin; Dijkstra, Gerard; Woude, C. Janneke van der; Duijvestein, Marjolijn; Veenendaal, R. A.; Zwaginga, Jaap‐Jan; Verspaget, Hein W.; Fibbe, Willem E.; Jong, Andrea E. van der Meulen–de; Hommes, Daniël W.

doi:10.1053/j.gastro.2015.06.014

Cited by 281 publications

(260 citation statements)

References 30 publications

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“…Crohn's disease is associated with the development of complex fistulas that are challenging to treat 141,142 . Adipose derived allo geneic stem cells have been considered as new treatment approaches for such fistulas 142,143 .…”

Section: T Cellmentioning

confidence: 99%

Current and emerging therapeutic targets for IBD

Neurath

2017

Nat Rev Gastroenterol Hepatol

513

403

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Inflammatory bowel diseases (including IBD, exempli fied by Crohn's disease and ulcerative colitis) are chronic relapsing disorders affecting the gastrointestinal tract. IBD has a progressive and destructive nature and, there fore, can cause various complications including steno ses, abscesses, fistulas, extraintestinal manifestations and colitis associated neoplasias and cancer 1,2 . Thus, effective therapeutic approaches are of high clinical rele vance in patients with IBD. This Review summarizes current therapeutic strategies and highlights emerging new treatment approaches for IBD with special refer ence to the proposed molecular mechanisms of action of anti inflammatory drugs. Current IBD therapiesClassic anti-inflammatory drugs. 5 Aminosalicylates (5 ASAs) are important anti inflammatory drugs that are frequently used for anti inflammatory therapy in patients with ulcerative colitis 3 . By contrast, 5 ASA based drugs show little or no efficacy in inducing res olution of clinical symptoms and tissue inflammation in patients with Crohn's disease 4 .5 ASAs are effective for induction and mainten ance of remission in ulcerative colitis and might also reduce the risk of developing colitis associated tumours in these patients 5 . Several mechanisms of action for 5 ASAs have been proposed, including reduction of prostaglandin synthesis via inhibition of cyclooxygenase, suppression of proinflammatory cytokine production and oxygen free radicals, inhib ition of lipoxygenase, blockade of neutrophil chemo taxis and mast cell activation, and impairment of nuclear factor κB activation (NF κB) in immune cells 3 . Moreover, studies in mice revealed that 5 ASA based drugs augment peroxisome proliferator activated receptor γ (PPARγ) expression and promote PPARγ translocation from the cytoplasm to the nucleus where they result in activation of peroxisome proliferator hormone response element driven genes to suppress colitis activity 6,7 .In addition to 5 ASAs, corticosteroids (systemically or topically delivered) have been used for remission induction in ulcerative colitis 2 . Although cortico steroids favour induction of remission in both ulcer ative colitis and Crohn's disease, they are not suitable for mainten ance of remission in IBD 1,2 . Mechanistically, gluco corticoids bind to a specific cytosolic receptor fol lowed by translocation of the complex to the nucleus to either activate or repress gene transcription (via bind ing to DNA corticosteroid response elements) 8,9 . Additionally, the glucocorticoid-receptor complex can inactivate pro inflammatory transcription factors such as NF κB and activator protein 1 (AP1) via proteinprotein inter actions, thereby preventing their activation of inflammatory mediators (for example, leukotrienes and cytokines such as IL 1 and IL 6). REVIEWS© 2 0 1 7 M a c m i l l a n P u b l i s h e r s L i m i t e d , p a r t o f S p r i n g e r N a t u r e . A l l r i g h t s r e s e r v e d .

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Section: T Cellmentioning

confidence: 99%

Current and emerging therapeutic targets for IBD

Neurath

2017

Nat Rev Gastroenterol Hepatol

513

403

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“…A summary of study characteristics is shown in Table 1, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75.…”

Section: Resultsmentioning

confidence: 99%

“…Six studies reported the outcome of stem cell therapy; five open label/phase I or II trials59 60, 63 65, 66, with longer‐term follow‐up61 of the cohort initially reported by Cho et al 60. in 2013.…”

Section: Resultsmentioning

confidence: 99%

“…Improvement in symptoms was noted in a large proportion of patients. This was assessed at 8 weeks 60 , defined as a variable time point of ‘no discharge for 6 weeks’59, or at clinic appointments at 12 and 24 months 61 .…”

Section: Resultsmentioning

confidence: 99%

“…Local complications included anal pain in 19 per cent66, anal inflammation in 7 per cent61, perianal swelling in 29 per cent59 and perianal abscess in 17–19 per cent59 66 of patients.…”

Section: Resultsmentioning

confidence: 99%

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Systematic review of surgical interventions for Crohn's anal fistula

Lee

Heywood²,

Adegbola

et al. 2017

BJS Open

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BackgroundAnal fistula occurs in approximately one in three patients with Crohn's disease and is typically managed through a multimodal approach. The optimal surgical therapy is not yet clear. The aim of this systematic review was to identify and assess the literature on surgical treatments of Crohn's anal fistula.MethodsA systematic review was conducted that analysed studies relating to surgical treatment of Crohn's anal fistula published on MEDLINE, Embase and Cochrane databases between January 1995 and March 2016. Studies reporting specific outcomes of patients treated for Crohn's anal fistula were included. The primary outcome was fistula healing rate. Bias was assessed using the Cochrane ROBINS‐I and ROB tool as appropriate.ResultsA total of 1628 citations were reviewed. Sixty‐three studies comprising 1584 patients were ultimately selected in the analyses. There was extensive reporting on the use of setons, advancement flaps and fistula plugs. Randomized trials were available only for stem cells and fistula plugs. There was inconsistency in outcome measures across studies, and a high degree of bias was noted.ConclusionData describing surgical intervention for Crohn's anal fistula are heterogeneous with a high degree of bias. There is a clear need for standardization of outcomes and description of study cohorts for better understanding of treatment options.

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