Enterocutaneous fistulas (ECF) are abnormal communications between the gastrointestinal tract and the skin. Although rare, they are associated with considerable morbidity and mortality. Death related to ECF remains disproportionately high when compared with other surgical conditions. Mortality rates for ECF vary from 6 - 33% [1–5].
The incidence and aetiology of fistula are highly dependent on the surgical experience and case load at particular institutions and on patient and disease related cofactors. Much of the published data relate to experience at specialised centres treating complex cases in particularly unstable patients. St. Mark's Hospital is a national and international referral centre for intestinal and colorectal disorders. It is one of two national intestinal failure centres in England. The Intestinal Failure Unit has a long standing interest in inflammatory bowel disease (IBD), and this is reflected in the high prevalence of IBD patients treated. A recently completed audit has revealed 177 patients with enterocutaneous fistulas managed at St. Mark's Hospital over 8 years (January 2003 to June 2010). Inflammatory bowel disease was present in 85 (48.0%) patients. Of these, 69 patients had Crohn's disease and 16 ulcerative colitis.
It is estimated that 75-85% of ECF that form after an operation occurs as a result of bowel injury or anastomotic leakage[1, 7]. Fistula formation is usually associated with surgery in the presence of IBD, malignancy or with division of dense adhesions[1, 7]. In the remaining 15-25% of cases, ECF form spontaneously secondary to the underlying pathology, with the most occurring in those with Crohn's disease[1, 7].
Fistula formation can result in a number of serious or debilitating complications, varying from disturbance of fluid and electrolyte balance to sepsis and even death. The patient will almost always suffer from severe discomfort and pain. They may also have psychological problems, including anxiety over the course of their disease, and a poor body image due to the malodorous drainage fluid. Post-operative fistula formation often results in prolonged hospitalisation, patient disability, and enormous cost. Therapy has improved over time with the introduction of parental nutrition, intensive post-operative care, and advanced surgical techniques, which has reduced mortality rates.
Although ECF can close spontaneously, those that remain open after 2 months, surgical intervention is likely to be needed as spontaneous closure is unlikely after this interval [1, 9]. It should be noted that major abdominal surgery stimulates the formation of dense adhesions. This reaction is most severe between 3 weeks and 3 months after an operation, and further surgery during this time is more likely to be complicated by fistula recurrence [1, 10, 11].
The local production of tumour necrosis factor alpha (TNF-α) is thought to have a key role in the initiation and propagation of Crohn's disease. Production of TNF-α in the intestinal mucosa, serum and stool is increased in patients with Crohn's disease.
There are numerous biological activities that are attributed to TNF-α activation. Some of these include induction of the pro inflammatory cytokines such as IL-1, IL-6 and enhancement of leukocyte movement or migration from the blood vessels into the tissues by increasing the permeability of the endothelial layer of blood vessels.
In animal models, antibodies to TNF-α prevent or reduce inflammation[13–17], suggesting that therapy with such antibodies may be useful for chronic inflammatory disorders.
Infliximab has been approved for treating ankylosing spondylitis, Crohn's disease, fistulising Crohn's disease, psoriatic arthritis, psoriasis, rheumatoid arthritis, and Ulcerative colitis. It has also been used in the treatment of Behçet's disease  and sciatica due to slipped discs.
Infliximab is a genetically constructed IgG1 murine - human chimeric monoclonal anti TNF antibody that inhibits a broad range of biological activities of TNF-α, potentially by blocking the interaction of TNF-α with its receptors, or causing lysis of cells that produce TNF-α .
Infliximab was first used for closure of fistulae in Crohn's disease in 1999. In a phase II clinical trial with 94 patients who had draining abdominal or perianal fistula, the researchers showed that Infliximab was effective in closing fistula in 56-68% of patients.
A Phase III clinical trial (ACCENT 2) showed that infliximab was additionally beneficial in maintaining closure of fistula, with almost two-thirds of all patients treated with the 3 initial doses of infliximab having a fistula response after 14 weeks, and 36% of patients maintaining closure of fistula after a year, compared with 19% who received placebo therapy .
It is likely that persistent inflammation prevents adequate healing of these fistulas and that TNF-α and the subsequent stimulation of the pro-inflammatory cascade promotes their existence.
Infliximab is currently not indicated for ECF caused by conditions other than IBD. A recent small case series of three patients has reported healing of persistent ECF not associated with IBD to have healed following a single infusion of infliximab. There are no other studies to support this series in the use of infliximab for non-IBD ECF. The inflammatory activity of non-IBD ECF has not been assessed in the past and the level of TNF- α activity in these cases is not known.
There is also no study of association of TNF-α with Dendritic cells (DC). DC are potent antigen presenting cells that bridge the adaptive and innate immune systems to induce and regulate immune responses. They present as 'immature' cells specialised for antigen uptake in most tissues of the body, particularly at sites of interface with the external environment such as the skin and mucosae and ECF. A property that distinguishes DC from other types of antigen presenting cell is their potency in activating naïve T cells, which interaction generally occurs in secondary lymphoid tissue. Upon activation DC produce pro-inflammatory cytokines such as IL-12, IL-6 and TNF-α. They also up-regulate and imprint homing markers such as cutaneous leukocyte antigen (CLA), also known as skin homing marker and β7, a gut homing marker, on T cells .
Immunological factors and their interaction are in operation within non-IBD ECF. The level of TNF-α activity is similar in non-IBD ECF and IBD ECF but elevated when compared with control small bowel.
The aim of this study is to assess the inflammatory activity, with a particular emphasis on TNF-α of non-IBD ECF when compared with IBD ECF and control small bowel. If this study can show the presence of TNF-α in the fistula tract then there would be a potential for a novel therapy for patients with persistent ECF not associated with IBD. This would be an alternative option and benefit an already surgically challenging group of patients associated with a high morbidity and mortality where it is deemed conservative management has failed.
We will assess prospectively immunological factors involved in the pathogenesis in non-IBD ECF. We will compare immunological factors in three groups of patients;
Group (i) non-inflammatory bowel disease ECF
Group (ii) inflammatory bowel disease ECF
Group (iii) normal bowel mucosa (control group)