Leflunomide-induced colitis in association with enterocutaneous fistula in an immunosuppressed patient with renal transplant and rheumatoid arthritis.

We describe the case of a 68-year-old man who has a complex medical background that included renal transplantation, rheumatoid arthritis and atrial fibrillation. Because of this, he was taking a number of immunosuppressant medications including leflunomide, prednisone and tacrolimus. He had experienced chronic diarrhoea over 18 months which had acutely worsened over the 6 weeks prior to hospital presentation. Recent colonoscopies had been performed to investigate this diarrhoea with biopsies revealing acute and chronic inflammatory changes in the terminal ileum and colon. No infectious cause could be found, with all bacterial and viral stool cultures returning negative. An enterocutaneous fistula had also spontaneously developed through his renal transplant scar in the days preceding hospital admission which complicated the clinical picture. Following dose reduction of leflunomide, there was a significant improvement in the frequency and severity of the patient's diarrhoea. He continues to be managed non-operatively for his fistula as he is at high risk of peri-operative morbidity and mortality.

Pilot study of immunological factors in non-inflammatory bowel disease enterocutaneous fistulas.

BACKGROUND: Tumour necrosis factor alpha (TNF-α) is a cytokine elevated in inflammatory bowel disease enterocutaneous fistula (IBD ECF). Dendritic cells are antigen presenting cells that orchestrate the immune responses and regulate the production of cytokines by immune cells including T cells. No study to date has assessed the level of TNF-α or the presence of dendritic cells in non-IBD ECF. The aim of this study was to assess the inflammatory activity, with a particular emphasis on TNF-α in non-IBD ECF when compared with control small bowel tissue. METHODS: Tissue biopsies were obtained from ECF at operation from non-IBD patients and from terminal ileum in normal colonoscopy control patients. After overnight culture, accumulation of intracellular TNF-α was measured by flow cytometry in cells treated with monensin to assess the on-going cytokine production. Data were acquired using FACS Canto II. Unpaired Student's t-test was used to compare variables between groups and p < 0.05 was regarded as significant. RESULTS: The on-going production of TNF-α from dendritic cells (p = 0.0007), putative monocyte and B cell populations (p = 0.04) and CD3+ T cells (p = 0.04) was significantly higher in non-IBD ECF tissue than that from control tissue. CONCLUSIONS: This study reveals results which provide evidence for the potential use of anti-TNF-α agents in the treatment of non-IBD ECF. A pilot study to evaluate this treatment as an alternative option in an already surgically challenging group of patients is planned. Positive findings would be a major medical advance with a new use for anti-TNF-α agents.

Immunoglobulin G4-related periaortitis complicated by aortic rupture and aortoduodenal fistula after endovascular AAA repair.

PURPOSE: To report a rare and complicated case of immunoglobulin (Ig) G4-related periaortitis involving both the aortic wall and the retroperitoneum without aneurysmal formation. CASE REPORT: A 79-year-old man with IgG4-related periaortitis suffered aortic rupture despite a normal caliber aorta after 6 months of steroid therapy (20 mg/d). Endovascular repair with an aortic cuff sealed the rupture. Steroid therapy was halted 2 weeks later due to infection. Four months later, a biopsy during esophagogastroduodenoscopy to investigate gastrointestinal bleeding suggested a relapse of IgG4-RD in the duodenum. Subsequent aortoduodenal fistula formation proved fatal. Generally, IgG4-related periaortitis does not result in such complications due to the absence of aneurysm formation and a thick aortic wall. CONCLUSIONS: Our report highlights a rare case of IgG4-related periaortitis where complications resulted following steroid therapy and surgical intervention, emphasizing the difficulties in dealing with IgG4-related cardiovascular lesions.

[The symptoms and surgical tactics for complicated forms of the abdominal cavity tuberculosis].

The results of treatment of 12 patients, suffering complicated forms of abdominal tuberculosis and external intestinal fistulas, were presented. Late diagnosis of abdominal tuberculosis in the patients, suffering the complications phase of the disease, is caused by unclear symptoms presence in early stages of the disease. Clinical and laboratory indices in peritonitis of a phthisis origin are nonspeciphic. In 91% of patients, admitted to the hospital for complicated forms of abdominal tuberculosis and external intestinal fistulas, the operative treatment was indicated. Surgical intervention (more frequently right-sided hemicolectomy, enterostomy, the abscesses opening, the caseously-changed lymph nodes excision, formation of anastomosis) was performed in 11 patients for peritonitis and external intestinal fistulas. The method of a secure invagination anastomoses formation was elaborated, permitting to perform primary restoration operations. An early diagnosis, early effective therapy and radical surgical intervention conduction for complicated abdominal tuberculosis promote the patients to survive.

ASCA IgG and CBir antibodies are associated with the development of Crohn's disease and fistulae following ileal pouch-anal anastomosis.

BACKGROUND: For ulcerative colitis (UC) patients undergoing ileal pouch-anal anastomosis (IPAA), postoperative complications include chronic pouchitis and development of Crohn's disease (CD) of the pouch. AIMS: The aim of this study was to determine if serologic markers obtained postoperatively are associated with the development of complications in UC patients after IPAA. METHODS: A retrospective chart review was conducted of UC patients with IPAA were tested for expression of serologic markers. Complications abstracted from medical records included postoperative fistula, CD of the pouch, chronic pouchitis, and diversion or excision of the pouch. RESULTS: 142 patients were enrolled, 44 of whom developed complications. Positive serologic profiles for ASCA IgG and anti-CBir1 markers were found to be associated with the development of any complication, (P = 0.017 and P = 0.002, respectively). A positive anti-CBir1 test was also found to be associated with CD of the pouch and/or fistula formation (P < 0.001). Similarly, both ASCA IgG and anti-CBir1 titers were significantly associated with postoperative IPAA complications (P = 0.034 and P = 0.001, respectively), and anti-CBir1 titers were associated with CD of the pouch and/or fistula formation (P < 0.001). Complications developed after a median follow-up of 216 months (range 1-264). CONCLUSIONS: ASCA IgG and anti-CBir1 markers were associated with the development of complications after IPAA, specifically fistulae and/or CD of the pouch. The ability to identify patients at high risk for adverse outcomes may allow for early aggressive therapy, which may decrease the rate of pouch failure. A prospective study of patients with preoperative serology is ongoing.

Cellular infiltration and cytokine expression correlate with fistulizing state in Crohn's disease.

The purpose of this study was to determine the degree of infiltration of different cell subpopulations (tissue dendritic macrophages, T-helper cells, cytotoxic T lymphocytes, monocytes, neutrophils, and B cells) and the expression of the cytokines interleukin-12 (IL-12) and tumor necrosis factor alpha (TNF-α) in inflamed and noninflamed resected tissues from Crohn's disease (CD) and non-CD patients. Twenty-one resected full-thickness intestinal tissue specimens representing 13 subjects (8 CD and 5 non-CD patients) were included in this study. Sections of 20 µm in thickness were cut and then stained using immunohistochemistry. The sections were analyzed using confocal laser scanning microscopy (CLSM). Patterns of staining for inflamed CD and noninflamed CD tissues versus non-CD tissues demonstrated significant differences in the macrophage and T-helper subpopulations. Surprisingly, the T-helper subset was decreased significantly in the inflamed CD sections compared to the noninflamed CD and non-CD sections. The staining patterns also suggested differences in the expression of both IL-12 and TNF-α between the groups, with cytokine overexpression directly relating to the fistulizing state in CD patients. Cytokine expression is upregulated in chronic CD patients; therefore, the degree of inflammation and tissue damage in CD is dependent on the expression of specific cytokines within the tissue. Differentiation of cell subpopulations may be important for establishing a direct relationship with each state of CD (inflammatory, stricturing, and fistulizing states).

Prospective study of immunological factors in non-inflammatory bowel disease enterocutaneous fistulas.

BACKGROUND: Enterocutaneous fistulas (ECF) are debilitating and usually result following complex abdominal surgery. While there is an association with inflammatory bowel disease (IBD), a large number of fistulas occur after surgery not related to IBD. The consequences of ECF include short bowel syndrome and the need for long term parenteral nutrition.ECF can heal spontaneously and in the case of IBD can be cured by medical therapy in some instances. Those that do not resolve spontaneously have to be cured by surgery which is complex and associated with a high morbidity. It is not considered traditional treatment to use the same medical therapy as in IBD to cure ECF caused by other conditions.A small case series has reported three patients with persistent ECF not related to IBD to have healed following use of Infliximab which is the treatment commonly used for ECF caused by IBD. Infliximab acts by inhibiting the activity of the inflammatory cytokine TNF- alpha. It is not known if this cytokine is present in ECF tissue in the absence of IBD.The aim of this study is to demonstrate the presence of inflammatory markers in tissue surrounding non-IBD ECF and in particular to quantify the presence of the cytokine TNF- alpha. We hypothesise that TNF - alpha levels are raised in non-IBD ECF. METHODS/DESIGN: Tissue and serum from ECF of IBD and non-IBD patients will be prospectively collected at St. Mark's Hospital Intestinal Failure Unit. The control group will consist of patients undergoing colonoscopy for bowel cancer screening, with normal findings. Biopsies of the terminal ileum will be obtained from this group during colonoscopy. The fistula tract and serum cytokine profiles of interleukins (IL)-1a, IL-1b, IL-2, IL-4, IL-6, IL-8, IL-10, TNF- alpha, IFN-y, MCP-1, EGF and VEGF will be assessed. DISCUSSION: This study aims to assess the presence or absence of TNF- alpha expression in the ECF tissue in non-IBD origin. If our hypothesis is correct we would then be able to study the use of the TNF- alpha inhibitor Infliximab as a therapeutic option in the treatment of non-IBD ECF. Secondary aims include assessing the spectrum of inflammatory cytokines and markers present in tissue and serum of non-IBD ECF when compared with IBD ECF and normal controls. TRIAL REGISTRATION: ISRCTN44000447.

Regulation of galectin-3 function in mucosal fibroblasts: potential role in mucosal inflammation.

Recently we identified galectin-3 (gal-3), which is secreted by colonic epithelial cells (CEC), to be a strong activator of colonic lamina propria fibroblasts (CLPF). Modulation of CLPF function may play a role during stricture and fistula formation in inflammatory bowel disease (IBD). Therefore, we investigated further the expression of gal-3 and effects on CLPF. The aim of this study is to perform a direct comparison of gal-3 between tissue from healthy controls and from patients with either Crohn's disease (CD) or ulcerative colitis (UC). CEC, CLPF and intestinal macrophages (IMAC) were isolated from control and IBD colonic tissue. Interleukin-8 secretion as a readout of CLPF activation was quantified by enzyme-linked immunosorbent assay. Gal-3 in cell cultures and tissue samples was evaluated by Western blot, immunofluorescence and immunohistochemistry. CLPF-migration was assayed in the 48-well modified Boyden chamber. Gal-3 expression was found in all segments of the colon. In the terminal ileum, less gal-3 was found compared with the colon. Immunohistochemistry and immunofluorescence revealed a homogenous distribution of gal-3 in CEC and IMAC of control mucosa and UC. However, significantly less gal-3 was found in IMAC from CD patients. In CD fistulae and stenoses, gal-3 expression was reduced significantly and barely detectable. In co-incubation studies lactose reduced significantly the CLPF-stimulatory potential of gal-3, indicating that the C-terminal domain of gal-3 is responsible for CLPF activation. Gal-3 stimulated CLPF migration in CLPF derived from fistulae. In conclusion, gal-3 expression is down-regulated in CD-fistulae and stenoses as well as in IMAC in CD patients. Gal-3 induces migration of CLPF derived from fistulae. Its role for stricture and fistula formation warrants further investigation.

[Interest of serologic markers in inflammatory bowel disease. About 105 cases]. / Interet du dosage des marqueurs serologiques au cours des maladies inflammatoires cryptogenetiques de l'intestin. A propos d'une serie de 105 malades.

BACKGROUND: The serum markers ASCA and pANCA can help the clinician in certain difficult situations of colites in IBD. The aim of this study was to determine the sensitivity and the specificity of each one of these markers and to establish the characteristics of the positive patients for each one. METHODS: We included patients having a Crohn's disease (CD) or an ulcerative colitis (UC). These patients was compared to a control group. RESULTS: 80 CD patients with an average age of 35.62 years, 25 UC cases with an average age of 34.92 years and 79 healthy subjects with an average age of 34.2 years were included. The ASCA were detected in 33.8% of CD cases , 8% of UC cases of RCH and 2.5% of contro group (p < 000.1). The pANCA were detected in 48% of UC cases, 27.5% of CD patients and 1.3% of controls (p < 000.1). The sensitivity and the specificity of the ASCA and the pANCA for the diagnosis respectively of CD and UC were 33.8%, 97.5% and of 48%, 97.8%. During the CD, the positivity of the ASCA was significantly associated with ileal location (p = 0.001), with the sténosant and/or fistulisant phenotyp of the disease (p = 0.006), the young age at the time of the diagnosis of the CD (p = 0.067) and at a greater frequency of surgical treatment (p = 00.7). The pANCA were more frequently found in colic location of CD (p = 0.09). During UC, the positivity of the pANCA was not associated with the sex, age, loca tion of the disease, medical treatment nor chiurgical treatment. CONCLUSION: The ASCA and pANCA are useful during some clinical situations such as differentiation between IBD otherss colitis and to distinguish CD from UC.

Anti-Saccharomyces cerevisiae antibodies are associated with the development of postoperative fistulas following ileal pouch-anal anastomosis.

Although serologic testing for perinuclear antineutrophil cytoplasmic antibodies (pANCA) and anti-Saccharomyces cerevisiae antibodies (ASCA) is reportedly useful in distinguishing ulcerative colitis (UC) from Crohn's disease (CD), there are few and conflicting reports assessing their utility in predicting postoperative complications after ileal pouch-anal anastomosis (IPAA). We examined the associations between postoperative complications such as pouchitis or fistulas and pANCA and ASCA antibodies in a group of patients who underwent IPAA for UC. We conducted a retrospective chart review of 34 patients initially diagnosed with UC (four of these patients had a diagnosis of indeterminate colitis) who underwent IPAA by a single surgeon, and who had pANCA and ASCA antibody levels measured during their clinical course. Study patients were assigned to four groups based on the pattern of antibody reactivity: pANCA+/ASCA- (16 patients), pANCA-/ASCA+ (nine patients), pANCA+/ASCA+ (five patients), and pANCA-/ASCA- (four patients). The median length of follow-up was 16 months (3-144 months). None of the patients (0 of 16) who were pANCA+/ASCA- had their preoperative diagnosis of UC changed after a median follow-up of 14 months (3-118 months). Of the nine patients with a preoperative diagnosis of UC who were pANCA-/ASCA+, four patients (44%) had their diagnosis changed postoperatively to CD based on clinical findings, with a median follow-up: 15 months (5-98 months). Of 16 patients who underwent IPAA and who were pANCA+/ASCA-, 15 of 16 (93.75%), were free of fistulas postoperatively, with a median follow-up of 14 months (3-118 months). Of nine patients with a preoperative diagnosis of UC who underwent IPAA and who were pANCA-/ASCA+, four of nine (44%; p = 0.04) developed fistulas postoperatively, with a median length of follow-up of 55 months (15-67 months). No relationship between serologic profiles or antibody titer levels and the development of pouchitis was identified. In a cohort of patients undergoing IPAA for UC, serologic profiles may be useful in identifying patients at risk of postoperative fistula formation. Patients who were pANCA-/ASCA+ were at increased risk for the development of fistulas postoperatively compared to patients who were pANCA+/ASCA-, and were also more likely to have their diagnosis changed postoperatively to CD. A larger study is needed to validate these observations.

Anti-TNF strategies in stenosing and fistulizing Crohn's disease.

BACKGROUND: Stenoses and fistulas are frequent complications in patients with Crohn's disease (CD). They represent a major diagnostic and therapeutic challenge and surgical intervention is often required. The availability of novel, anti-TNF strategies for therapy has raised the question as to what extent these new treatment options have impact on the clinical decision-making process regarding the necessity for surgery. DISCUSSION: A short overview of the current pathophysiological understanding of CD, focusing on the immunology of the intestinal mucosa, is given. Then the problems of proper clinical management of stenoses and fistulas are addressed. With regard to symptomatic stenoses, attention will be given to novel diagnostic tools for the distinction between inflammatory and fibrotic stenoses, and our clinical experience with the treatment of symptomatic inflammatory stenoses with infliximab will be discussed. With regard to fistulizing CD, the data that are currently available for medical therapy are summarized with special reference to the studies on the efficacy of anti-TNF treatment. CONCLUSION: With regard to moderately and severe inflammatory stenoses, medical treatment with infliximab may be an option after careful assessment of the inflammatory nature of the stenosis and exclusion of a septic focus. With regard to fistulas, anti-TNF treatment is a valuable option that is likely to improve the clinical outcome. Based on the available data, however, anti-TNF treatment cannot yet replace surgical intervention when necessary. Prospective trials of medical therapy and a combination of medical and surgical therapy for complex fistulas and internal fistulas are needed to define the potential and the limitations of these novel therapeutic approaches.

Morphological characterisation of Crohn's disease fistulae.

BACKGROUND: Fistulae are a common complication in up to 35% of all patients with Crohn's disease. Their therapy is difficult and frequently unsatisfactory. To date, no histological comparison of Crohn's disease fistulae with non-inflammatory bowel disease fistulae has been performed. In addition, Crohn's disease fistulae have not been well characterised morphologically. METHODS: Eighty four fistulae from Crohn's disease patients were compared with 13 fistulae from controls. Haematoxylin-eosin staining, electron microscopy, and immunohistochemistry for panCytokeratin (epithelial cells), CD20 (B cells), CD45R0 (T cells), and CD68 (macrophages) were performed according to standard techniques. In addition, histopathological findings were compared with clinical and laboratory data. RESULTS: In 31.0% of controls and 27.4% of Crohn's disease specimens, fistulae had a lining of flattened intestinal epithelium without goblet cells or, in the case of cutaneous/perianal disease, narrow squamous epithelium. Non-epithelialised fistulae were covered by a thin layer of (myo)fibroblasts, focally forming a new basement membrane, as demonstrated by electron microscopy. All fistulae were surrounded by granulation tissue. Crohn's disease fistulae presented with central infiltration by CD45R0+ T cells, followed by a small band of CD68+ macrophages and dense accumulation of CD20+ B cells. In contrast, in controls, there was dense infiltration by CD68+ macrophages with only few CD20+ B cells and CD45R0+ T lymphocytes. CONCLUSIONS: Fistulae in Crohn's disease differ markedly from non-Crohn's disease fistulae with regard to their cellular composition. The presence of an epithelial lining in a subgroup of fistulae may be important for the therapeutic approach and healing process.

[Antibody titer to Bacteroides fragilis is increased in Crohn disease patients with fistula development]. / Antikörpertiter gegen Bacteroides fragilis bei M. Crohn-Patienten mit Fistelbildung erhöht.

We compared antibody levels to Bacteroides fragilis in patients with different stages of Crohn's disease and ulcerative colitis to normal controls using an ELISA. IgM-titers were low in patients with Crohn's disease who had undergone surgery of small or large bowel but normal in all other groups of patients. Similarly, IgG-titers were similar to control values in all patients with uncomplicated Crohn's disease but elevated in patients with complicating fistula, colonic Crohn's disease and resected small or large bowel. IgM- and IgG-titers were elevated in patients with ulcerative colitis. However, only sera from patients with fistula inhibited increased the binding of a monoclonal antibody specific for B. fragilis thus demonstrating their specificity for B. fragilis. This findings could point to an involvement of B. fragilis in the formation of fistula in patients with Crohn's disease.

Factors determining the occurrence of serum agglutinins to eubacterium and peptostreptococcus species in patients with Crohn's disease and ulcerative colitis.

Recently, the demonstration of serum agglutinins to Eubacterium and Peptostreptococcus strains has been found to be useful as a diagnostic test for Crohn's disease. Therefore, conditions determining the occurrence of these antibodies were studied in patients with Crohn's disease and ulcerative colitis. Localization of Crohn's disease in the colon, the presence of fistulae and serum levels of immunoglobulins were found to be contributory determinants for the occurrence of the agglutinins.

Investigation of the immune response to aerobic and anaerobic intestinal bacteria in a patient with Crohn's disease.

The immune response to aerobic and anaerobic intestinal bacteria in a patient with Crohn's disease with an intestinal fistula was investigated with various serological techniques. Two aerobic bacterial species, E. dispar and P. mirabilis, and four strict anaerobic bacterial species, B. fragilis ss. fragilis, F. varium and two different strains of C. perfringens, were isolated from fistula secretion of the patient. These strains were used as antigens for tube agglutination, passive hemagglutination, indirect immunofluorescence and immune hemolysis assays with serum specimens obtained before and after operation of the patient. Immune responses were demonstrated to the aerobic as well as to the anaerobic bacterial strains isolated from the patient's fistula. In connection with the operation an active immune response was demonstrated to the aerobic and anaerobic bacterial isolates. Antibodies belonging to IgG and IgA took part in the active immune response while IgM was very little involved. Antibodies responsible for passive hemagglutination reactions were resistant to treatment with beta-mercaptoethanol. Antibodies to aerobic and anaerobic Gram-negative rods were shown to have complement fixing activity. The importance of the demonstrated antibodies for the host's defence against normal intestinal microorganisms and the inflammatory reaction as a consequence of chronic antigenic stimulation in the diseased part of the intestine in patients with Crohn's disease is discussed.