Treatment of severe Crohn''s disease using antimycobacterial triple therapy — approaching a cure?

BACKGROUND: Mycobacterium avium subspecies paratuberculosis is probably the best candidate for a microbial cause of Crohn's disease although arguments to the contrary can be equally convincing. Growing evidence suggests that prolonged antimycobacterial combination therapy can improve Crohn's disease in some patients. AIM: To report long-term observations in patients with severe Crohn's disease treated with triple macrolide-based antimycobacterial therapy. PATIENTS: A series of 12 patients (7 male, 5 female; aged 15-42 years) with severe, obstructive or penetrating Crohn's disease were recruited. METHODS: Patients failing maximal therapy were commenced prospectively on a combination of rifabutin (450 mg/d), clarithromycin (750 mg/d) and clofazimine (2 mg/kg/d). Progress was monitored through colonoscopy, histology, clinical response and Harvey-Bradshaw activity index. RESULTS: Follow-up data were available for up to 54 months of therapy Six out of 12 patients experienced a full response to the antiMycobacterium avium subspecies paratuberculosis combination achieving complete clinical, colonoscopic and histologic remission of Crohn's disease. Four of these patients were able to cease treatment after 24-46 months, 3 of whom remained in total remission without treatment for up to 26 months and one patient relapsed after six months off treatment. A partial response to the anti-Mycobacterium avium subspecies paratuberculosis combination was seen in 2 patients showing complete clinical remission with mild histologic inflammation. Return to normal of terminal ileal strictures occurred in 5 patients. Harvey-Bradshaw activity index in patients showing a full or partial response to therapy fell from an initial 13.4 +/- 1. 91 to 0. 5 +/- 0. 47 [n = 8, p < 0. 001) after 52-54 months. CONCLUSIONS: Reversal of severe Crohn's disease has been achieved in 6/12 patients using prolonged combination anti-Mycobacterium avium subspecies paratuberculosis therapy alone. Three patients remain in long-term remission with no detectable Crohn's disease off all therapy These results support a causal role for Mycobacterium avium subspecies paratuberculosis in Crohn's disease while also suggesting that a cure may become possible.     

Molecular evidence for Mycobacterium avium subspecies paratuberculosis (MAP) in Crohn''s disease correlates with enhanced TNF-α secretion

BACKGROUND: Support for a role of Mycobacterium avium subspecies paratuberculosis in Crohn's disease is largely based on epidemiological evidence, as no data on mechanisms linking the presence of M. avium subspecies paratuberculosis with gut damage is available. AIMS: To determine whether the presence of M. avium subspecies paratuberculosis contributes to the pathogenesis of Crohn's disease by promoting cytokine secretion within gut mucosa. PATIENTS AND METHODS: A total of 235 subjects were recruited: 63 with Crohn's disease, 53 with ulcerative colitis, 45 with irritable bowel syndrome and 74 normal controls. M. avium subspecies paratuberculosis status was defined by nested PCR using IS900 sequence. Gut mucosal organ cultures were established to detect cytokine secretion patterns. RESULTS: Significantly higher tumour necrosis factor-alpha concentrations were found in culture supernatants for Crohn's disease compared to ulcerative colitis (p<0.05), irritable bowel syndrome (p<0.01) and controls (p<0.0001). When tumour necrosis factor-alpha levels were correlated with the presence of M. avium subspecies paratuberculosis, significantly greater concentrations were only found in M. avium subspecies paratuberculosis-positive Crohn's disease patients (p<0.05). Tumour necrosis factor-alpha levels in M. avium subspecies paratuberculosis-positive Crohn's disease were significantly higher than in M. avium subspecies paratuberculosis-positive ulcerative colitis (p<0.01), M. avium subspecies paratuberculosis-positive irritable bowel syndrome (p<0.05) and M. avium subspecies paratuberculosis-positive controls (p<0.01) and all M. avium subspecies paratuberculosis-negative specimens. CONCLUSIONS: The data link M. avium subspecies paratuberculosis with a pathogenic mechanism in Crohn's disease and is consistent with abnormal macrophage handling of M. avium subspecies paratuberculosis.     

Open clinical trial of rifabutin and clarithromycin therapy in Crohn''s disease

BACKGROUND: Crohn's disease, an inflammatory bowel disease in humans, has a suspected aetiology of Mycobacterium avium subsp. Paratuberculosis. AIMS: To evaluate the role of rifabutin and clarithromycin anti-Mycobacterium avium subsp. Paratuberculosis treatment in Crohn's disease patients using an open clinical trial. METHODS:. A total of 36 patients with acute presentations of Crohn's disease, whose sera tested positive against p35 and p36 antigens (two recombinant proteins of Mycobacterium avium subsp. Paratuberculosis), were selected for treatment with rifabutin and macrolide antibiotic therapy Rifabutin and macrolide antibiotic therapy medications included 250 mg 1 po bid clarithromycin and 150 mg 1 po bid Ri-fabutin accompanied with a probiotic. Crohn's disease patients' response to rifabutin and macrolide antibiotic therapy was monitored over a period ranging from 4 to 17 months. RESULTS: Seven patients (19.4%) withdrew from the study since they were unable to tolerate medications. Of the remaining 29 patients, 21 (58.3%) reached a sustained state of improvement, traditionally defined as a decrease of 70 points between their entrance and exit Crohn's disease activity index scores together with the absence of the need of all other Crohn's medications, such as immunosuppressants and corticosteroids. Three Crohn's disease patients [8. 3%) noticed significant improvements, but required other Crohn's medications, concurrently with rifabutin and macrolide antibiotic therapy, to achieve and sustain improvement. Only 5 Crohn's disease patients (13.8%) were non-responders, noticing no marked improvement while on rifabutin and macrolide antibiotic therapy. CONCLUSION: The data add further evidence to support the role of rifabutin and macrolide antibiotic therapy in the treatment of Crohn's disease specifically in those patients with evidence of Mycobacterium avium subsp. Paratuberculosis infection. A large multi-centre clinical trial is needed to further explore these findings.     

Detection and Isolation of Mycobacterium avium subspecies paratuberculosis from intestinal mucosal biopsies of patients with and without Crohn's disease in Sardinia

OBJECTIVES: Sardinia is an island community of 1.6 million people. There are also about 3.5 million sheep and one hundred thousand cattle in which Johne's disease and Mycobacterium avium subspecies paratuberculosis infection are endemic. The present study was designed to determine what proportion of people in Sardinia attending for ileocolonoscopy with or without Crohn's disease were infected with this pathogen. METHODS: Mycobacterium avium subspecies paratuberculosis was detected by IS900 PCR on DNA extracts of fresh intestinal mucosal biopsies as well as by isolation in culture using supplemented MGIT media followed by PCR with amplicon sequencing. RESULTS: Twenty five patients (83.3%) with Crohn's disease and 3 control patients (10.3%) were IS900 PCR positive (p = 0.000001; Odds ratio 43.3). Mycobacterium avium subspecies paratuberculosis grew in cultures from 19 Crohn's patients (63.3%) and from 3 control patients (10.3%) (p = 0.00001; Odds ratio 14.9). All patients positive by culture had previously been positive by PCR. Mycobacterium avium subspecies paratuberculosis first appeared in the liquid cultures in a Ziehl Neelsen (ZN) staining negative form and partially reverted through a rhodamine-auramine positive staining form to the classical ZN positive form. This resulted in a stable mixed culture of all 3 forms illustrating the phenotypic versatility of these complex chronic enteric pathogens. CONCLUSIONS: Mycobacterium avium subspecies paratuberculosis was detected in the majority of Sardinian Crohn's disease patients. The finding of the organism colonizing a proportion of people without Crohn's disease is consistent with what occurs in other conditions caused by a primary bacterial pathogen in susceptible hosts.     

Two-year combination antibiotic therapy with clarithromycin, rifabutin, and clofazimine for Crohn's disease

BACKGROUND & AIMS: Mycobacterium avium subspecies paratuberculosis has been proposed as a cause of Crohn's disease. We report a prospective, parallel, placebo-controlled, double-blind, randomized trial of 2 years of clarithromycin, rifabutin, and clofazimine in active Crohn's disease, with a further year of follow-up. METHODS: Two hundred thirteen patients were randomized to clarithromycin 750 mg/day, rifabutin 450 mg/day, clofazimine 50 mg/day or placebo, in addition to a 16-week tapering course of prednisolone. Those in remission (Crohn's Disease Activity Index 相似文献   

The evidence for Mycobacterium paratuberculosis in Crohn's disease.

PURPOSE OF REVIEW: Though long hypothesized, the putative link between Mycobacterium avium paratuberculosis and Crohn's disease remains neither confirmed nor refuted. This article reviews published contributions that directly or indirectly address this question. RECENT FINDINGS: Epidemiologic studies, looking for M. avium paratuberculosis DNA in Crohn's tissue, show a strong association between the agent and this disease. Supporting data, however, are presently inconclusive on a causal role. Genetic studies provide indirect support for a role of mycobacteria in Crohn's disease, by identifying susceptibility genes that encode proteins implicated in innate immunity to intracellular bacteria. Clinical trial data support at least a short-term benefit for antimycobacterial therapy in Crohn's disease, but the microbial specificity of this response is presently unknown. SUMMARY: There appears to be a strong association between M. avium paratuberculosis and Crohn's disease, but the causality of this association is unknown. Consequently, the therapeutic implications of this association require further study. A number of critical questions about the biology of M. avium paratuberculosis remain unanswered. Data from studies of this organism, and its interaction with the immune system, can help address proposed reasons for or against a role of M. avium paratuberculosis in the etiology of Crohn's disease.     

Antibodies to Mycobacterium paratuberculosis and nine species of environmental mycobacteria in Crohn's disease and control subjects.

Cultural and serological studies have provided limited, often conflicting, evidence of a role for mycobacteria in the pathogenesis of Crohn's disease. Interest has focussed on Mycobacterium paratuberculosis, previously considered to be common in the environment with no major role as a human pathogen. Whether a specific serum antibody response to mycobacteria occurs in Crohn's disease or ulcerative colitis was investigated. Sera from patients with Crohn's disease (n = 38), ulcerative colitis (n = 15), and a healthy control population (n = 30) were assayed in an enzyme linked immunosorbent assay (ELISA) using eight filtered sonicate mycobacterial preparations and a purified protein derivative made from the bovine tubercle bacillus. In addition, IgG, IgM, and IgA levels to M paratuberculosis were determined in sera from patients with active (n = 24) or inactive (n = 29) Crohn's disease and the control populations. There was strong evidence of contact with environmental mycobacteria in all patients and control populations, with the greatest responses to preparations of M avium, M tuberculosis, and M kansasii. A large proportion of patients with Crohn's disease had antibodies that bound most antigens tested but there were no statistical differences between these values and those of the control population. Similarly, there were no differences in antibody levels to M paratuberculosis in patient and control groups. Although a subset of patients with active Crohn's disease (25%) had IgG concentrations that exceeded the control mean by more than 2 SD, this phenomenon may not be specific to Crohn's disease: 20% of a small group of patients with coeliac disease had similarly raised IgG levels to M paratuberculosis. These findings do not provide serological evidence of a role for this organism in the pathogenesis of Crohn's disease.     

Specific detection of Mycobacterium paratuberculosis DNA associated with granulomatous tissue in Crohn's disease.

The role of mycobacteria, specifically Mycobacterium paratuberculosis, in Crohn's disease has aroused considerable controversy for many years. Using the ultra sensitive polymerase chain reaction some studies have reported detection of M paratuberculosis DNA in as many as 65% of Crohn's disease patients but also in patients without disease. Other studies have been negative for both groups. We therefore designed a double blind control trial to investigate the presence of mycobacterial DNA in age, sex, and tissue matched paraffin wax embedded tissues from 31 Crohn's disease tissues, 20 diseased gut control tissues, and 10 ulcerative colitis tissues. The specimens were coded and analysed blind with three separate polymerase chain reactions (PCR) based on DNA sequences specific for M paratuberculosis (IS900), M avium (RFLP type A/1) (IS901), and the Mycobacterium genus (65 kDa gene, TB600). The number of granulomata and presence of acid fast bacilli in each Crohn's disease tissue was also investigated. The sensitivity of the system was determined using similarly prepared gut tissue from an animal infected with M paratuberculosis. Four of 31 Crohn's disease tissues and none of the 30 control and ulcerative colitis derived tissues amplified M paratuberculosis DNA. Crohn's disease tissues containing granulomata were significantly more likely to amplify M paratuberculosis specific DNA on PCR than the non-Crohn's disease tissues (p = 0.02). All the positive Crohn's disease tissues contained granulomata, and none contained acid fast bacilli. Equivalent numbers of Crohn's and non-Crohn's disease tissues amplified the region of the 65 kD gene on PCR for non-specific mycobacterial DNA (11/31 and 9/30 respectively). No sections produced an amplified product with the IS901 PCR. These results suggest that few Crohn's disease gut biopsy sections contain M paratuberculosis DNA in association with granulomata. The absence of such DNA in any control and ulcerative colitic tissue strengthens the case for it having a specific association, which may be pathogenic, with Crohn's disease in this minority of patients.     

Presence and characterization of Mycobacterium avium subspecies paratuberculosis from clinical and suspected cases of Crohn's disease and in the healthy human population in India.

OBJECTIVES: To investigate and characterize Mycobacterium avium subspecies paratuberculosis (MAP) in patients with Crohn's disease, attendants of animals with suspected infection, and healthy humans, using multiple diagnostic tests. METHODS: A total of 119 samples (35 stool, 76 serum, three blood clots, and five biopsies) were collected from five patients with Crohn's disease, eight attendants of animals with Johne's disease, and 93 apparently normal control subjects (Agra region) from North India. Samples were screened for the presence of MAP by smear examination, culture of stool, blood clot and biopsies, and ELISA. Colonies obtained by culture were further characterized using polymerase chain reaction (PCR) with IS900 MAP-specific primers. RESULTS: Using all diagnostic modalities, MAP and/or MAP antibodies were identified in 100% (5/5) of subjects with Crohn's disease; 75.0% (6/8) of attendants of MAP infected animals were positive and 38.0% (27/71) of apparently normal controls were also positive. Most sensitive test was ELISA (100%, 5/5), followed by culture (80.0%, 4/5), and acid-fast staining. Ziehl-Neelsen staining was positive in 37.5% (3/8) of subjects with active animal husbandry practices. In 71 serum samples from control subjects, seroprevalence of MAP was 38.0% using indigenous protoplasmic antigens (PPA) and 36.6% using commercial PPA. Of the serum samples from the Crohn's disease patients, 100% (5/5) were positive by ELISA using indigenous PPA and 40.0% (2/5) were positive by ELISA using commercial PPA. IS900 PCR was used to characterize tiny colonies of MAP that grew extremely slowly on Herrold's egg yolk medium, and of 15 (42.8%) cultures, 14 (93.3%) were typed as MAP. CONCLUSIONS: Paper documented the presence of MAP in all patients with Crohn's disease, in some animal attendants who had the history of working with goat herds infected with Johne's disease and in few normal healthy individuals. Presence of Ziehl Neelsen positive MAP. In the stool of attendants working with MAP-infected animals was unique to humans. ELISA based on antigens derived from indigenous MAP 'bison type' genotype of goat origin was most sensitive modality for screening Crohn's disease patients.     

Detection of Mycobacterium avium subspecies paratuberculosis in Crohn's diseased tissues by in situ hybridization

OBJECTIVES: Reports about the association between Crohn's disease (CD) and cell wall-deficient (CWD) forms of Mycobacterium avium subspecies paratuberculosis (M. paratuberculosis) are controversial. This may be due to the heterogeneous nature of CD where only about 50% of the patients show granulomatous inflammation. Detection of CWD forms of M. paratuberculosis in tissues from patients with CD would support its association with the disease. To help identify these forms in inflamed tissues, a previously developed and optimized nonradioactive in situ hybridization method was applied on well-defined tissue materials obtained from patients with CD, ulcerative colitis (UC), and controls. METHODS: Specimens from 37 patients with CD (15 with epitheloid cell granulomas and 22 without granulomas), 21 UC, and 22 noninflammatory bowel disease (IBD) patients were analyzed by the in situ hybridization method based on the digoxigenin-labeled M. paratuberculosis IS900 fragment, previously shown to be species specific. Samples were counterstained with hematoxylin and eosin to show the location of the positive signal. Positive controls made of beef cubes injected with CWD and acid-fast M. paratuberculosis and negative controls were included in each experiment to monitor for nonspecific hybridization or staining. RESULTS: Six of 15 (40%) patients with CD and granulomas showed positive signals in myofibroblasts and macrophages. Interestingly, no positive signals were observed within granulomas. Only 4.5% of 22 CD samples from patients with nongranulomatous disease, 9.5% of 21 UC, and remarkably, none of the 22 non-IBD patients were M. paratuberculosis positive. CONCLUSION: The demonstration of DNA from CWD forms of M. paratuberculosis in this limited number of CD tissues further supports and confirms previous reports of its association with the granulomatous type of the disease.     

Mycobacteria in the Intestine of Japanese Patients with Inflammatory Bowel Disease

Objectives : It is still controversial whether or not a mycobacterial infection may be a cause of Crohn's disease. Mycobaclerium paratuberculosis may be very difficult to detect using routine culture techniques. To clarify this, we delected mycobacterial DNA in patients with inflammatory bowel disease. Methods : IS900 sequences highly specific to M. paratuberculosis and groEL gene encoding a conserved mycobacterial antigen were studied in colonic mucosa using polymerase chain reaction (PCR). PCR products were analyzed by Southern blot hybridization. Results : IS900 sequences were detected in all (100%)of 10 patients with Crohan's disease, in 11 (61.1%) of 18 patients with ulcerative colitis, and in 14 (87.5%) of 16 control patients with noninflammatory bowel disease. All IS900 positive samples had groEL PCR products. Conclusions : Our results, on the basis of the prevalence, do not support the hypothesis that M. paratuberculosis is involved in the pathogenesis of Crohn's disease.     

Agglutinins to bacteria in Crohn's disease.

Sera from patients with Crohn's disease were tested for antibodies against organisms which are thought to cause inflammatory bowel disease in animals, or have been implicated in human Crohn's disease. Control sera were collected from healthy individuals and patients with ulcerative colitis. Sera from Crohn's disease and controls failed to agglutinate Clostridium colinum or Campylobacter sputorum subsp. mucosalis and two strains of Mycobacterium paratuberculosis (M26 and M27). Most of the sera agglutinated a Citrobacter freundii variant, Mycobacterium paratuberculosis (M28) and Mycobacterium avium (M41) but Crohn's disease sera did not differ from controls. A complement fixation test against Chlamydia gave more positive reactions in patients with Crohn's disease and colitis than in healthy controls. There was a clear difference between the sera from patients with Crohn's disease and other sera, including ulcerative colitis, in agglutination tests with the commensal coccoid rods of the genera Eubacterium and Peptostreptococcus; in these tests 54% of sera from Crohn's disease were positive compared with 11% in ulcerative colitis and none of the sera from healthy controls. All the results were essentially negative with the exception of those from Eubacterium and Peptostreptococcus and these bacteria merit investigation.     

T-cellular immune reactions (in macrophage inhibition factor assay) against Mycobacterium paratuberculosis, Mycobacterium kansasii, Mycobacterium tuberculosis, Mycobacterium avium in patients with chronic inflammatory bowel disease.

A mycobacterial aetiology has been suggested for Crohn's disease. A slow growing mycobacterium, biochemically and genetically identical to M paratuberculosis, the causative agent of enteritis in ruminants (Johne's disease), has been isolated from gut specimens of patients affected by Crohn's disease. If M paratuberculosis or other mycobacteria play a role in the pathogenesis of Crohn's disease, then patients may have been sensitised to these mycobacteria or show an anergy immune reaction. We therefore investigated the T-cell mediated immune response to sonicates of M paratuberculosis, M kansasii, M avium, and M tuberculosis in 35 patients with Crohn's disease, 28 with ulcerative colitis, and 25 controls using a macrophage inhibition factor assay on peripheral blood lymphocytes. Two types of reaction patterns were identified--that is, 'responders' (subjects with a macrophage inhibition factor assay in which a dose response relation was present and a percentage of inhibition exceeding 20%), and 'non-responders'. There was no significant difference in the prevalence of responders (59%-80%) and non-responders (20%-41%) to these mycobacteria between the group of Crohn's disease, ulcerative colitis, and control group. We found also that a large proportion of controls showed T-cell immunisation to the mycobacteria which supports the contention that the antigens are practically commensal. Our results do not support the proposed involvement of mycobacteria in the pathogenesis of Crohn's disease.     

Polymerase chain reaction detection of Mycobacterium paratuberculosis and Mycobacterium avium subsp silvaticum in long term cultures from Crohn''s disease and control tissues.

Thirty one cultures were established in MG3 medium from the intestinal tissues of 29 patients, including 18 with Crohn's disease, five with ulcerative colitis, and six non-inflammatory bowel disease controls. All cultures grew either acid fast bacilli or uncharacterized spheroplasts. Pellets from these cultures were coded and assayed blind for M paratuberculosis and M avium subsp silvaticum using IS900- and IS902-PCR (polymerase chain reaction) assays, respectively. IS900 and IS902 are multicopy DNA insertion elements specific for these two organisms. Six Crohn's disease cultures and a single non-inflammatory bowel disease control were positive for M paratuberculosis. A further six cultures were positive for M avium subsp silvaticum, of which two each were from Crohn's disease, ulcerative colitis, and non-inflammatory bowel disease controls. The intensity of the IS900-PCR signals indicated very low numbers of M paratuberculosis organisms and bore no relation to visible spheroplastic or bacillary mycobacterial growth. The results suggest that M paratuberculosis isolated from man exists in a form which hardly replicates if at all when cultured in MG3 medium in vitro, and are consistent with the involvement of this known animal enteric pathogen in a proportion of chronic enteritis in man.     

The Broad Street pump revisited: dairy farms and an ongoing outbreak of inflammatory bowel disease in Forest, Virginia

ABSTRACT: We report an ongoing outbreak of ulcerative colitis and Crohn's disease in Forest, Virginia involving 15 unrelated children and teenagers who resided in close proximity to dairy farms. Some of our cases demonstrated serologic evidence of Mycobacterium avium subspecies paratuberculosis infection, suggesting its potential role as an etiologic agent.     

Mycobacterium avium subspecies paratuberculosis and Crohn's disease: a systematic review and meta-analysis

This systematic review assesses the evidence for an association between Mycobacterium avium subspecies paratuberculosis (MAP) and Crohn's disease. We analysed 28 case-control studies comparing MAP in patients with Crohn's disease with individuals free of inflammatory bowel disease (IBD) or patients with ulcerative colitis. Compared with individuals free of IBD, the pooled odds ratio (OR) from studies using PCR in tissue samples was 7.01 (95% CI 3.95-12.4) and was 1.72 (1.02-2.90) in studies using ELISA in serum. ORs were similar for comparisons with ulcerative colitis patients (PCR, 4.13 [1.57-10.9]; ELISA, 1.88 [1.26-2.81]). The association of MAP with Crohn's disease seems to be specific, but its role in the aetiology of Crohn's disease remains to be defined.     

Endoscopic and histologic healing of Crohn's (ileo-) colitis with azathioprine.

BACKGROUND: The correlation between disease activity and endoscopic findings in Crohn's disease is poor. Corticosteroids induce symptom relief without consistent improvement of endoscopic lesions. Our aim was to examine the effect of azathioprine therapy on healing of inflammatory lesions in patients with severe Crohn's disease. METHODS: The study included 20 consecutive patients with Crohn's colitis or ileocolitis in clinical remission while taking azathioprine for at least 9 months and no corticosteroids for at least 3 months who had had an ileocolonoscopy less than 1 year before the start of azathioprine. All 20 patients underwent a new ileocolonoscopy with biopsies. RESULTS: The duration of azathioprine therapy was 24.4 +/- 13.7 months. In the colon, we observed complete healing in 14 of 20 patients (70%), near-complete healing in 2 of 20 (10%), partial healing in 3 of 20 (15%), and no healing in 1 of 20 (5%). In the ileum complete healing was seen in 7 of 13 (54%) patients with ileitis, near-complete healing in 2 of 13 (15%), partial healing in 1 of 13 (8%), and no healing in 2 of 13 (15%); the ileum was not reached in 1 patient. Histologic examination revealed disappearance of the inflammatory infiltrate, with a certain degree of architectural disturbance remaining. CONCLUSIONS: Successful azathioprine therapy is accompanied by mucosal healing and disappearance of the inflammatory infiltrate.     

Healing of Transsphincteric Perianal Fistulas in Crohn's Disease Using a New Technique

Objectives : Transsphincteric perianal fistulas in Crohn's disease are often refractory to medical therapy and difficult to treat surgically. Our objective was to determine whether a new method of anal fistulotomy was effective in healing these fistulas. Methods : In this new method, the internal opening of the fistula tract was displaced distally to the region of the anal mucosa in 26 patients with Crohn's disease. Results : Healing was achieved within 5 weeks of surgery in 45/49 (92%) of the fistulas and was not influenced by perioperative medication, site of preexisting Crohn's disease, or condition of the rectum. There has been no alteration of preoperative continence. Conclusions : We conclude that this method is highly effective in treating transsphincteric perianal fistulas in Crohn's disease.