Long-term outcomes of thalidomide in refractory Crohn's disease.

BACKGROUND: Several open-label and retrospective studies have indicated that thalidomide may be beneficial in patients with refractory Crohn's disease (CD). AIM: To report our long-term experience with the use of thalidomide for adults with refractory Crohn's disease. METHODS: We conducted a retrospective study of long-term clinical and safety outcomes among adults treated with thalidomide for refractory Crohn's disease. Response was defined as a clinician's assessment of improvement after at least 7 days treatment of one or more of the following: bowel movement frequency, fistula output, rectal bleeding, abdominal pain, extraintestinal manifestations, or well-being. Remission required all of the following: <3 stools/day, no bleeding, abdominal pain or extraintestinal manifestations and increased well-being. RESULTS: Thirty-seven adults with refractory Crohn's disease were treated with thalidomide for a median of 4.4 months and followed up for a median of 58 months. Clinical response and remission rates were 54% and 19%, respectively. About 40% of patients were able to stop steroids. Response rates were higher for those treated with more than 50 mg/day (85%) than for those treated with a maximum of 50 mg/day (40%; P = 0.01). An adverse event occurred in 68% of patients. Approximately one-third of patients (38%) experienced neuropathy. CONCLUSIONS: Thalidomide appears to be safe and effective in some patients with refractory Crohn's disease. Although side effects may limit long-term use, thalidomide has potential to induce significant clinical responses.

Split-dose administration of thiopurine drugs: a novel and effective strategy for managing preferential 6-MMP metabolism.

BACKGROUND: Mercaptopurine and azathioprine (AZA) are efficacious in treating IBD. 6-tioguanine (6-TGN) levels correlate with therapeutic efficacy, whereas high 6-methylmercaptopurine (6-MMP) levels are associated with hepatotoxicity and myelotoxicity. Some IBD patients exhibit dose-limiting preferential 6-MMP production, which may lead to undesired side effects and impact efficacy. AIM: To review the outcomes of thiopurine split-dosing in patients with preferential 6-MMP metabolism. METHODS: A retrospective chart review of 179 IBD patients treated at the Cedars-Sinai IBD Center with AZA or mercaptopurine was performed. Preferential 6-MMP metabolisers with 6-MMP levels greater than 7000 pmol/8 × 10(8) erythrocytes who underwent split-dosing were identified and assessed for biochemical and clinical responses to these dose modifications. RESULTS: A total of 20 of 179 patients met the criteria for preferential 6-MMP metabolism and underwent thiopurine split-dosing. Dividing the total daily thiopurine dose led to a reduction in 6-MMP levels (11785 vs. 5324 pmol/8 × 10(8) erythrocytes; P < 0.0001) without negatively affecting clinical disease activity or 6-TGN levels (239 vs. 216 pmol/8 × 10(8) erythrocytes; P = N.S.) and led to resolution of 6-MMP associated side effects (elevated transaminases, leucopenia and flu-like symptoms) in all but two patients. After mean follow-up of 36 months, 12 patients remained in clinical remission on split-dose mercaptopurine. Five of the remaining eight patients escalated to anti-TNF therapy, two progressed to surgery, and one switched to tioguanine therapy. CONCLUSION: Split-dose administration of mercaptopurine/AZA represents an alternative option in IBD patients with preferential 6-MMP metabolism who might otherwise require steroid exposure or escalation of therapy.

Linkage of Crohn's disease-related serological phenotypes: NFKB1 haplotypes are associated with anti-CBir1 and ASCA, and show reduced NF-kappaB activation.

BACKGROUND AND AIMS: Genetics studies of the serum expression of antibodies to microbial antigens may yield important clues to the pathogenesis of Crohn's disease. Our aim was to conduct a linkage study using expression of anti-CBir1, anti-I2, anti-OmpC and ASCA as quantitative traits. METHODS: Expression of antibodies to microbial antigens was measured by enzyme-linked immunosorbant assay (ELISA) and a standard approximately 10 cM whole genome microsatellite study was conducted. Single nucleotide polymorphism genotyping was performed using either Illumina or TaqMan MGB technology. Nuclear factor Kappa B (NF-kappaB) activation in cells from Epstein-Barr virus (EBV)-transformed cell lines was assessed using an electrophoretic mobility shift assay and protein was measured using ELISA and western blotting. RESULTS: Evidence for linkage to anti-CBir1 expression was detected on human chromosome 4 (logarithm of odds (LOD) 1.82 at 91 cM). We therefore directly proceeded to test the association of haplotypes in NFKB1, a candidate gene. One haplotype, H1, was associated with anti-CBir1 (p = 0.003) and another, H3, was associated with ASCA (p = 0.023). Using cell lines from Crohn's disease patients with either H1 or H3, NF-kappaB activation and NF-kappaB p105 and p50 production were significantly lower for patients with H1 compared to patients with H3. CONCLUSIONS: These results suggest that NFKB1 haplotypes induce dysregulation of innate immune responses by altering NF-kappaB expression. The results also show the use of EBV-transformed lymphoblastoid cell lines to conduct phenotypic studies of genetic variation.

Diagnostic yield of capsule endoscopy in ulcerative colitis and inflammatory bowel disease of unclassified type (IBDU).

BACKGROUND AND STUDY AIMS: Capsule endoscopy is increasingly reported as an important diagnostic procedure in patients with known or suspected Crohn's disease, but its clinical utility in patients with ulcerative colitis or unclassified type inflammatory bowel disease (IBDU) is unclear. The aim of our study was to determine the diagnostic yield of capsule endoscopy for small-bowel disease in patients with ulcerative colitis and IBDU. PATIENTS AND METHODS: All data from patients with a history of ulcerative colitis or IBDU who underwent capsule endoscopy between October 2001 and August 2005 were analyzed for procedure indications and findings. Images were reviewed by an experienced capsule endoscopist. The finding of multiple ulcerations (three or more) on capsule endoscopy was classified as diagnostic of small-bowel Crohn's disease. RESULTS: 120 patients had undergone 122 capsule endoscopy procedures. Overall, 19 of 120 patients (15.8 %) had capsule endoscopy findings consistent with the diagnosis of Crohn's disease. The proportion of patients with small-bowel disease was significantly higher among patients with a history of colectomy (7 of 21 patients, 33 %) compared with those without colectomy (12/99, 12 %) ( P = 0.04). Among patients with positive findings on capsule endoscopy, 18 had also previously undergone a small-bowel follow-through study and only one showed findings consistent with Crohn's disease. CONCLUSIONS: Many patients with a diagnosis of ulcerative colitis and atypical features or IBDU may have small-bowel findings on capsule endoscopy that are consistent with Crohn's disease. Capsule endoscopy should be considered in ulcerative colitis patients with atypical clinical features particularly after colectomy.

Measurement of vitamin D levels in inflammatory bowel disease patients reveals a subset of Crohn's disease patients with elevated 1,25-dihydroxyvitamin D and low bone mineral density.

OBJECTIVES: Many patients with Crohn's disease (CD) have low bone mineral density (BMD) that may not be solely attributable to glucocorticoid use. We hypothesised that low BMD in patients with CD is associated with elevated circulating levels of the active form of vitamin D, 1,25-dihydroxyvitamin D (1,25(OH)(2)D). We further hypothesised that this was secondary to increased synthesis of 1,25(OH)(2)D by inflammatory cells in the intestine. The aim of this study was to examine the relationship between 1,25(OH)(2)D levels and BMD in patients with CD. METHODS: An IRB approved retrospective review of medical records from patients with CD (n = 138) or ulcerative colitis (UC, n = 29). Measurements of vitamin D metabolites and immunoreactive parathyroid hormone (iPTH) were carried out. BMD results were available for 88 CD and 20 UC patients. Immunohistochemistry or real time reverse transcription-polymerase chain reaction (RT-PCR) for the enzyme 1alpha-hydroxylase was performed on colonic biopsies from patients with CD (14) or UC (12) and normal colons (4). RESULTS: Inappropriately high levels of serum 1,25(OH)(2)D (>60 pg/ml) were observed in 42% of patients with CD compared with only 7% in UC, despite no differences in mean iPTH. Serum 1,25(OH)(2)D levels were higher in CD (57 pg/ml) versus UC (41 pg/ml) (p = 0.0001). In patients with CD, there was a negative correlation between 1,25(OH)(2)D levels and lumbar BMD (r = -0.301, p = 0.005) independent of therapeutic glucocorticoid use. 1,25(OH)(2)D levels also correlated with CD activity. Lastly, immunohistochemistry and RT-PCR demonstrated increased expression of intestinal 1alpha-hydroxylase in patients with CD. CONCLUSIONS: These data demonstrate that elevated 1,25(OH)(2)D is more common in CD than previously appreciated and is independently associated with low bone mineral density. The source of the active vitamin D may be the inflamed intestine. Treatment of the underlying inflammation may improve metabolic bone disease in this subgroup of patients.

Infliximab in the treatment of medically refractory indeterminate colitis.

AIM: To examine the outcome of infliximab intervention in refractory indeterminate colitis. METHODS: Twenty patients with severe, medically refractory indeterminate colitis were treated with infliximab. All patients initially received infliximab, 5 mg/kg, intravenously and, in some patients, the dose was subsequently increased to 10 mg/kg. The number of infusions ranged from one to 16 per patient. Indeterminate colitis was defined as colitis that could not be classified with certainty as Crohn's disease or ulcerative colitis based on traditional clinical, endoscopic and histopathological criteria. The clinical response to infliximab was classified as complete response, partial response or non-response. RESULTS: Fourteen of the 20 patients (70%) showed a complete response to infliximab treatment, two showed a partial response and four showed no response. The four non-responders underwent colectomy with ileal pouch-anal anastomosis. The resected colon specimen was consistent with ulcerative colitis in all four cases, although two were subsequently re-classified as Crohn's disease. Eight additional patients were subsequently re-classified as having Crohn's disease on longer follow-up evaluation, whilst eight continued to have features of indeterminate colitis. The response rate to infliximab treatment was similar in both groups. CONCLUSIONS: Infliximab is effective in approximately two-thirds of patients with indeterminate colitis, and thus may be considered for patients with refractory disease prior to colectomy. The follow-up time afforded by infliximab treatment may allow for more accurate classification of the disease in a significant proportion of patients whose colitis has indeterminate features at initial presentation.

High level perinuclear antineutrophil cytoplasmic antibody (pANCA) in ulcerative colitis patients before colectomy predicts the development of chronic pouchitis after ileal pouch-anal anastomosis.

BACKGROUND: The reported cumulative risk of developing pouchitis in ulcerative colitis (UC) patients undergoing ileal pouch-anal anastomosis (IPAA) approaches 50% after 10 years. To date, no preoperative serological predictor of pouchitis has been found. AIMS: To assess whether preoperative perinuclear antineutrophil cytoplasmic antibody (pANCA) expression was associated with acute and/or chronic pouchitis after IPAA. METHODS: Patients were prospectively assessed for the development of clinically and endoscopically proved pouchitis. Serum obtained at the time of colectomy in 95 UC patients undergoing IPAA was analysed for pANCA by ELISA and indirect immunofluorescence. pANCA+ patients were stratified into high level (>100 ELISA units (EU)/ml) (n=9), moderate level (40-100 EU/ml) (n=32), and low level (<40 EU/ml) (n=19) subgroups. RESULTS: Sixty of the 95 patients (63%) expressed pANCA. After a median follow up of 32 months (range 1-89), 32 patients (34%) developed either acute (n=14) or chronic (n=18) pouchitis. Pouchitis was seen in 42% of pANCA+ patients compared with 20% of pANCA- patients (p=0.09). There was no significant difference in the incidence of acute pouchitis between the three pANCA+ patient subgroups. The cumulative risk of developing chronic pouchitis among patients with high level pANCA (56%) before colectomy was significantly higher than in patients with medium level (22%), low level (16%), and those who were pANCA- (20%) (p=0.005). Multivariate analysis revealed that the sole parameter significantly associated with the development of chronic pouchitis after IPAA was the presence of high level pANCA before colectomy (p=0.005). CONCLUSION: High level pANCA before colectomy is significantly associated with the development of chronic pouchitis after IPAA.

An open-label pilot study using thioguanine as a therapeutic alternative in Crohn's disease patients resistant to 6-mercaptopurine therapy.

BACKGROUND AND AIMS: A substantial number of patients with inflammatory bowel disease (IBD) fail to achieve a complete clinical response with 6-mercaptopurine (6-MP) and azathioprine (AZA). Inability to achieve therapeutic 6-thioguanine nucleotide (6-TGN) levels due to the preferential overproduction of 6-methylmercaptopurine ribonucleotides (6-MMPR) upon dose escalation characterizes a newly described subgroup of IBD patients resistant to 6-MP/AZA therapy. Treatment with 6-thioguanine (6-TG), a related thiopurine, which forms 6-TGNs more directly may be beneficial in such patients. This pilot study evaluated the safety, tolerance, and efficacy of 6-TG in the subgroup of Crohn's disease (CD) patients failing to attain adequate disease control with traditional 6-MP/AZA therapy. METHODS: Ten CD patients with preferential 6-MMPR production upon 6-MP/AZA dose escalation were enrolled in an open-label pilot study. Seven of 10 patients had experienced dose-related 6-MP toxicities. RESULTS: Seventy percent of the patients (7 of 10) responded or were in remission at week 16. Clinical response was evident by week 4 in most. 6-TGN levels were nine-fold higher with 6-TG treatment than with 6-MP, whereas 6-MMPR levels were undetectable. No patient developed a recurrence of hepatic or hematological toxicity. CONCLUSIONS: 6-TG was a safer and more efficacious thiopurine in this subgroup of IBD patients resistant to 6-MP therapy. Larger controlled trials are warranted to further evaluate both the short- and long-term safety and efficacy in this subgroup of patients as well as a broader spectrum of IBD patients.

Outcome of cytomegalovirus infections in patients with inflammatory bowel disease.

OBJECTIVE: The aim of this study was to determine the outcome of cytomegalovirus (CMV) infections complicating the course of inflammatory bowel disease (IBD). METHODS: The records and clinical courses were reviewed for all IBD patients who were evaluated at the IBD Center of the Cedars-Sinai Medical Center and who developed CMV infection. RESULTS: Ten patients with severe, medically refractory IBD (five ulcerative colitis, three Crohn's colitis, and two indeterminate colitis) developed CMV infection. All but two were hospitalized with exacerbation of their underlying disease and were receiving immunosuppressive treatment with steroids, thiopurines, and/or cyclosporine at the time CMV infection was recognized. Eight patients had documented colonic CMV (one had concurrent upper GI tract involvement), one developed interstitial CMV and Pneumocystis carinii pneumonia, and one developed primary CMV mononucleosis. Prompt treatment with ganciclovir and withdrawal of immunosuppressive treatment resulted in gradual improvement and induction of remission of the underlying IBD in five patients. The patient with concomitant CMV and P. carinii pneumonitis died. In two patients, treatment with ganciclovir did not alter the clinical course of their IBD, and one of them underwent colectomy. In one patient CMV was found on the resected colonic specimen. One patient with primary CMV infection responded also to ganciclovir treatment. CONCLUSIONS: CMV infection may aggravate the course of seemingly refractory IBD in patients who either fail to respond or experience worsening of symptoms despite immunosuppressive therapy. Expedient evaluation, prompt treatment intervention with ganciclovir, and withdrawal of immunosuppressive treatment may avoid complications and mortality. This regimen leads to improvement of the underlying IBD in most patients.

Anti-tumor necrosis factor monoclonal antibody therapy for gastrointestinal Behçet's disease: a case report.

Behçet's disease (BD) is a multisystem immune-mediated inflammatory disorder that involves the intestine in 3%-26% of cases. Corticosteroids, 5-aminosalicylic acid derivatives, immunomodulators, and more recently thalidomide and pentoxifylline have been used to treat BD with varying degrees of success. Tumor necrosis factor (TNF)-alpha is believed to play a pivotal role in this T helper cell type 1 (Th1)-mediated disease. Infliximab, a chimeric monoclonal antibody to TNF-alpha, has been demonstrated to be an effective therapy for Crohn's disease and rheumatoid arthritis, 2 other Th1-mediated disorders. We describe a patient with chronically active, steroid-dependent BD involving the gastrointestinal tract who received 4 doses of infliximab during a 6-month period. Because most of her symptoms were gastrointestinal, the Crohn's Disease Activity Index (CDAI) was used to assess response. A rapid and dramatic improvement in both gastrointestinal and extraintestinal symptoms was observed. The CDAI score decreased from 270 points (preinfusion) to 13 points by week 2, and remission was sustained despite complete withdrawal of steroids. Colonoscopy performed 10 weeks after the first infusion showed marked endoscopic and histologic improvement. This report suggests that infliximab may be an effective new therapy for gastrointestinal BD, and perhaps other manifestations of BD as well.

Pediatric Inflammatory Bowel Disease.

The combination of an unprecedented number of new therapeutic options (Fig. 1), along with new insights in how to optimize currently available therapies and advances in our understanding of disease pathogenesis, present many exciting new aspects to the management of patients with inflammatory bowel disease (IBD). Clinical management paradigms must evolve in parallel to keep pace with these advances. Traditional pediatric IBD regimens have underutilized combination therapies (Fig. 2) and immunomodulatory agents. Increased appreciation for steroid side effects is leading to a shift away from their inclusion in maintenance regimens. Immunomodulators are being introduced earlier in the course of disease for maintenance of remission and growth promotion. Recognition that the sole signs of active disease in children and adolescents may be growth and maturational delay, despite a relative lack of gastrointestinal symptoms, should prompt earlier, more aggressive interventions. When more potent, rapidly acting interventions such as infliximab, cyclosporine (CSA), or tacrolimus are considered, they should generally be co-administered with agents such as 6-mercaptopurine (6-MP) or azathioprine (AZA) for longer-term disease suppression.

Marker antibody expression stratifies Crohn's disease into immunologically homogeneous subgroups with distinct clinical characteristics.

BACKGROUND: Perinuclear antineutrophil cytoplasmic antibodies (pANCA) have been detected in a clinically distinct Crohn's disease subpopulation. Antibodies to Saccharomyces cerevisiae (ASCA) have been demonstrated in the majority of patients with Crohn's disease. AIMS: To examine the relationship between selective marker antibody expression in Crohn's disease and disease onset, location, and clinical behaviour patterns. METHODS: Sera from 156 consecutive patients with established Crohn's disease were evaluated in a blinded fashion for the presence of ASCA and ANCA. Clinical profiles were generated by investigators blinded to immune marker status. RESULTS: Using multiple regression analyses, higher ASCA levels were shown to be independently associated with early age of disease onset as well as both fibrostenosing and internal penetrating disease behaviours. Higher ANCA levels were associated with later age of onset and ulcerative colitis-like behaviour. Substratification of the Crohn's disease population using selective ANCA and ASCA expression (high levels of a single marker antibody): (1) distinguished homogeneous subgroups that manifested similar disease location and behaviours; and (2) identified patients with more aggressive small bowel disease. CONCLUSIONS: The findings suggest that by taking into account the magnitude of the host immune response, Crohn's disease can now be stratified on an immunological basis into more homogeneous clinically distinct subgroups, characterised by greater uniformity among anatomical distribution of disease and disease behaviour.

Factors predictive of response to cyclosporin treatment for severe, steroid-resistant ulcerative colitis.

OBJECTIVE: Cyclosporin-A (CSA) has been demonstrated to be effective for treatment of severe, steroid-resistant ulcerative colitis (UC). Use of CSA has been limited, however, because of low 1-yr response rates and the potential for complications. The aim of this study is to define clinical and laboratory factors predictive of response in severe, steroid-resistant UC. METHODS: A retrospective review of 36 cases of severe, steroid-resistant UC treated with CSA was performed. Intravenous (i.v.) CSA was administered at an initial dose of 2.5 mg/kg, and oral (p.o.) CSA was given as twice the i.v. dose. Clinical response was recorded and logistic regression analysis was performed on clinical and laboratory factors for prediction of response to CSA. RESULTS: Of 36 patients, 25 responded to i.v. CSA and were switched to p.o. CSA. Of the 25, 13 required colectomy by 9 months. The other 12 patients had a sustained response to CSA and avoided colectomy at 9 months. Overall, 24 of 36 patients treated with CSA required colectomy by 9 months. A high percentage of band neutrophils (bands) on admission was found to be a significant predictor of response to CSA. CONCLUSIONS: Bands on admission are predictive of response to CSA and ultimately, the requirement for surgery in steroid-resistant UC.

Efficacy of mycophenolate mofetil in patients failing 6-mercaptopurine or azathioprine therapy for Crohn's disease.

Mycophenolate mofetil (MMF) is a novel immunomodulator that may be effective in the treatment of chronic active and perianal Crohn's disease (CD). The aim of this study is to assess the efficacy of MMF in CD patients who failed or were intolerant of 6-mercaptopurine (6-MP) or azathioprine (AZA). Eleven CD patients were treated with MMF after a failed course of 6-MP/AZA, and their records reviewed retrospectively. Reasons for 6-MP/AZA intolerance or failure were recorded. Response to MMF was determined by calculation of the Harvey-Bradshaw index and ability to taper steroids. Adverse reactions to MMF were recorded. Eleven patients were identified who failed a previous trial of 6-MP/AZA and other immunomodulators and required immunomodulator therapy. Of 11 patients who started MMF, four had early adverse reactions within 8 weeks and stopped the medication. Of the remaining seven patients who took MMF for at least 8 weeks, one had a complete response, two had a partial response, and four had no response to the medication. In patients who failed 6-MP/AZA, MMF was of benefit in 3 of 11 patients with only one complete responder. This lower-than-expected response rate may indicate that patients who are resistant to 6-MP or AZA may also be resistant to MMF.

An open-label pilot study of low-dose thalidomide in chronically active, steroid-dependent Crohn's disease.

BACKGROUND & AIMS: Thalidomide decreases production of tumor necrosis factor alpha, a proinflammatory cytokine associated with Crohn's disease (CD). In this study the safety, tolerance, and efficacy of low-dose thalidomide were evaluated for treatment of moderate-to-severe, steroid-dependent CD. METHODS: Twelve adult male patients with Crohn's Disease Activity Index (CDAI) scores of > or = 250 and < or = 500 despite > or = 20 mg prednisone/day were enrolled. The first 6 patients received 50 mg thalidomide every night, the next 6 received 100 mg every night. Steroid doses were stable during the first 4 weeks of treatment, then tapered during weeks 5-12. CDAI was used to assess response. RESULTS: (1) Disease activity improved consistently in all patients during weeks 1-4: 58% response, 17% remission. (2) Clinical improvement was generally maintained despite steroid taper during weeks 5-12. All patients were able to reduce steroids by >/=50%. Forty-four percent discontinued steroids entirely. In weeks 5-12, 70% of patients responded and 20% achieved remission. (3) Side effects were mild and mostly transient, with the most common being drowsiness, peripheral neuropathy, edema, and dermatitis. CONCLUSIONS: Low-dose thalidomide appears to be well tolerated and effective over a 12-week period. Results of this pilot study support the need for controlled multicenter trials of thalidomide for treatment of CD.

Efficacy and safety of retreatment with anti-tumor necrosis factor antibody (infliximab) to maintain remission in Crohn's disease.

BACKGROUND & AIMS: Infliximab, an anti-tumor necrosis factor monoclonal antibody, rapidly reduces signs and symptoms of active Crohn's disease. The aim of this study was to determine whether repeated infusions of infliximab would effectively and safely maintain the remitting benefit. METHODS: The efficacy, safety, pharmacokinetics, and immunogenicity of 4 repeated treatments with 10 mg/kg infliximab given every 8 weeks were compared with the effects of placebo in a randomized, double-blind, placebo-controlled, parallel group trial. Seventy-three patients with active Crohn's disease who had not adequately responded to conventional therapies and then had demonstrated a clinical response (>/=70-point decrease in the Crohn's Disease Activity Index) to an initial infusion of infliximab (or placebo) were studied. RESULTS: Retreatment with infliximab maintained the clinical benefit through the retreatment period and 8 weeks after the last infusion in nearly all patients retreated with infliximab. Median values for Crohn's Disease Activity Index, inflammatory bowel disease questionnaire (a quality of life measurement), and serum C-reactive protein concentration were maintained at remission levels with infliximab retreatment, but not with placebo retreatment. Retreatment with infliximab every 8 weeks maintained serum infliximab concentration and was well tolerated with a low incidence of immunogenicity. One case of lymphoma and 1 case of suspected lupus were reported; the complete long-term safety profile of infliximab requires additional clinical investigation. CONCLUSIONS: Long-term treatment with infliximab showed efficacy and tolerability in managing symptoms of patients with active Crohn's disease not responding to conventional treatments.

Crohn's disease-associated genetic marker is seen in medically unresponsive ulcerative colitis patients and may be associated with pouch-specific complications.

PURPOSE: Genetic markers have been used to define subgroups of patients within the broad categories of Crohn's disease and ulcerative colitis that may differ in clinical course and response to medical therapy. The tumor necrosis factor microsatellite haplotype a2blc2d4e1 has been found previously to be present in 24 percent of patients with Crohn's disease and only 5 percent of patients with ulcerative colitis. This study examined associations between this microsatellite haplotype and the postoperative clinical course of patients with ulcerative colitis undergoing ileal pouch-anal anastomosis. METHODS: As part of a large, controlled, prospective study to correlate genetic markers with clinical phenotypes, tumor necrosis factor microsatellite alleles at five loci (a, b, c, d, and e) were determined from genomic DNA by polymerase chain reaction in 32 patients with a clinical and histopathologic diagnosis of ulcerative colitis who underwent ileal pouch-anal anastomosis for medically unresponsive disease. All patients with ileal pouch-anal anastomosis were also studied prospectively for pouch-specific complications. RESULTS: The tumor necrosis factor haplotype a2blc2d4e1 was present in 11 patients. Median follow-up was 19 months. Thirteen patients had a pouch-specific complication (12 pouchitis and 1 pouch-perineal fistula). Six of 11 patients (55 percent) with the haplotype had a pouch-specific complication compared with 7 of the 21 patients (33 percent) who did not possess this haplotype (P = 0.22). Median time from surgery to pouch-specific complication was eight months. Patients with the haplotype had a median time to pouch-specific complication of three months, whereas patients without the haplotype had a median time of 11 months (P = 0.04). In addition, 36 percent of patients with the haplotype had chronic pouch complications vs. only 10 percent of patients without the haplotype (P = 0.05). CONCLUSION: The Crohn's disease-associated tumor necrosis factor haplotype a2blc2d4e1 may define a subgroup of medically unresponsive patients with ulcerative colitis who are predisposed to a higher incidence of pouch-specific complications after ileal pouch-anal anastomosis.