Long-term efficacy and safety of ustekinumab for Crohn's disease through the second year of therapy.

BACKGROUND: In Phase 3 studies of ustekinumab, a fully human monoclonal IL-12/23p40 antibody approved for moderate-to-severe Crohn's disease, patients entered a long-term extension after completing 8 weeks of induction and 44 weeks of maintenance treatment. Efficacy through 92 weeks and safety through 96 weeks of IM-UNITI maintenance are reported. METHODS: UNITI-1 (TNF-antagonist failures) and UNITI-2 (conventional therapy failures) patients (N = 1281) entered IM-UNITI, including 397 ustekinumab intravenous induction responders randomised to subcutaneous ustekinumab 90 mg every 12 weeks, every 8 weeks, or placebo and 884 nonrandomised patients. Dose-adjustment to 90 mg every 8 weeks occurred in patients randomised to 90 mg every 12 weeks and placebo patients with loss of response (Weeks 8-32). All Week 44 completers could enter the long-term extension without further dose adjustment. Placebo patients discontinued following study unblinding. RESULTS: A total of 718 patients (all treated) entered the long-term extension (298 randomised and 420 not randomised). Overall, 86.5% (621/718) completed Week 96. The proportions of randomised patients in clinical remission were generally maintained from Week 44 through 92 in ustekinumab 90 mg every 12 weeks (77.4% to 72.6%), every 8 weeks (84.1% to 74.4%), and prior dose adjustment groups (63.4% to 53.5%). At Week 92, the proportions of patients in clinical remission were similar in the ustekinumab 90 mg every 12 weeks and every 8 weeks groups and lower in patients with prior dose adjustment. Proportions of patients in clinical remission at Week 92 for all treated every 8 weeks (64.4%) and every 12 weeks (64.3%) groups were lower than randomised every 8 weeks (74.4%) and every 12 weeks (72.6%) groups, but similarly maintained. Safety events (per hundred patient-years) were similar among all placebo and ustekinumab patients (Week 0-96), including adverse events (484.39 vs 447.76), serious adverse events (19.24 vs 18.82), and serious infections (4.09 vs 4.02). No dose effect was observed. CONCLUSIONS: Subcutaneous ustekinumab maintained clinical response and remission through Week 92. No new safety signals were observed. ClinicalTrials.gov number NCT01369355.

Cathelicidin suppresses lipid accumulation and hepatic steatosis by inhibition of the CD36 receptor.

BACKGROUND AND OBJECTIVES: Obesity is a global epidemic which increases the risk of the metabolic syndrome. Cathelicidin (LL-37 and mCRAMP) is an antimicrobial peptide with an unknown role in obesity. We hypothesize that cathelicidin expression correlates with obesity and modulates fat mass and hepatic steatosis. MATERIALS AND METHODS: Male C57BL/6 J mice were fed a high-fat diet. Streptozotocin was injected into mice to induce diabetes. Experimental groups were injected with cathelicidin and CD36 overexpressing lentiviruses. Human mesenteric fat adipocytes, mouse 3T3-L1 differentiated adipocytes and human HepG2 hepatocytes were used in the in vitro experiments. Cathelicidin levels in non-diabetic, prediabetic and type II diabetic patients were measured by enzyme-linked immunosorbent assay. RESULTS: Lentiviral cathelicidin overexpression reduced hepatic steatosis and decreased the fat mass of high-fat diet-treated diabetic mice. Cathelicidin overexpression reduced mesenteric fat and hepatic fatty acid translocase (CD36) expression that was reversed by lentiviral CD36 overexpression. Exposure of adipocytes and hepatocytes to cathelicidin significantly inhibited CD36 expression and reduced lipid accumulation. Serum cathelicidin protein levels were significantly increased in non-diabetic and prediabetic patients with obesity, compared with non-diabetic patients with normal body mass index (BMI) values. Prediabetic patients had lower serum cathelicidin protein levels than non-diabetic subjects. CONCLUSIONS: Cathelicidin inhibits the CD36 fat receptor and lipid accumulation in adipocytes and hepatocytes, leading to a reduction of fat mass and hepatic steatosis in vivo. Circulating cathelicidin levels are associated with increased BMI. Our results demonstrate that cathelicidin modulates the development of obesity.

A validated web-based tool to display individualised Crohn's disease predicted outcomes based on clinical, serologic and genetic variables.

BACKGROUND: Early treatment for Crohn's disease (CD) with immunomodulators and/or anti-TNF agents improves outcomes in comparison to a slower 'step up' algorithm. However, there remains a limited ability to identify those who would benefit most from early intensive therapy. AIM: To develop a validated, individualised, web-based tool for patients and clinicians to visualise individualised risks for developing Crohn's disease complications. METHODS: A well-characterised cohort of adult patients with CD was analysed. Available data included: demographics; clinical characteristics; serologic immune responses; NOD2 status; time from diagnosis to complication; and medication exposure. Cox proportional analyses were performed to model the probability of developing a CD complication over time. The Cox model was validated externally in two independent CD cohorts. Using system dynamics analysis (SDA), these results were transformed into a simple graphical web-based display to show patients their individualised probability of developing a complication over a 3-year period. RESULTS: Two hundered and forty three CD patients were included in the final model of which 142 experienced a complication. Significant variables in the multivariate Cox model included small bowel disease (HR 2.12, CI 1.05-4.29), left colonic disease (HR 0.73, CI 0.49-1.09), perianal disease (HR 4.12, CI 1.01-16.88), ASCA (HR 1.35, CI 1.16-1.58), Cbir (HR 1.29, CI 1.07-1.55), ANCA (HR 0.77, CI 0.62-0.95), and the NOD2 frameshift mutation/SNP13 (HR 2.13, CI 1.33-3.40). The Harrell's C (concordance index for predictive accuracy of the model) = 0.73. When applied to the two external validation cohorts (adult n = 109, pediatric n = 392), the concordance index was 0.73 and 0.75, respectively, for adult and pediatric patients. CONCLUSIONS: A validated, web-based tool has been developed to display an individualised predicted outcome for adult patients with Crohn's disease based on clinical, serologic and genetic variables. This tool can be used to help providers and patients make personalised decisions about treatment options.

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.

Inhibition of a novel fibrogenic factor Tl1a reverses established colonic fibrosis.

Intestinal fibrostenosis is among the hallmarks of severe Crohn's disease. Patients with certain TNFSF15 (gene name for TL1A) variants over-express TL1A and have a higher risk of developing strictures in the small intestine. In addition, sustained Tl1a expression in mice leads to small and large intestinal fibrostenosis under colitogenic conditions. The aim of this study was to determine whether established murine colonic fibrosis could be reversed with Tl1a antibody (Ab). Treatment with neutralizing Tl1a Ab reversed colonic fibrosis back to the original pre-inflamed levels, potentially as a result of lowered expression of connective tissue growth factor, Il31Ra, transforming growth factor ß1 and insulin-like growth factor-1. In addition, blocking Tl1a function by either neutralizing Tl1a Ab or deletion of death domain receptor 3 (Dr3) reduced the number of fibroblasts and myofibroblasts, the primary cell types that mediate tissue fibrosis. Primary intestinal myofibroblasts expressed Dr3 and functionally responded to direct Tl1a signaling by increasing collagen and Il31Ra expression. These data demonstrated a direct role for TL1A-DR3 signaling in tissue fibrosis and that modulation of TL1A-DR3 signaling could inhibit gut fibrosis.

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.

CD161 DEFINES EFFECTOR T CELLS THAT EXPRESS LIGHT AND RESPOND TO TL1A-DR3 SIGNALING.

Expression of NK cell markers identifies pro-inflammatory T cell subsets in the liver and intestinal immune compartments. Specifically, CD161 is expressed on Th17 cells which play an important role in the regulation of mucosal inflammation. In this study, we characterized human peripheral blood CD161+ T cells as an effector population partially resembling a gut T cell phenotype. CD161+ CD4+ T cells express the gut-associated TNF family member, LIGHT, and respond to crosslinking of DR3, a receptor to another gut-associated cytokine, TL1A. Robust IFN-γ production in response to DR3 signaling correlated with enhanced expression of surface DR3 on CD161+ T cells and co-stimulation with IL12 and IL18. CD161+ T cell effector function was directly demonstrated by activation of responder monocytes in co-culture leading to CD40 upregulation and CD14 downregulation. CD161+ T cells reciprocally responded to activated monocytes, inducing expression of activation marker, CD69, and production of IL2 and IFN-γ, further demonstrating effective CD161+ T cell cross-talk with monocytes. Finally, CD161 defined a subset of T cells that co-express CD56, a second NK marker. Our findings implicate human CD161+ T cells in gut-associated signaling mechanisms, and suggest a monocyte mediated effector function in mucosal inflammation.

Randomised clinical trial: herbal extract HMPL-004 in active ulcerative colitis - a double-blind comparison with sustained release mesalazine.

BACKGROUND: Andrographis paniculata is an herbal mixture used to treat inflammatory diseases. An extract of the herb, HMPL-004, inhibits TNF-α and IL-1ß, and prevents colitis in animal models. AIM: To determine the efficacy and safety of HMPL-004 in patients with mild-to-moderate ulcerative colitis. METHODS: A randomised, double-blind, multicentre, 8-week parallel group study was conducted using HMPL-004 1200 mg/day compared with 4500 mg/day of slow release mesalazine (mesalamine) granules in patients with mild-to-moderately active ulcerative colitis. Disease activity was assessed at baseline and every 2 weeks for clinical response, and at baseline and 8 weeks by colonoscopy. RESULTS: One hundred and twenty patients at five centres in China were randomised and dosed. Clinical remission and response were seen in 21% and 76% of HMPL-004-treated patients, and 16% and 82% of mesalazine-treated patients. By colonoscopy, remission and response were seen in 28% and 74% of HMPL-004-treated patients and 24% and 71% of mesalazine-treated patients, respectively. There was no significant difference between the two treatment groups. CONCLUSION: HMPL-004 may be an efficacious alternative to mesalazine in ulcerative colitis.

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.

Differences in the management of Crohn's disease among experts and community providers, based on a national survey of sample case vignettes.

BACKGROUND: When faced with the same set of facts, healthcare providers often make different diagnoses, employ different tests and prescribe disparate therapies. AIM: To perform a national survey to measure process of care and variations in decision-making in Crohn's disease, and the compared results between experts and community providers. METHODS: We constructed a survey with five vignettes to elicit provider beliefs regarding the appropriateness of diagnostic tests and therapies in Crohn's disease. We measured agreement between community gastroenterologists and Crohn's disease experts, and measured variation within each group using the RAND Disagreement Index (DI), which is a validated measure of provider variation. RESULTS: We received 186 responses (42% response rate). Experts and community providers generally agreed on diagnostic testing decisions in Crohn's disease. However, there was a significant disagreement between groups for several decisions (use of 5-aminosalicylate in particular), and there was evidence of 'extreme variation' (defined as DI > 1.0) within groups across a range of decisions. CONCLUSIONS: Although experts and community providers are in general consensus about diagnostic decision-making in Crohn's disease, extreme variation exists both between and within groups for key therapeutic decisions in Crohn's disease. We must understand and decrease this variation prior to future efforts of creating explicit quality indicators in Crohn's disease.

An IFNG SNP with an estrogen-like response element selectively enhances promoter expression in peripheral but not lamina propria T cells.

This study examines mucosa-specific regulatory pathways involved in modulation of interferon-gamma (IFN-gamma) in lamina propria T cells. Previous studies identified mucosa-specific CD2 cis-elements within the -204 to -108 bp IFNG promoter. Within this region, a single-site nucleotide polymorphism, -179G/T, imparts tumor necrosis factor-alpha stimulation of IFNG in peripheral blood lymphocytes, and is linked with accelerated AIDS progression. We discovered a putative estrogen response element (ERE) introduced by the -179T, which displays selective activation in peripheral blood mononuclear cells (PBMC) vs lamina propria mononuclear cells (LPMC). Transfection of PBMC with constructs containing the -179G or -179T site revealed CD2-mediated enhancement of the -179T compared to -179G allele, although, in LPMC, a similar level of expression was detected. Electrophoretic mobility shift assay (EMSA) analysis demonstrated CD2-mediated nucleoprotein binding to the -179T but not the -179G in PBMC. In LPMC, binding is constitutive to both -179G and -179T regions. Sequence and EMSA analysis suggests that the -179T allele creates an ERE-like binding site capable of binding recombinant estrogen receptor. Estrogen response element transactivation is enhanced by CD2 signaling, but inhibited by estrogen in PBMC but not in LPMC, although expression of estrogen receptor was similar. This is the first report to describe a potential molecular mechanism responsible for selectively controlling IFN-gamma production in LPMC.

Daclizumab, a humanised monoclonal antibody to the interleukin 2 receptor (CD25), for the treatment of moderately to severely active ulcerative colitis: a randomised, double blind, placebo controlled, dose ranging trial.

BACKGROUND: An uncontrolled pilot study demonstrated that daclizumab, a humanised monoclonal antibody to the interleukin 2 receptor (CD25), might be effective for the treatment of active ulcerative colitis. METHODS: A randomised, double blind, placebo controlled trial was conducted to evaluate the efficacy of daclizumab induction therapy in patients with active ulcerative colitis. A total of 159 patients with moderate ulcerative colitis were randomised to receive induction therapy with daclizumab 1 mg/kg intravenously at weeks 0 and 4, or 2 mg/kg intravenously at weeks 0, 2, 4, and 6, or placebo. The primary end point was induction of remission at week 8. Remission was defined as a Mayo score of 0 on both endoscopy and rectal bleeding components and a score of 0 or 1 on stool frequency and physician's global assessment components. Response was defined as a decrease from baseline in the Mayo score of at least 3 points. RESULTS: Two per cent of patients receiving daclizumab 1 mg/kg (p = 0.11 v placebo) and 7% of patients receiving 2 mg/kg (p = 0.73) were in remission at week 8, compared with 10% of those who received placebo. Response occurred at week 8 in 25% of patients receiving daclizumab 1 mg/kg (p = 0.04) and in 33% of patients receiving 2 mg/kg (p = 0.30) versus 44% of those receiving placebo. Daclizumab was well tolerated. The most frequently reported adverse events in daclizumab treated patients compared with placebo treated patients were nasopharyngitis (14.6%) and pyrexia (10.7%). CONCLUSION: Patients with moderate ulcerative colitis who are treated with daclizumab are not more likely to be in remission or response at eight weeks than patients treated with placebo.

Evaluation of blends tincal waste, volcanic tuff, bentonite and fly ash for use as a cement admixture.

The evaluation of blends tincal waste (TW), fly ash (FA), bentonite (BE), volcanic tuff (VT) for use as a cement admixture was investigated. The properties examined include setting time, expansion, water requirement, specific surface and compressive strength of cement mixtures. The results revealed that the early compressive strength decrease with increasing tincal waste, due to tincal waste increasing initial setting time of the cement. The tincal waste and volcanic tuff of cement mixtures increased and there was reduction in compressive strength. The more the tincal waste increased the greater retardation there was initial setting time this may be attributed to containing high amount B2O3 and MgO content. The tincal waste and fly ash increased with expansion increased. Water requirement increased as the Blaine fineness of the cement mixtures increased. The results obtained were compared with standards and five batches were advised as suitable for the standard.

IgA and/or IgG subclass deficiency in children with recurrent respiratory infections and its relationship with chronic pulmonary damage.

Most patients with IgA and/or IgG subclass deficiency are asymptomatic but some may suffer from frequent mainly respiratory infections. The aim of our study was to determine the frequency of IgA and/or IgG subclass deficiencies and the rate of chronic pulmonary damage secondary to recurrent pulmonary infections in these children. Serum IgA and IgG subclass levels were measured in 225 children aged 6 months to 6 years with recurrent sinopulmonary infections (44 with recurrent upper respiratory tract infections, 100 with recurrent pulmonary infections and 81 with recurrent bronchiolitis). In order to determine chronic pulmonary damage due to recurrent infections in patients with recurrent pulmonary infections CT scans of thorax were also obtained. The overall frequency of antibody defects was found to be 19.1%. IgA deficiency was observed in 9.3%, IgG subclass deficiency in 8.4% and IgA + IgG subclass deficiency in 1.4%. The prevalance of IgA and/or IgG subclass deficiency was 25% in patients with recurrent upper respiratory tract infections, 22% in patients with recurrent pulmonary infections and 12.3% in patients with recurrent bronchiolitis (p>0.05). Chronic pulmonary damage in lungs was determined radiologically in 17 of 100 cases with recurrent pulmonary infection. In IgG subclass deficiencies sequel changes, although not statistically significant, were observed five times more frequently than that of IgA deficiencies. CT scans revealed pulmonary sequels in 5 of the 22 (22.7%) patients with recurrent pulmonary infections and immunodeficiency (bronchiectasis in 2 patients with IgG3 deficiency, fibrotic changes in one with IgA deficiency and in one with IgG3 deficiency, bronchiolitis obliterans in one with IgG2 + IgG3 deficiency). On the other hand, pulmonary sequels were observed in 12 patients (15.4%) with normal immunoglobulin levels. Eight of them were bronchiolitis obliterans, 2 of them were atelectasia and 1 of them was bronchiectasia. We therefore suggest that determination of antibody levels and evaluation of pulmonary alterations is crucial in patients with recurrent sinopulmonary infections since the deficiency of antibodies is associated with a greater pulmonary damage.

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.

Potent inhibition of cytokine production from intestinal lamina propria T cells by phosphodiesterase-4 inhibitory thalidomide analogues.

In Crohn's disease, intestinal lamina propria (LP) T cells overproduce TNF-alpha and IFN-gamma, and clinical and animal studies indicate that this is pathogenic. Thalidomide influences cytokine production by leukocytes, inhibiting macrophage TNF-alpha, and is beneficial in treating Crohn's disease. Chemical analogues have been synthesized that may lack teratogenic and other side effects of thalidomide. We tested three analogues [selective cytokine inhibitory drugs (SelCIDs) A, B, and C, all potent PDE4 inhibitors] for effect on TNF-alpha, IFN-gamma, and IL-10 production by and on proliferation of intestinal LP mononuclear cells after T-cell stimulation and results were compared with those for peripheral blood leukocytes (PBL). While thalidomide itself had little effect, the SelCIDs were potent inhibitors, with relative inhibitory potencies: A> or =B>>C. The LP T cells were less sensitive to inhibition by the SelCIDs than were PBL. Since highly pre-activated PBL were even less sensitive, activation state alone can account for the responsiveness of intestinal LP T cells. Thalidomide analogues could play a role in treating Crohn's disease and other inflammatory disorders.

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.