Veerle J. Nuij

Majority of patients with inflammatory bowel disease in clinical remission have mucosal inflammation.

Background: Management of inflammatory bowel disease (IBD) is increasingly focused on mucosal remission. We assessed the prevalence of mucosal inflammation during clinical remission, the clinical consequences, and the impact on disease course. Methods: IBD patients from two referral centers who underwent a surveillance colonoscopy while clinically in remission between January 2001 and December 2003 were included. Follow‐up ended May 1, 2009. Clinical data were collected from patient charts. Statistical analysis was performed using independent t‐tests and nonparametric tests. Results: In total, 152 IBD patients were included (98 [65%] ulcerative colitis, 46 [30%] Crohns disease; 85 [56%] males). Median follow‐up was 6.8 years (interquartile range [IQR] 6–8). Forty‐seven (31%) patients had no signs of inflammation during endoscopy (group A). Of the remaining 105 (68%) patients, 51 (49%) had both endoscopic and histological inflammation (group B), 51 (49%) histological inflammation only (group C), two (2%) endoscopic lesions only (group D). Two years later, 29% of all patients had endoscopic inflammation and another 27% had only microscopic inflammation. In 39% the inflammation had resolved spontaneously. Inflammation was more often found in group B+C (n = 62/102; 61%) than in group A (n = 17/47; 36%; P = 0.21). Inflammation was not associated with more frequent clinical relapses nor with stricture formation, nor with the need for surgery. Conclusions: A large proportion of IBD patients have mucosal inflammation without clinical symptoms. Although one‐third recover spontaneously, mucosal inflammation in patients who are clinically in remission is associated with more severe mucosal disease activity, but not with more complications or symptomatic flares during follow‐up. (Inflamm Bowel Dis 2012)

Disappointing durable remission rates in complex Crohn's disease fistula

Background:Despite potent drugs and surgical techniques, the treatment of perianal fistulizing Crohns disease (CD) remains challenging. We assessed treatment strategies for perianal fistulizing CD and their effect on remission, response, and relapse. Methods:Patients with perianal fistulizing CD visiting the Erasmus MC between January 1, 1980 and January 1, 2000 were identified. Demographics, fistula characteristics, and received treatments aimed at the outcome of these strategies were noted. Results:In total, 232 patients were identified (98 male; 42.2%). Median follow-up was 10.0 years (range, 0.5–37.5 yr). Complex fistulas were present in 78.0%. Medical treatment (antibiotics, steroids, immunosuppressants, and anti-tumor necrosis factor) commenced in 79.7% of the patients and in 53.2%, surgery (colectomy, fistulectomy, stoma, and rectum amputation) was performed. Simple fistulas healed more often than complex fistulas (88.2% versus 64.6%; P < 0.001). Rectum involvement was not associated with a lower remission rate, and anti-tumor necrosis factor therapy did not increase complete fistula healing rates in simple and complex fistula. Initially, healed fistulas recurred in 26.7% in case of simple fistulas and in 41.9% in case of complex fistulas (P = 0.051). Only 37.0% of the complex fistulas were in remission at the end of follow-up compared with 66.7% of the simple fistulas (P < 0.001). Conclusions:Only the minority of CD complex perianal fistulas were in remission after conventional treatment strategies after a median follow-up of 10 years. Simple fistulas were more likely to heal than complex fistulas, and less of these healed fistulas relapsed. However, more than 3 quarters of the patients had complex perianal fistulas.

Phenotype of inflammatory bowel disease at diagnosis in the Netherlands: a population-based inception cohort study (the Delta Cohort).

Background: To describe the clinical characteristics of inflammatory bowel disease (IBD) at diagnosis in The Netherlands at the population level in the era of biologics. Methods: All patients with newly diagnosed IBD (diagnosis made between January 1, 2006 and January 1, 2007) followed in 9 general hospitals in the southwest of the Netherlands were included in this population-based inception cohort study. Results: A total of 413 patients were enrolled, of which 201 Crohn’s disease (CD) (48.7%), 188 ulcerative colitis (UC) (45.5%), and 24 IBD unclassified (5.8%), with a median age of 38 years (range, 14–95). Seventy-eight patients with CD (38.8%) had ileocolonic disease and 73 patients (36.3%) had pure colonic disease. In 8 patients (4.0%), the upper gastrointestinal tract was involved. Nineteen patients with CD (9.5%) had perianal disease. Thirty-nine patients with CD (19.4%) had stricturing phenotype. Of the patients with UC and IBDU, 39 (18.4%) suffered from pancolitis and 61 (29%) from proctitis. Severe endoscopic lesions at diagnosis were seen in 119 patients (28.8%, 68 CD, 49 UC, and 2 IBDU), whereas 98 patients (23.7%) had severe histological disease activity. Thirteen patients (3.1%, 10 CD and 3 UC) had extraintestinal manifestations at diagnosis. Twenty-three patients (5.6%, 20 CD and 3 UC) had fistula at diagnosis. Conclusions: In this cohort, 31% of the patients with CD had complicated disease at diagnosis, 39% had ileocolonic disease, 9.5% had perianal disease, and in 4% the upper gastrointestinal tract was involved. Most patients with UC suffered from left-sided colitis (51%). Severe endoscopic lesions were reported in 34% of the patients with CD and 26% of the patients with UC. Three percent of the patients with IBD had extraintestinal manifestations.

Suppression of p21Rac Signaling and Increased Innate Immunity Mediate Remission in Crohn’s Disease

Overactivation of p21Rac1 is a rate-limiting step for innate immune function in Crohn’s disease and prevents remission. Crohn’s Disease on the Rac Crohn’s disease is a type of inflammatory bowel disease (IBD), wherein the body’s immune system attacks the gastrointestinal tract. In patients with Crohn’s, there are areas of apparently healthy tissue right next to damaged intestine, but it remains unclear what differentiates healthy and inflamed regions. Now, Parikh et al. examine signal transduction differences in healthy and inflamed tissue to find targets that may be protective in Crohn’s. The authors performed a comparative kinome profile in healthy controls as well as healthy and inflamed tissues from Crohn’s patients. They found that p21Rac1 GTPase signaling is suppressed in noninflamed tissue. What’s more, blocking p21Rac1 correlated with clinical improvement of IBD, potentially by boosting innate immune responses. These data suggest that blocking p21Rac1 may be protective for IBD. In inflammatory bowel disease (IBD), large areas of apparently healthy mucosa lie adjacent to ulcerated intestine. Knowledge of the mechanisms that maintain remission in an otherwise inflamed intestine could provide important clues to the pathogenesis of this disease and provide rationale for clinical treatment strategies. We used kinome profiling to generate comprehensive descriptions of signal transduction pathways in inflamed and noninflamed colonic mucosa in a cohort of IBD patients, and compared the results to non-IBD controls. We observed that p21Rac1 guanosine triphosphatase (GTPase) signaling was strongly suppressed in noninflamed colonic mucosa in IBD. This suppression was due to both reduced guanine nucleotide exchange factor activity and increased intrinsic GTPase activity. Pharmacological p21Rac1 inhibition correlated with clinical improvement in IBD, and mechanistically unrelated pharmacological p21Rac1 inhibitors increased innate immune functions such as phagocytosis, bacterial killing, and interleukin-8 production in healthy controls and patients. Thus, suppression of p21Rac activity assists innate immunity in bactericidal activity and may induce remission in IBD.

Prevalence and Phenotype of Concurrent Psoriasis and Inflammatory Bowel Disease

Background: Psoriasis, psoriatic arthritis (PsA), and inflammatory bowel disease (IBD) are related inflammatory immune-mediated diseases, with considerable overlap. However, it is as yet unclear whether co-occurrence of these diseases affects disease course and characteristics of the individual complaints. The objective of this study was to identify the prevalence of IBD and PsA in a psoriasis cohort and to examine whether patients with concurrent psoriasis and IBD carry a distinct phenotype. Methods: Data of all patients with psoriasis visiting a general hospital in the Netherlands between 2009 and 2014 were retrospectively retrieved from electronic patient files. In addition, clinical characteristics of patients with concurrent psoriasis and IBD (n = 40) were compared with psoriasis-only (n = 1643) and IBD-only (n = 385) cohorts. Results: Among 1669 hospital-based patients with psoriasis, prevalence of PsA was 12.2% (n = 203, 95% confidence interval, 10.5–13.7) and of IBD 1.6% (n = 26, 95% confidence interval, 1.0–2.2), including 12 Crohns disease (CD) and 14 ulcerative colitis. Psoriasis-PsA patients were more likely to have IBD than psoriasis-only patients (3.0 versus 1.4%). Psoriasis-CD patients were younger at CD diagnosis (20.0 versus 32.0 yr, P = 0.001), and psoriasis diagnosis (28.0 versus 43.5 yr, P = 0.004) than psoriasis-only patients. Psoriasis-IBD patients had a mild psoriasis phenotype similar to psoriasis-only patients, but the CD-phenotype was significantly more severe than in CD-only patients. Conclusions: The prevalence of IBD in psoriasis was approximately 4 times higher than that in the general population, with the highest risk for psoriasis-PsA patients. Psoriasis-CD patients have a mild (early-onset) psoriasis but an earlier-onset and severe CD-phenotype.

The ATG16L1 risk allele associated with Crohn’s disease results in a Rac1-dependent defect in dendritic cell migration that is corrected by thiopurines

Thiopurines are commonly used drugs in the therapy of Crohn’s disease, but unfortunately only show a 30% response rate. The biological basis for the thiopurine response is unclear, thus hampering patient selection prior to treatment. A genetic risk factor associated specifically with Crohn’s disease is a variant in ATG16L1 that reduces autophagy. We have previously shown that autophagy is involved in dendritic cell (DC)-T-cell interactions and cytoskeletal regulation. Here we further investigated the role of autophagy in DC cytoskeletal modulation and cellular trafficking. Autophagy-deficient DC displayed loss of filopodia, altered podosome distribution, and increased membrane ruffling, all consistent with increased cellular adhesion. Consequently, autophagy-deficient DC showed reduced migration. The cytoskeletal aberrations were mediated through hyperactivation of Rac1, a known thiopurine target. Indeed thiopurines restored the migratory defects in autophagy-deficient DC. Clinically, the ATG16L1 risk variant associated with increased response to thiopurine treatment in patients with Crohn’s disease but not ulcerative colitis. These results suggest that the association between ATG16L1 and Crohn’s disease is mediated at least in part through Rac1 hyperactivation and subsequent defective DC migration. As this phenotype can be corrected using thiopurines, ATG16L1 genotyping may be useful in the identification of patients that will benefit most from thiopurine treatment.

Increased suppressor of cytokine signaling-3 expression predicts mucosal relapse in ulcerative colitis

Background:Most biomarkers predicting mucosal relapse of ulcerative colitis (UC) patients in clinical remission represent low levels of mucosal inflammation. Since SOCS3 expression may increase the vulnerability of intestinal epithelial cells (IECs) to various insults, we investigated whether its expression predicts mucosal relapse in UC patients in clinical remission without any signs of mucosal inflammation. Methods:UC patients (n = 32) in clinical, endoscopic, and histological remission were followed up for 9 years. IEC expression of SOCS3, p-STAT3, and p-STAT1 were assessed with biopsies from the baseline colonoscopy, last colonoscopy before relapse, and colonoscopy at relapse. Clinical data, endoscopy, and histology reports were collected from patient charts. Results:Twenty-six (81%) patients had histological relapse, 19 (59%) developed an endoscopic relapse, and 17 (53%) had a clinical relapse during follow-up. SOCS3 expression at first colonoscopy during remission correlated with shorter time to histological, endoscopic, and clinical relapse. SOCS3 expression was increased at the last colonoscopy before relapse, approaching relapse levels, whereas p-STAT3 expression was low during the entire remission. A positive correlation between IEC SOCS3 and its inducer p-STAT1 was shown. Conclusions:SOCS3 IEC expression during remission may be useful in predicting mucosal relapse in patients without any signs of mucosal inflammation. These data strengthen our hypothesis that SOCS3 contributes to enhanced vulnerability of IEC during remission. Thus, SOCS3 levels during remission may function as a therapeutic target for clinical monitoring and early induction of mucosal healing.

Benefit of Earlier Anti-TNF Treatment on IBD Disease Complications?

BACKGROUND Anti-tumour necrosis factor [anti-TNF] treatment was demonstrated to have disease-modifying abilities in inflammatory bowel disease [IBD]. In this study, we aimed to determine the effect of anti-TNF treatment timing on IBD disease complications and mucosal healing [MH]. METHODS The following IBD-related complications were tested in relation to timing of anti-TNF therapy start in newly diagnosed IBD patients [n = 413]: fistula formation, abscess formation, extra-intestinal manifestations [EIM], surgery, referral to academic centre, and MH. RESULTS A total of 85 patients [21%] received anti-TNF (66 Crohns disease [CD], 16 ulcerative colitis [UC], 3 inflammatory bowel disease unclassified [IBDU]) of whom 57% [48 patients] were treated < 16 months after diagnosis. Patients receiving anti-TNF early [< 16 months] did not differ from patients receiving anti-TNF late [> 16 months] regarding gender, age, smoking status, and familial IBD. More importantly, patients receiving anti-TNF early did not suffer less IBD-related complications during follow-up as compared with patients started on anti-TNF late, nor was more MH observed. Similar results were obtained when anti-TNF treated patient were stratified more stringently, ie < 12 months [40 patients] vs >2 4 months [24 patients]. Cox regression analysis showed no beneficial correlations between anti-TNF timing and IBD-related complications. Anti-TNF treated patients achieving MH were 11 times less likely to develop EIMs compared with patients who did not achieved MH while on anti-TNF. CONCLUSIONS This study was unable to confirm a benefit of earlier anti-TNF treatment on IBD disease complications. This could be explained by more aggressive treatment earlier in disease, resulting in fewer IBD complications. However, it seems more likely that inappropriate selection of patients for therapy leads to suboptimal treatment and subsequently suboptimal outcome.

SOCS3 Expression is a Predictive Factor of Relapse of Mucosal Inflammation in Chronic UC

Background and aims: Ulcerative colitis (UC) is chronic relapsing-remitting disease. Whereas it has been well characterized how various drug induce remission, the mechanisms involved in relapse are not known. We have previously shown that the epithelial expression of SOCS3, a negative regulator of cytokine signaling, was persistently upregulated in both active and inactive UC. Since the expression of SOCS3 during inactive disease may make the epithelial cells more vulnerable to various insults, we investigated whether this expression during remission was associated with the time till relapse. Materials and methods: 41 chronic UC patients in clinical remission underwent a first surveillance colonoscopy between 20012004, and were followed up till 2010. Biopsies from the first surveillance colonoscopy after remission were stained for SOCS3 protein expression and scored according to percentage of positive epithelial cells. Only biopsies from patients with clinical remission and without signs of histological inflammation were included. Clinical data, endoscopy and histology reviews were collected from patient charts. Results: 23 Patients (57.0%) of the 41 chronic UC patients developed histological relapse, and 19 patients (46.3%) had endoscopic relapse of colitis during the course of surveillance. SOCS3 protein expression in colon biopsies of inactive UC patients had a negative correlation with the time till histological (p<0.001) and endoscopic (p=0.007) relapse. Patients with higher epithelial SOCS3 expression at early remission suffered from a significantly more severe colitis during relapse (p=0.001). There was no correlation with CRP levels. Conclusion: Here we found that high levels SOCS3 expression in epithelial cells during remission was associated with a shorter time till relapse and increased severity of inflammation during relapse. These data further strengthen our hypothesis that SOCS3 expression may contribute to enhanced vulnerability of the intestinal epithelial cells during remission. As such, the dynamic changes and the mechanisms involved in this SOCS3 expression during mucosal remission will be further investigated.

DOP087 Only one third of Crohn's disease patients have sustained remission of perianal fistulas

patients were colonoscoped at 18 months. HRQoL was assessed with a general (SF36) and disease-specific (IBDQ) questionnaire pre-operatively and at 6, 12 and 18 months. CRP, CDAI and faecal calprotectin (FC) were measured longitudinally. Results: 174 patients (median age 38, 55% female) were included. HRQoL was poor pre-operatively: median SF36 = 40 (where maximum=100, Australian normal = 70 90) and IBDQ= 120 (maximum=224, average score in Australian Crohn’s disease patients=156). For all patients both SF36 and IBDQ improved significantly at 6 months to 78 and 178 respectively, and this was sustained at 12 months (81 and 183) and 18 months (80 and 182 respectively). Females had lower HRQoL than males post-op at 6 (SF36 p = 0.012; IBDQ p = 0.007) and 12 months (SF36 p = 0.001, IBDQ p = 0.006). Smokers had poorer HRQoL compared to non-smokers at both 12 and 18 months: SF36 at 12 month p = 0.002, and IBDQ at 12 and 18 months (p = 0.046, p = 0.047 respectively). Persistent endoscopic remission, thiopurine or adalimumab therapy and treatment step up were not associated with changes in HRQoL. There was a significant inverse correlation between CDAI and both SF-36 and IBDQ at 6, 12 and 18 months. HRQoL did not correlate with endoscopic remission, CRP or FC. Conclusions: Intestinal resection of all macroscopic Crohn’s disease, with a focus on maintaining remission, is associated with significant and sustained improvement in general and disease-specific HRQoL. The lower HRQoL in female patients and smokers may reflect partly their lower QoL in the healthy and IBD populations, but this requires further investigation. A higher clinical disease activity index, but not direct measures of active disease or type of drug therapy, is associated with a lower HRQoL, suggesting that symptoms reflect subjective personal factors and not active mucosal disease or drug effects.