Background NOD2variants are the strongest genetic predictors for susceptibility to Crohn's disease (CD). However, the clinical value ofNOD2on an individual patient level remains controversial. We aimed to define the predictive power of the majorNOD2mutations regarding complicated CD in a large single center cohort. Methods 1076 CD patients were prospectively genotyped for the three common CD-associatedNOD2mutations rs2066844, rs2066845, and rs2066847, followed by detailed genotype-phenotype analyses. Results Overall, 434 CD patients (40.3%) carried at least one of the three mainNOD2mutations. A significantly higher minor allele frequency (15.6%) of theNOD2frameshift mutation p.Leu1007fsX1008 (rs2066847) was seen in patients with aggressive disease compared to 8.2% in patients with mild disease (p = 2.6 x 10(-5)). Moreover, a total of 54 CD patients (5.0%) were homozygous for thisNOD2frameshift mutation. 100% of these patients had ileal disease compared to 82% ofNOD2wild-type carriers (p<0.0001). In homozygous carriers of theNOD2frameshift mutation, 87% presented with ileal stenosis, 68.5% had fistulas, and 72.2% required CD-related surgery despite immunosuppressive therapy in 87% of these patients. All homozygous carriers of the 1007fs mutation who were active smokers had ileal stenosis and required CD-related surgery. Conclusion Homozygosity for Leu1007fsX1008 is an excellent biomarker for predicting complicated CD on an individual patient level. Active smoking and homozygosity for this mutation is associated with a 100% risk for developing ileal stenosis requiring CD-related surgery. In these patients, smoking cessation and early initiation of immunosuppressive strategies may be beneficial.

Background: DEVELOP is a multi-centre, international, prospective, observational registry of the long-term safety and clinical status of 6070 paediatric patients with inflammatory bowel disease (IBD) diagnosed prior to 18 years of age who were treated with anti-tumour necrosis factor biologics (aTNF) and/or other medical therapies for IBD.Our aim was to assess the risk factors that lead to first serious infection (SI): an infection requiring hospitalisation and/ or IV therapy.Methods: Physicians participating in the registry prescribe IBD treatments based on their usual clinical practice and standards of care.Patients are categorised into cohorts according to their IBD medication exposure representing prevalent or incident exposure.The registry started enrolment in 2007 and completed enrolment in 2017.After the initial enrolment visit, data are obtained by the registry physician or designee every 6 months.SI data includes infections that occurred within 91 days of exposure to aTNF relative to nonbiologics.The most recent available data cut (30 June 2018) includes 33 586 patient-years (PY) of follow-up in the registry.Results: The analysis of the stepwise Cox regression model for time to first SI among aTNF only patients relative to the non-biologics cohort included 3,566 Crohn's disease (CD) patients and 1063 ulcerative colitis (UC) patients who had at least 1 post-baseline follow-up visit, complete baseline covariate data, and complete disease severity data at event.Results of this analysis are seen in Table 1.In CD patients, combination therapy with aTNF/IMM, monotherapy with aTNF or CS, disease severity (hazard ratio [HR] 3.193), recent hospitalisation, gender, length of diagnosis and geographic region were all significantly associated with shorter duration of time to first SI.In UC patients, monotherapy with aTNF or CS (HR 3.913), combination therapy with aTNF and IMM, disease severity and recent hospitalisation were significantly associated with shorter duration of time to first SI.Conclusions: In both CD and UC patients, combination therapy with aTNF and IMM was significantly associated with shorter time to first SI, as was monotherapy with CS or aTNF, disease severity and recent hospitalisation.Monotherapy with IMM was not associated with shorter duration in either disease state.Disease severity was the strongest predictor by hazard ratio in the CD cohort while CS use was the strongest predictor in the UC cohort.

BackgroundRecently, ustekinumab a monoclonal antibody targeting interleukin‐12 and −23 and successfully used in Crohn’s disease also has been shown to be effective in induction and maintaining remission in patients with moderate to severe ulcerative colitis in a large phase 3 trial. However, no observational data on the use of ustekinumab in ulcerative colitis in daily clinical practice is available.AimThe purpose of this study was to assess the clinical outcomes achieved with ustekinumab as rescue treatment in therapy‐refractory or ‐intolerant ulcerative colitis in a real‐life setting.MethodsA retrospective data analysis was performed in 19 ulcerative colitis patients who were intolerant or refractory to all of the following drugs: steroids, purine‐analogues, tumour necrosis factor antibodies and vedolizumab. To all patients ustekinumab was provided as a rescue treatment (intravenous induction with 6 mg/kg, followed by week subcutaneous injection once every eight weeks of 90 mg). The primary outcome was achievement of clinical remission at one year, defined as score of ≤ 3 points in the Lichtiger score (colitis activity index). Patients were evaluated regularly and a colonoscopy was performed before the start and at the end of the observation. Ethical approval was provided by Ethikkommission Ärztekammer Hamburg (PV 5539).ResultsIn five patients, therapy was stopped due to refractory disease or side effects. In all remaining 14 patients the median colitis activity index dropped from 8.5 points (range 1–12) at start to 2.0 points at one year (range 0–5.5) and Mayo endoscopy scores fell from a median of two points (range 1–3, mean of 2.3) at start to a median of one point (range 1–3, mean of 1.4) at one year. Including the five drop‐outs, clinical remission was achieved in 53% of the 19 patients at one year.ConclusionsIn accordance with the UNIFI (A Study to Evaluate the Safety and Efficacy of Ustekinumab Induction and Maintenance Therapy in Participants With Moderately to Severely Active Ulcerative Colitis) trial our real‐life data support ustekinumab as an effective and safe treatment option in therapy refractory moderate to severe ulcerative colitis with a history of biological therapies.

Die Therapie der chronisch entzündlichen Darmerkrankungen (CED) Morbus Crohn (MC) und Colitis ulcerosa (CU) ist durch den Einsatz von Immunsuppressiva und Antikörpern zwar fundamental effektiver, aber auch anspruchsvoller geworden und daher heute fast ausschließlich in der Hand von CED-Spezialisten. Hausärzte spielen aber eine wichtige Rolle bei der Früherkennung der Erkrankung und der Begleitung der Patienten. Lesen Sie hier einen auf Leitlinien, Studien und Erfahrungswerten basierenden, pragmatischen Überblick über Diagnose und Therapie.

Zusammenfassung Die Therapie der chronisch entzündlichen Darmerkrankungen (CED) Morbus Crohn (MC) und Colitis ulcerosa (CU) ist durch den Einsatz von Immunsuppressiva und Antikörpern zwar fundamental effektiver, aber auch anspruchsvoller geworden und daher heute fast ausschließlich in der Hand von CED-Spezialisten. Hausärzte spielen aber eine wichtige Rolle bei der Früherkennung der Erkrankung und der Begleitung der Patienten. Lesen Sie hier einen auf Leitlinien, Studien und Erfahrungswerten basierenden, pragmatischen Überblick über Diagnose und Therapie.

Ustekinumab is a monoclonal antibody targeting interleukins-12 and -23, commonly and successfully used in Crohn's disease. Pre-approval trials are on-going and so far no clinical observation data on the use of ustekinumab in ulcerative colitis (UC) is available. AIM: To assess the clinical outcomes achieved with ustekinumab as rescue treatment in therapy-refractory or -intolerant UC. A retrospective data analysis was performed in 17 UC patients of our tertiary referral center who received ustekinumab between 2016 and 2017 as rescue therapy. All patients were intolerant or refractory to purine-analogues, TNF-antibody therapy, and the anti-integrin vedolizumab. To all patients ustekinumab was provided as a rescue treatment after colectomy had been offered to them as only other option. The primary outcome was achievement of clinical remission at 3 and 6 months. Clinical remission was defined as score of ≤5 points in the modified Truelove and Witts colitis activity index (CAI). A total of 17 UC patients were treated with ustekinumab. All patients (17/17) previously had been steroid-refractory or -dependant and had recently failed all of the following drugs: purine-analogues, anti-TNF-antibodies and anti-integrin-antibodies. Of those, 41% (7/17) had failed infliximab and either golimumab or adalimumab, and 29% (5/17) had also failed i.v. ciclosporine. At the start of the rescue therapy, 65% of patients (11/17) had moderately or severely active disease and 35% (6/17) were in remission, but had intolerable side effects under TNF- or integrin blocking treatment, which had to be stopped. Therefore, the CAI at the start of the therapy ranged between 1 and 11 with a median of 8. All patients received ustekinumab as approved for Crohn’s disease (6 mg/kg body weight as an infusion and 90 mg ustekinumab as s.c. injection every 8 weeks). Median follow-up was 27 weeks (range: 15–40). In two patients therapy was stopped due to refractory disease at months 6 and 24 and in 1 patient, therapy was stopped due to drowsiness at week 4. All 3 patients underwent colectomy. Median CAI at 4 weeks was 5 points (range 1–8). Median CAI at 3 months was 4.5 points (range 0–9). Median CAI at 6 months was 2 points (range 0–7). Including the three drop-outs, clinical remission was achieved in 65% (11/17) at 1, 3, and 6 months, whereas only 35% (6/17) of patients were in remission at the start of the study. Ustekinumab was effective as rescue medication in therapy-refractory or -intolerant UC in a large IBD referral center. It seems possible that large ongoing trials will confirm our findings and ustekinumab could become a new therapeutic option for refractory UC.

in those with at least one or more special situations (17.4%) (Figure 1A).AEs significantly occurred in elderly patients with anemia (21.9%) and on multiple concomitant IMs (23.8%) compared to those without any special situation (3.6%).Anemia and multiple concomitant IMs were identified as independent predictors for a higher incidence of AEs (Table 1).The effectiveness of GMA was assessed in 92 patients with UC.The remission rate was 48.9%.No difference was observed in the remission rate between elderly patients without any special situation (52.2%) and those with at least one or more special situations (45.7%) (Figure 1B).Conclusions: A low incidence of AEs (3.6%) was found in elderly IBD patients receiving GMA without any special situation.Remission was achieved by GMA in 48.6% of the elderly UC patients.Care should be taken when using GMA in elderly IBD patients with anemia or on multiple concomitant IMs.

BackgroundCurrently, limited data of the outcome of inflammatory bowel disease (IBD) in patients after solid organ transplantation (SOT) are available. We aimed to analyze effects of SOT on the IBD course in a large IBD patient cohort.MethodsClinical data from 1537 IBD patients were analyzed for patients who underwent SOT (n = 31) between July 2002 and May 2014. Sub-analyses included SOT outcome parameters, IBD activity before and after SOT, and efficacy of IBD treatment.Results4.74% of patients with ulcerative colitis (UC) and 0.84% of patients with Crohn's disease (CD) underwent SOT (p = 2.69 x 10(-6), UC vs. CD). 77.4% of patients with SOT underwent liver transplantation (LTx) with tacrolimus-based immunosuppressive therapy after SOT. All LTx were due to primary sclerosing cholangitis (PSC) or PSC overlap syndromes. Six patients (19.4%) required renal transplantation and one patient (3.2%) heart transplantation. A survival rate of 83.9% after a median follow-up period of 103 months was observed. Before SOT, 65.0% of patients were in clinical remission and 5 patients received immunosuppressive therapy (16.1%). After SOT, 61.0% of patients were in remission (p = 1.00 vs. before SOT) and 29.0% required IBD-specific immunosuppressive or anti-TNF therapy (p = 0.54 vs. before SOT). 42.9% of patients with worsening of IBD after SOT were at higher risk of needing steroid therapy for increased IBD activity (p = 0.03; relative risk (RR): 10.29; 95% CI 1.26-84.06). Four patients (13.0%) needed anti-TNF therapy after SOT (response rate 75%).ConclusionsSOT was more common in UC patients due to the higher prevalence of PSC-related liver cirrhosis in UC. Despite mainly tacrolimus-based immunosuppressive regimens, outcome of SOT and IBD was excellent in this cohort. In this SOT cohort, concomitant immunosuppressive therapy due to IBD was well tolerated.

BACKGROUND:A previous study suggested an association of the single nucleotide polymorphism (SNP) rs72796353 (IVS4+10 A>C) in the NOD2 gene with susceptibility to Crohn's disease (CD). However, this finding has not been confirmed. Given that NOD2 variants still represent the most important predictors for CD susceptibility and phenotype, we evaluated the association of rs72796353 with inflammatory bowel disease (IBD) susceptibility and the IBD phenotype.METHODOLOGY:Genomic DNA from 2256 Caucasians, including 1073 CD patients, 464 patients with ulcerative colitis (UC), and 719 healthy controls, was genotyped for the NOD2 SNP rs72796353 and the three main CD-associated NOD2 mutations rs2066844, rs2066845, and rs2066847. Subsequently, IBD association and genotype-phenotype analyses were conducted.RESULTS:In contrast to the strong associations of the NOD2 SNPs rs2066844 (p=3.51 x 10(-3)), rs2066845 (p=1.54 x 10(-2)), and rs2066847 (p=1.61 x 10(-20)) with CD susceptibility, no significant association of rs72796353 with CD or UC susceptibility was found. However, in CD patients without the three main CD-associated NOD2 mutations, rs72796353 was significantly associated with the development of perianal fistulas (p=2.78 x 10(-7), OR 5.27, [95% CI 2.75-10.12] vs. NOD2 wild-type carriers).CONCLUSION/SIGNIFICANCE:Currently, this study represents the largest genotype-phenotype analysis of the impact of the NOD2 variant rs72796353 on the disease phenotype in IBD. Our data demonstrate that in CD patients the IVS4+10 A>C variant is strongly associated with the development of perianal fistulas. This association is particularly pronounced in patients who are not carriers of the three main CD-associated NOD2 mutations, suggesting rs72796353 as additional genetic marker for the CD disease behaviour.

ABSTRACT Purpose We aimed to analyse malignancy rates and predictors for the development of malignancies in a large German inflammatory bowel disease (IBD) cohort treated with thiopurines and/or anti‐tumour necrosis factor (TNF) antibodies. Methods De novo malignancies in 666 thiopurine‐treated and/or anti‐TNF‐treated IBD patients were analysed. Patients ( n = 262) were treated with thiopurines alone and never exposed to anti‐TNF antibodies (TP group). In addition, patients ( n = 404) were exposed to anti‐TNF antibodies (TNF+ group) with no (7.4%), discontinued (80.4%) or continued (12.1%) thiopurine therapy. Results In the TP group, 20 malignancies were observed in 18 patients compared with 8 malignancies in 7 patients in the TNF+ group (hazard ratio 4.15; 95% CI 1.82–9.44; p = 0.0007; univariate Cox regression). Moreover, 18.2% of all patients in the TP group ≥50 years of age developed a malignancy, compared with 3.8% of all patients <50 years of age ( p = 0.0008). In the TNF+ group, 6.5% of all patients ≥50 years of age developed malignancies compared with 0.3% of all patients <50 years of age ( p = 0.0007). In both groups combined, thiopurine treatment duration ≥4 years was associated with the risk for skin cancer ( p = 0.0024) and lymphoma ( p = 0.0005). Conclusions Our data demonstrate an increased risk for the development of malignancies in IBD patients treated with thiopurines in comparison with patients treated with anti‐TNF antibodies with or without thiopurines. Copyright © 2014 John Wiley & Sons, Ltd.

Background Very recently, a sub-analysis of genome-wide association scans revealed that the non-coding single nucleotide polymorphism (SNP) rs12212067 in the FOXO3A gene is associated with a milder course of Crohn's disease (CD) (Cell 2013;155:57–69). The aim of our study was to evaluate the clinical value of the SNP rs12212067 in predicting the severity of CD by correlating CD patient genotype status with the most relevant complications of CD such as stenoses, fistulas, and CD-related surgery. Methodology/Principal Findings We genotyped 550 CD patients for rs12212067 (FOXO3A) and the three common CD-associated NOD2 mutations rs2066844, rs2066847, and rs2066847 and performed genotype-phenotype analyses. Results No significant phenotypic differences were found between the wild-type genotype TT of the FOXO3A SNP rs12212067 and the minor genotypes TG and GG independently from NOD2 variants. The allele frequency of the minor G allele was 12.7%. Age at diagnosis, disease duration, body mass index, surgery rate, stenoses, fistula, need for immunosuppressive therapy, and disease course were not significantly different. In contrast, the NOD2 mutant p.Leu1007fsX1008 (rs2066847) was highly associated with penetrating CD (p = 0.01), the development of fistulas (p = 0.01) and stenoses (p = 0.01), and ileal disease localization (p = 0.03). Importantly, the NOD2 SNP rs2066847 was a strong separator between an aggressive and a mild course of CD (p = 2.99×10−5), while the FOXO3A SNP rs12212067 did not separate between mild and aggressive CD behavior in our cohort (p = 0.35). 96.2% of the homozygous NOD2 p.Leu1007fsX1008 carriers had an aggressive disease behavior compared to 69.3% of the patients with the NOD2 wild-type genotype (p = 0.007). Conclusion/Significance In clinical practice, the NOD2 variant p.Leu1007fsX1008 (rs2066847), in particular in homozygous form, is a much stronger marker for a severe clinical phenotype than the FOXO3A rs12212067 SNP for a mild disease course on an individual patient level despite its important impact on the inflammatory response of monocytes.

Background: Anti-tumor necrosis factor (TNF) therapy-induced psoriasiform skin lesions are a recently described side effect in patients with inflammatory bowel disease. Interleukin (IL)-12/IL-23 neutralization is an effective therapy for these lesions. As Th17 cytokines, such as IL-17A, and IL-1 family members, such as IL-36, play a significant role in plaque psoriasis, we analyzed the involvement of IL-17C and IL-36 gamma in anti-TNF-induced skin lesions of patients with Crohn's disease.Methods: IL-36 gamma and IL-17C levels in biopsies of anti-TNF-induced psoriasiform skin lesions of patients with Crohn's disease were assessed by immunohistochemical analysis and correlated to additional immunohistochemical data. IL-36 gamma and IL-17C messenger RNA, protein, and induced gene expression in human primary keratinocytes were analyzed using quantitative real-time polymerase chain reaction, immunoblotting, and enzyme-linked immunosorbent assay.Results: IL-36 gamma and IL-17C are increased in anti-TNF-induced psoriasiform skin lesions of patients with Crohn's disease, compared with healthy controls. Epidermal IL-36 gamma and IL-17C levels strongly correlate with each other (r = 0.748, P = 0.003). In contrast to IL-12 and IL-23, IL-36 gamma increases the expression of proinflammatory signals and effector molecules of innate immunity in keratinocytes. However, IL-17C affects keratinocyte defensin gene expression only in combination with TNF-alpha. IL-36 gamma induces TNF-alpha expression in keratinocytes and sustains a self-amplifying proinflammatory loop with IL-17C by inducing its own expression and that of IL-17C.Conclusions: Our study demonstrates a unique role of the previously unknown self-amplifying, proinflammatory IL-36 gamma/IL-17C loop in the pathogenesis of anti-TNF-induced psoriasiform skin lesions. These findings suggest a beneficial effect of IL-36 gamma/IL-17C inhibition during anti-TNF-induced psoriasiform lesions in patients with inflammatory bowel disease.

Background & Aims: Genome-wide association studies identified the autophagy gene IRGM to be strongly associated with Crohn's disease (CD) but its impact in ulcerative colitis (UC), its phenotypic effects and potential epistatic interactions with other IBD susceptibility genes are less clear which we therefore analyzed in this study.Methodology/Principal Findings: Genomic DNA from 2060 individuals including 817 CD patients, 283 UC patients, and 961 healthy, unrelated controls (all of Caucasian origin) was analyzed for six IRGM single nucleotide polymorphisms (SNPs) (rs13371189, rs10065172 = p.Leu105Leu, rs4958847, rs1000113, rs11747270, rs931058). In all patients, a detailed genotype-phenotype analysis and testing for epistasis with the three major CD susceptibility genes NOD2, IL23R and ATG16L1 were performed. Our analysis revealed an association of the IRGM SNPs rs13371189 (p = 0.02, OR 1.31 [95% CI 1.05-1.65]), rs10065172 = p.Leu105Leu (p = 0.016, OR 1.33 [95% CI 1.06-1.66]) and rs1000113 (p = 0.047, OR 1.27 [95% CI 1.01-1.61]) with CD susceptibility. There was linkage disequilibrium between these three IRGM SNPs. In UC, several IRGM haplotypes were weakly associated with UC susceptibility (p<0.05). Genotype-phenotype analysis revealed no significant associations with a specific IBD phenotype or ileal CD involvement. There was evidence for weak gene-gene-interaction between several SNPs of the autophagy genes IRGM and ATG16L1 (p<0.05), which, however, did not remain significant after Bonferroni correction.Conclusions/Significance: Our results confirm IRGM as susceptibility gene for CD in the German population, supporting a role for the autophagy genes IRGM and ATG16L1 in the pathogenesis of CD.

Background and Aims: We analyzed iron deficiency and the therapeutic response following intravenous ferric carboxymaltose in a large single-center inflammatory bowel disease (IBD) cohort. Methods: 250 IBD patients were retrospectively analyzed for iron deficiency and iron deficiency anemia. A subgroup was analyzed regarding efficacy and side effects of iron supplementation with ferric carboxymaltose. Results: In the cohort (n = 250), 54.4% of the patients had serum iron levels ≤60 µg/dl, 81.2% had ferritin ≤100 ng/ml, and 25.6% had hemoglobin (Hb) of ≤12 g/dl (females) or ≤13 g/dl (males). In the treatment subcohort (n = 80), 83.1% of the patients had iron ≤60 µg/dl, 90.4% had ferritin ≤100 ng/ml, and 66.7% had Hb ≤12/13 g/dl before ferric carboxymaltose treatment. After a median dose of 500 mg ferric carboxymaltose, 74.7% of the patients reached iron >60 µg/dl, 61.6% had ferritin >100 ng/ml, and 90.7% reached Hb >12/13 g/dl at follow-up (p < 0.0001 for all parameters vs. pretreatment values). The most frequent adverse event was a transient increase of liver enzymes with male gender as risk factor (p = 0.008, OR 8.62, 95% CI 1.74–41.66). Conclusions: Iron deficiency and anemia are frequent in IBD patients. Treatment with ferric carboxymaltose is efficious, safe and well tolerated in iron-deficient IBD patients.

BACKGROUND:We analysed incidence, predictors, histological features and specific treatment options of anti-tumour necrosis factor α (TNF-α) antibody-induced psoriasiform skin lesions in patients with inflammatory bowel diseases (IBD).DESIGN:Patients with IBD were prospectively screened for anti-TNF-induced psoriasiform skin lesions. Patients were genotyped for IL23R and IL12B variants. Skin lesions were examined for infiltrating Th1 and Th17 cells. Patients with severe lesions were treated with the anti-interleukin (IL)-12/IL-23 p40 antibody ustekinumab.RESULTS:Among 434 anti-TNF-treated patients with IBD, 21 (4.8%) developed psoriasiform skin lesions. Multiple logistic regression revealed smoking (p=0.007; OR 4.24, 95% CI 1.55 to 13.60) and an increased body mass index (p=0.029; OR 1.12, 95% CI 1.01 to 1.24) as main predictors for these lesions. Nine patients with Crohn's disease and with severe psoriasiform lesions and/or anti-TNF antibody-induced alopecia were successfully treated with the anti-p40-IL-12/IL-23 antibody ustekinumab (response rate 100%). Skin lesions were histologically characterised by infiltrates of IL-17A/IL-22-secreting T helper 17 (Th17) cells and interferon (IFN)-γ-secreting Th1 cells and IFN-α-expressing cells. IL-17A expression was significantly stronger in patients requiring ustekinumab than in patients responding to topical therapy (p=0.001). IL23R genotyping suggests disease-modifying effects of rs11209026 (p.Arg381Gln) and rs7530511 (p.Leu310Pro) in patients requiring ustekinumab.CONCLUSIONS:New onset psoriasiform skin lesions develop in nearly 5% of anti-TNF-treated patients with IBD. We identified smoking as a main risk factor for developing these lesions. Anti-TNF-induced psoriasiform skin lesions are characterised by Th17 and Th1 cell infiltrates. The number of IL-17A-expressing T cells correlates with the severity of skin lesions. Anti-IL-12/IL-23 antibody therapy is a highly effective therapy for these lesions.

Background: IL12B encodes the p40 subunit of IL-12, which is also part of IL-23. Recent genome-wide association studies identified IL12B and IL23R as susceptibility genes for inflammatory bowel disease (IBD). However, the phenotypic effects and potential gene-gene interactions of IL12B variants are largely unknown.Methodology/Principal Findings: We analyzed IL12B gene variants regarding association with Crohn's disease (CD) and ulcerative colitis (UC). Genomic DNA from 2196 individuals including 913 CD patients, 318 UC patients and 965 healthy, unrelated controls was analyzed for four SNPs in the IL12B gene region (rs3212227, rs17860508, rs10045431, rs6887695). Our analysis revealed an association of the IL12B SNP rs6887695 with susceptibility to IBD (p = 0.035; OR 1.15 [95% CI 1.01-1.31] including a trend for rs6887695 for association with CD (OR 1.41; [0.99-1.31], p = 0.066) and UC (OR 1.18 [0.97-1.43], p = 0.092). CD patients, who were homozygous C/C carriers of this SNP, had significantly more often non-stricturing, non-penetrating disease than carriers of the G allele (p = 6.8x10(-5); OR = 2.84, 95% CI 1.66-4.84), while C/C homozygous UC patients had less often extensive colitis than G allele carriers (p = 0.029; OR = 0.36, 95% CI 0.14-0.92). In silico analysis predicted stronger binding of the minor C allele of rs6887695 to the transcription factor ROR alpha which is involved in Th17 differentiation. Differences regarding the binding to the major and minor allele sequence of rs6887695 were also predicted for the transcription factors HSF1, HSF2, MZF1 and Oct-1. Epistasis analysis revealed weak epistasis of the IL12B SNP rs6887695 with several SNPs (rs11889341, rs7574865, rs7568275, rs8179673, rs10181656, rs7582694) in the STAT4 gene which encodes the major IL-12 downstream transcription factor STAT4 (p < 0.05) but there was no epistasis between IL23R and IL12B variants.Conclusions/Significance: The IL12B SNP rs6887695 modulates the susceptibility and the phenotype of IBD, although the effect on IBD susceptibilty is less pronounced than that of IL23R gene variants.