Non-caseating granulomas may indicate a more aggressive phenotype of Crohn disease (CD). Genetic associations of granulomatous CD (GCD) may help elucidate disease pathogenesis. Whole-exome sequencing was performed on peripheral blood-derived DNA from 17 pediatric patients with GCD and 19 with non-GCD (NGCD), and from an independent validation cohort of 44 GCD and 19 NGCD cases. PLINK (a tool set for whole-genome association and population-based linkage analyses) analysis was used to identify single nucleotide polymorphisms (SNPs) differentiating between groups, and subgroup allele frequencies were also compared to a public genomic database (gnomAD). The Combined Annotation Dependent Depletion scoring tool was used to predict deleteriousness of SNPs. Human leukocyte antigen (HLA) haplotype findings were compared to a control group (n = 8496). PLINK-based analysis between GCD and NGCD groups did not find consistently significant hits. gnomAD control comparisons, however, showed consistent subgroup associations with DGKZ , ESRRA , and GXYLT1 , genes that have been implicated in mammalian granulomatous inflammation. Our findings may guide future research and precision medicine.

Epithelioid granulomas are characteristics of a subset of patients with Crohn's disease (CD), but their significance, with regard to disease progression and severity, is unclear. We investigated the relationship between granulomas and CD severity over a 6-year time period in a large cohort of patients.

We performed a retrospective study of patients with CD seen at the Inflammatory Bowel Disease Center at the University of Pittsburgh; data were collected from 2009 through 2014 and patients were assigned to groups with and without histologic evidence of granuloma. Demographic, clinical (including disease activity, quality of life, medication use, and healthcare utilization), and laboratory data were used in association and survival analyses. Differences between groups were evaluated using the Mann-Whitney U-test for continuous variables.

Of 1466 patients with CD, granulomas were identified in 187 (12.8%). In the subset of patients who underwent surgery, 21.0% had granulomas. The presence of granuloma was associated with increased serum levels of c-reactive protein (odds ratio [OR], 2.9; 95% CI, 2.078-4.208; P < .0001), younger mean age at diagnosis (23.6 ± 11.3 years in patients with granulomas vs 27.9 ± 13.3 years in patients without; P = .0005), higher rates of stricturing or penetrating disease phenotype, higher rates of steroid and narcotic use, and higher healthcare utilization. Among patients that underwent surgery, the presence of granulomas was associated with need for repeat surgery during the 6-year observation period (OR, 2.5; 95% CI, 1.54-4.02; P = .0002). Infliximab use was associated with detection of granuloma in a significantly lower proportion of surgical specimens compared to patients who had not been treated with a biologic agent (OR, 0.22; 95 CI, 0.05-0.97; P = .03).

Epithelioid granulomas develop in less than 13% of patients with CD, and are associated with a more aggressive disease phenotype. Patients who have undergone surgery for CD and have granulomas are at increased risk for repeat surgery within 6 years.

Although orofacial granulomatosis (OFG) may present as a separate clinical entity, it often seems in conjunction with various systemic diseases, of which Crohn's disease (CD) is one of the most common. The aim of this study was to investigate whether CD with concomitant OFG represents a distinctive disease subtype.

Twenty-one patients with CD and concomitant OFG (CD+OFG group) were included in the study. As the reference group, a cohort of 39 patients with CD but without OFG (CD-R group) was used. Demographic data and clinical characteristics were recorded at the time of diagnosis. The 2 groups were compared using multivariate analyses.

The percentage of patients with intestinal inflammation in the upper gastrointestinal tract was significantly higher in the CD+OFG group, as compared with the CD-R group (81% versus 33%; P < 0.001). Furthermore, ileocolonic inflammation was significantly more common in the CD+OFG patients (81% versus 46%; P = 0.013). In addition, perianal disease was more frequently observed in the CD+OFG group (48% versus 18%; P = 0.033). Significantly more patients showed evidence of granulomas in the primary endoscopy in the CD+OFG group than in the CD-R group (81% versus 38%; P = 0.003).

The data from this study suggest that the presence of CD in conjunction with OFG represents a distinctive subphenotype of CD that is characterized by extensive inflammation, perianal disease, and pronounced granuloma formation in the intestine.

Childhood onset Crohn's disease (CD) is considered more aggressive than adult onset disease. Epithelioid cell granulomas in intestinal biopsies are one, non-obligate, criterion of CD. We investigated granulomas as markers of CD severity in children followed to adulthood.

Forty-five individuals with childhood onset CD were studied from diagnosis until attainment of final height, with data on disease location, medical and surgical management and with detailed growth data analyses. A blinded review of diagnostic biopsies was also performed.

We found granulomas in 22/45 (49%) children at diagnosis, altogether in 28/45 (62%) patients during the disease course (median overall follow-up - 12.3 years, range 9.3-18). Granulomas were found in 9/11 (82%) with upper gastrointestinal involvement (cumulatively 17/20, 85%) (p = 0.017 and p = 0.006, respectively). The time from diagnosis to initiating immune modulating treatment (median 4.5 months, range 0-75) was shorter in the granuloma-positive group (16/22) compared to the granuloma-negative group (18/23) (median 33 months, range 2-105; p = 0.01). The median standard deviation score height at diagnosis and final adult height (both adjusted for target height) did not correlate to findings of granulomas.

Epithelioid cell granulomas were associated with a shorter time to initiating immune modulating drugs, as a possible sign of more severe disease, but growth was not affected.

Genetic susceptibility loci for Crohn's disease (CD) are numerous, complex, and likely interact with undefined components of the environment. It has been a challenge to link the effects of particular loci to phenotypes of cells associated with pathogenesis of CD, such as Paneth cells. We investigated whether specific phenotypes of Paneth cells associated with particular genetic susceptibility loci can be used to define specific subtypes of CD.

We performed a retrospective analysis of 119 resection specimens collected from patients with CD at 2 separate medical centers. Paneth cell phenotypes were classified as normal or abnormal (with disordered, diminished, diffuse, or excluded granule phenotypes) based on lysozyme-positive secretory granule morphology. To uncover the molecular basis of the Paneth cell phenotypes, we developed methods to determine transcriptional profiles from whole-thickness and laser-capture microdissected, formalin-fixed, paraffin-embedded tissue sections.

The proportion of abnormal Paneth cells was associated with the number of CD-associated NOD2 risk alleles. The cumulative number of NOD2 and ATG16L1 risk alleles had an additive effect on the proportion of abnormal Paneth cells. Unsupervised clustering analysis of demographic and Paneth cell data divided patients into 2 principal subgroups, defined by high and low proportions of abnormal Paneth cells. The disordered and diffuse abnormal Paneth cell phenotypes were associated with an altered transcriptional signature of immune system activation. We observed an inverse correlation between abnormal Paneth cells and presence of granuloma. In addition, high proportions of abnormal Paneth cells were associated with shorter time to disease recurrence after surgery.

Histologic analysis of Paneth cell phenotypes can be used to divide patients with CD into subgroups with distinct pathognomonic and clinical features.

It has been more than 25 years since Mycobacterium paratuberculosis was first proposed as an etiologic agent in Crohn's disease based on the isolation of this organism from several patients. Since that time, a great deal of information has been accumulated that clearly establishes an association between M. paratuberculosis and Crohn's disease. However, data are conflicting and difficult to interpret and the field has become divided into committed advocates and confirmed skeptics. This review is an attempt to provide a thorough and objective summary of current knowledge from both basic and clinical research from the views and interpretations of both the antagonists and proponents. The reader is left to draw his or her own conclusions related to the validity of the issues and claims made by the opposing views and data interpretations. Whether M. paratuberculosis is a causative agent in some cases or simply represents an incidental association remains a controversial topic, but current evidence suggests that the notion should not be so readily dismissed. Remaining questions that need to be addressed in defining the role of M. paratuberculosis in Crohn's disease and future implications are discussed.

Granulomas are a characteristic microscopic finding in Crohn's disease. Their clinical significance is controversial and their pathogenesis is unknown, but impaired processing of bacterial components has been suggested. Autophagy is a fundamental process involved in the elimination of intracellular bacteria. Genetic variants in autophagy genes IRGM and ATG16L1 have been associated with susceptibility to Crohn's disease. We therefore investigated whether variants in autophagy genes contribute to granuloma formation.

Surgical specimens from 464 clinically well-documented Crohn's patients were reviewed and scored for the presence and distribution of granulomas. All patients were genotyped for the CD-associated SNPs in ATG16L1 and IRGM as well as for 77 haplotype tagging SNPs in 13 additional autophagy genes.

Granulomas were found in 75% of the patients. Their frequency increased with more distal involvement of the GI tract. Granuloma positive patients were significantly younger at the time of diagnosis and surgery, and were more likely to smoke. We identified associations between granulomas and autophagy gene variants ATG4A (rs5973822), FNBP1L (rs17109951) and ATG4D (rs7248026; rs2304165; rs10439163).

These findings suggest that granuloma formation is a marker of a more aggressive disease course, and that variants in autophagy genes ATG4A, ATG2A, FNBP1L and ATG4D, may contribute to granuloma formation.

The effect of race on Crohn's disease (CD) remains uncertain. This study compared the characteristics of American white patients and Chinese patients with CD.

A retrospective chart review was conducted for patients who required management of colorectal CD between 1985 and 2004 at either Cleveland Clinic Florida (CCF) or at the 301 Hospital in China. Data included a family history of CD, smoking history, location of the CD and histopathology.

The mean age of onset in the 153 patients was 29.8 ± 16.4 years for American white patients and 32.4 ± 15.3 years for Chinese patients (not significant). Sixty per cent of American white patients were women vs 37% of Chinese patients (P = 0.003). Twelve per cent of American white patients vs 1% of Chinese patients had a family history of CD (P = 0.016). American white patients had significantly higher rates of arthritis (32%vs 4%), abscess (19%vs 0%), rectal and perineal fistula (52%vs 0%), and disease involving the colon and rectum when compared with Chinese patients (all P < 0.05). American white patients had more colorectal sites involved and higher rates of extraintestinal diseases (40%vs 20%) than Chinese patients (all P < 0.05). Chinese patients had higher rates of ileocaecal disease (82%vs 52%) and deep ulcers (66%vs 24%) in the colorectum (all P < 0.001). There were no statistical differences in the incidence of smoking, perforation, intra-abdominal fistula, stenosis, bowel obstruction, toxic megacolon or granuloma formation.

This study found that colorectal CD had a more severe clinical presentation and pathological involvement in American white patients than in Chinese patients.

Non-caseating granulomas exist in a substantial portion of patients with Crohn's disease (CD). Several single nucleotide polymorphisms (SNPs) have been identified as a having strong association with CD, including SNPs within the autophagy related 4 homolog A (ATG4A) gene and the neutrophil cytosolic factor 4 (NCF4) gene. We hypothesized a possible association between the presence of granulomas in CD patients and variants in the ATG4A and NCF4 genes.

To investigate whether variants in the NCF4 and ATG4A genes are associated with granuloma formation in a cohort of Israeli patients with CD, exploring demographic and clinical characteristics that differ between granuloma positive and granuloma negative patients.

307 Israeli patients with CD were studied. Patients with CD who underwent biopsy or resection of the intestine were classified according to presence or absence of granulomas. Using PCR-RFLP we determined the allele frequency in SNP rs4821544 (NCF4 gene) and SNP rs807185 (ATG4A gene) for all patients.

Granulomas were found in 85 out of 307 CD patients (27%). There were no significant differences between patients with or without granulomas in allele frequency in SNPs rs4821544 and rs807185. CD Patients with granuloma were younger at diagnosis than patients without granuloma (mean age 19 vs. 27, respectively, P<0.0001) and were more likely to undergo surgery (55.3% vs. 34.8%, respectively, P=0.002).

No association was found between SNPs rs4821544 and rs807185 and the presence of granulomas in CD patients. Granuloma positive patients were more likely to be younger and to undergo surgery.

Early-onset disease is frequently examined in genetic studies because it is presumed to contain a more severe subset of patients under a higher influence of genetic effects. In light of the dramatic success of Crohn's disease (CD) gene discovery efforts, we aimed to characterize the contribution of established common risk variants to pediatric CD.

Using 35 confirmed CD risk alleles, we genotyped 384 parent-child trios (mean age of onset 11.7 years) along with 321 healthy controls. We performed association tests on the independent pediatric cohort and compared results to those previously published.1 We also computed a weighted CD genetic risk score for each affected person. Six variants not previously validated in children (at 5q33, 1q24, 7p12, 12q12, 8q24, and 1q32) were significantly associated with pediatric CD (P < 0.03).

We detected no significant association between risk score and age at onset through age 30. This analysis illustrates that the genetic effect of established CD risk variants is similar in early and later onset CD.

These results motivate joint analyses of genome-wide association data in early and late onset cohorts and suggest that, rather than established risk variants, independent variants or environmental exposures should be sought as modulators of age of onset.

Disease behavior in Crohn's disease (CD) may be modified by disease location and genotype. Disease behavior may change over time, and thus analysis requires follow-up. To date, there have been few pediatric studies that have evaluated the association between disease behavior and genotype with prolonged follow-up. The aim of our study was to evaluate the effect of genotype, phenotype, and ethnicity on disease behavior in pediatric CD.

Evaluation of 128 pediatric CD was followed by analysis of 232 pediatric and adult-onset CD patients. Inclusion required at least 2 years of follow-up. Phenotype, ethnicity, and disease duration were recorded. Patients were genotyped for polymorphisms in the NOD2/CARD15 gene.

Colonic involvement was more frequent in younger patients. Pediatric disease at end of follow-up was classified as inflammatory (78%), penetrating (7%), and stricturing (17%). Duration of follow-up (mean 4.9 pediatric and 6.4 years mixed) was associated with more stricturing and penetrating disease. There was no association between mean age of onset and NOD2/CARD15, or either of these with disease behavior. These observations were replicated in the mixed cohort. Sephardic Jewish origin was inversely correlated with inflammatory behavior (P = 0.006), independent of NOD2/CARD15 genotype.

Duration of disease and ethnicity, irrespective of NOD2/CARD15 genotype and age of onset, were the only predictors for penetrating or stricturing disease.

Gastrointestinal mucins produced by goblet cells comprise the main structural components of the mucus layer. Mucins play a critical role in the maintenance of mucosal homeostasis and are responsible for the differential effector and regulatory responses against a plethora of microorganisms, including commensals and pathogens. In this review, we present a comprehensive overview on mucin biology, its properties, classification and gene assembly. We also consider the structure of the mucin gene, its proteins and its role in innate host defenses. We compare the various mucin secretagogues and the differential regulatory pathways involved in mucin biosynthesis and secretion during normal and diverse pathogenic conditions. Finally, we summarize the putative uncharted aspects of mucin-derived innate host defenses, whose exploration will help drug developers to identify factors that can strengthen mucosal integrity and will facilitate basic science research into curative treatments for gastrointestinal diseases.

Granulomas are pathognomonic findings of Crohn disease (CD); however, their occurrence and clinical significance are not well characterized. Our aim was to determine the frequency and distribution of granulomas in untreated and treated patients with CD and their relation to age and disease severity.

Records from patients with CD undergoing colonoscopy with terminal ileum biopsy over 7 years were reviewed. Clinical information and laboratory, pathology, and radiology results were recorded. The frequency and distribution of granulomas were determined.

From 376 patients with CD, 75% underwent concurrent esophagogastroduodenoscopy and colonoscopy. Of those, 65% (184/282) were untreated. Granulomas were identified in 48% (136/282) of all patients and in 61% (112/184) of untreated patients and 24.5% (24/98) of treated patients (P < 0.0005). The upper tract and terminal ileum biopsies were essential to the identification of 42% of patients with granulomas. The presence of granulomas at diagnosis was related to anti-Saccharomyces cerevisiae antibodies, hypoalbuminemia, perianal disease, and gastritis at presentation (P = 0.03, P = 0.008, P = 0.03, and P = 0.001), respectively, and to perianal disease and infliximab treatment at the latest visit (P = 0.02 and P = 0.01), respectively. Granulomas were not related to age, sex, ethnicity, weight and height z scores, hemoglobin, C-reactive protein, erythrocyte sedimentation rate, CARD15/NOD2 mutations, abdominal surgery, or stricturing or fistulizing disease.

Granulomas were identified in 61% of fully investigated pediatric patients with CD at diagnosis, including a substantial proportion of patients in whom colonoscopy to the cecum would have been insufficient for diagnosis. Granulomas were more frequent in untreated patients (P < 0.0005), and their prevalence was not affected by age. The presence of granulomas at diagnosis was associated with perianal disease, gastritis, hypoalbuminemia, anti-Saccharomyces cerevisiae antibodies, and infliximab treatment.

Genetic variants at the CARD15 and IBD5 loci are strongly associated with Crohn's disease (CD), but evidence of the effect of these variants on the clinical expression of CD is conflicting and has often been hampered by small sample sizes. We studied 630 well-characterized patients to clarify the genotype/phenotype relationship in CD.

Patients and healthy controls were genotyped for three common mutations in CARD15 and a marker of the IBD5 risk haplotype. Allele frequencies were compared between phenotypic subgroups using chi2 or Fisher's exact tests. Genotype/phenotype analysis was carried out using multinomial logistic regression modelling allowing for adjustment for correlated or confounding factors.

The mean age at diagnosis was significantly lower in carriers of the CARD15 or IBD5 risk alleles. After correction for age and smoking, CARD15 mutations were strongly associated with both ileal disease (P=8.8 x 10(-6)) and stenotic disease (P=0.003), but the association with stenotic disease appeared to be due to a confounding effect with ileal disease. CARD15 mutations were also associated with the presence of granulomas (P=5.7 x 10(-5)), which remained significant after adjustment for age at diagnosis and disease location (P=0.0047). The IBD5 risk haplotype frequency was significantly elevated in cases with perianal disease (P=0.028) and axial spondyloarthropathy (P=0.012).

Genetic variants at the CARD15 and IBD5 loci have diverse effects on clinical expression in CD. CARD15 mutations are significantly correlated with the presence of granulomas.

The objective of this study was to determine gender differences in pediatric patients with Crohn disease.

We conducted a retrospective cohort study of 989 consecutive pediatric patients (566 boys, 423 girls) who had Crohn disease (aged 0 to 17 years at diagnosis) by using the Pediatric IBD Consortium Registry. Uniform data were analyzed to compare the presentation and course of disease according to gender.

Median follow-up time was 2.8 years. Mean +/- SD age at diagnosis of inflammatory bowel disease (11.5 +/- 3.8 years) did not differ by gender. Compared with boys, girls had a higher prevalence of mouth sores at symptom onset and a higher prevalence of hypoalbuminemia at the time of diagnosis. Location of disease did not differ by gender. A higher proportion of girls had abnormal anti-outer membrane porin of Escherichia coli levels compared with boys. Girls were at increased risk for erythema nodosum/pyoderma gangrenosum and decreased risk for growth failure compared with boys.

Girls appear to have an overall more severe course of disease; however, boys are at increased risk for developing growth failure. Disease course and the impact of disease severity on growth according to gender in pediatric Crohn disease require prospective study.

Genetic defects along the interleukin (IL)-12/interferon (IFN)-gamma pathway have been found in patients with mendelian susceptibility to mycobacterial disease (MSMD) caused by live BCG vaccine or non-tuberculous Mycobacterium (NTM) species, highlighting the crucial role of this axis in human immunity to Mycobacterium. The aims of this study were to characterize healthy children presenting with cervical lymphadenitis caused by NTM and to investigate their IL-12/IFN-gamma pathway. Epidemiological, clinical, laboratory and pathological findings were reviewed retrospectively. Blood samples from five patients and healthy controls were in vitro activated with BCG, BCG + IL-12 and BCG + IFN-gamma and levels of IL-12p40 and IFN-gamma were measured. Fourteen patients (11 males, median age 24 months, range 12-78 months) were studied. The mean duration of illness before diagnosis was 9.1 weeks. Mycobacterium tuberculosis purified protein derivate (PPD) was positive in all patients (mean 14.5 +/- 9.8 mm). Caseous granuloma was found in all ten patients who underwent excision biopsy. However, acid fast stain was positive in only five children and cultures were positive in only three cases. The amplified M. tuberculosis direct test was negative in all tested cases. No significant differences in IL-12p40 and IFN-gamma levels were found between patients and controls. In spite of the normal response as measured in the screening test, it is still possible that patients might have a monogenic/mendelian disease for which the genetic defect(s) have yet to be elucidated. Alternatively, some single nucleotide polymorphisms along the IL-12/IFN-gamma axis might be associated with an isolated cervical lymph node infection and not a disseminated disease in children.

To investigate the contribution of variants of CARD15, OCTN1/2 and DLG5 genes in disease predisposition and phenotypes in a large Italian cohort of pediatric patients with inflammatory bowel diseases (IBD).

Two hundred patients with Crohn's disease (CD), 186 ulcerative colitis (UC) patients, 434 parents (217 trios), and 347 healthy controls (HC) were studied. Polymorphisms of the three major variants of CARD15, 1672C/T and -207G/C SNPs for OCTN genes, IGR2096a_1 and IGR2198a_1 SNPs for the IBD5 locus, and 113G/A variant of the DLG5 gene were evaluated. Potential correlations with clinical sub-phenotypes were investigated.

Polymorphisms of CARD15 were significantly associated with CD, and at least one variant was found in 38% of patients (15% in HC, OR = 2.7, P < 0.001). Homozygosis for both OCTN1/2 variants was more common in CD patients (1672TT 24%, -207CC 29%) than in HC (16% and 21%, respectively; P = 0.03), with an increased frequency of the TC haplotype (44.8% vs 38.3% in HC, P = 0.04). No association with the DLG5 variant was found. CD carriers of OCTN1/2 and DLG5 variants more frequently had penetrating disease (P = 0.04 and P = 0.01), while carriers of CARD15 more frequently had ileal localization (P = 0.03). No gene-gene interaction was found. In UC patients, the TC haplotype was more frequent (45.4%, P = 0.03), but no genotype/phenotype correlation was observed.

Polymorphisms of CARD15 and OCTN genes, but not DLG5 are associated with pediatric onset of CD. Polymorphisms of CARD15, OCTN, and DLG5 genes exert a weak influence on CD phenotype.

We investigated the contribution of variants of tumour necrosis factor (TNF)-alpha and MDR1 genes in the predisposition and response to medical therapy in a large pediatric cohort of patients with Crohn disease (CD) and ulcerative colitis (UC).

In this study, 200 patients with CD, 186 patients with UC, 434 parents (217 trios), and 347 healthy unrelated controls were investigated. Single-nucleotide polymorphisms -G308A and -C857T of the TNF-alpha gene and C3435T of the MDR1 gene were investigated and correlated with clinical subphenotypes and efficacy of medical therapy.

The frequency of the -308A allele of the TNF-alpha gene was significantly increased in both patients with CD (15%; odds ratio [OR] = 2.79; P < 0.01) and patients with UC (11%; OR = 1.96; P < 0.003) compared with controls (6%). Carriers of this allele were 27% in CD (OR = 2.94; P < 0.01) and 19% in UC (OR = 1.86; P = 0.015) compared with 11% in healthy controls. No significant difference was found for both the -C857T and C3435T single-nucleotide polymorphisms. With the genotype/phenotype analysis, no correlation in patients with UC with the MDR1 gene was found. CD carriers of the -308A allele had a higher frequency of surgical resection (35% vs 20%; OR = 2.1; P = 0.035) and more frequent resistance to steroids (22% vs 8%; OR = 0.29; P = 0.032) compared with noncarriers. These findings were confirmed by stepwise logistic regression.

In our pediatric cohort, the promoter -308A polymorphism of TNF-alpha but not the MDR1 gene is significantly involved in the predisposition to both CD and UC. This polymorphism carries a significant reduction in response to steroid therapy, probably leading to a more frequent need for surgical resection.

Granulomas may be found in 30-70% of patients with Crohn's disease (CD). The etiology of granuloma formation in CD is presently unknown. Elevated levels of TNF-alpha are found within granuloma tissue, and are required to maintain granuloma formation in animal models. TNF-alpha production has been shown to influenced by TNF-alpha promoter polymorphisms. We hypothesized that heterogeneity for granulomas in CD might be influenced by the TNF-alpha promoter genotype. Patients with confirmed CD that had undergone full colonoscopy with multiple biopsies and/or surgical resection, served as the study group. One hundred healthy individuals served as a control population for genotyping. Patients and controls underwent genotyping for four TNF-alpha polymorphisms: 238G/A, 308 G/A,857 C/T, and 863 C/A. Inclusion and exclusion criteria were met in 155 patients (1-68 y). Polymorphisms in the TNF promoter were found in 16.6% (238G/A), 14.5% (308 G/A), 36.6% (857 C/T) and 30.7% (863G/A). No significant association was found for any of the individual polymorphisms with presence or absence of granulomas. In conclusion, we did not find an association between individual polymorphisms in the TNF-alpha promoter and presence of granulomas in CD. The reason for heterogeneity in granuloma formation in patients with CD remains elusive.

Crohn's disease (CD) is a heterogenous disease characterized by variable manifestations and outcomes, and increasing in incidence in China. Phenotypic classification has been proposed to assist in subtyping of disease. Non-caseating intestinal granulomas are a hallmark of CD, but whether intestinal granulomas help predict Chinese CD phenotypes or determine severity, is not known.

To determine the association between intestinal granulomas with CD phenotype, severity, risk factors, and serological markers.

This was a single-centre study of consecutive definite Chinese CD cases. Granulomas were diagnosed by an experienced GI pathologist. Correlation with the Vienna Classification and other parameters was performed.

Eighty Chinese CD patients were recruited, 40 (50%) of whom had intestinal granulomas. Intestinal granulomas were independently associated with the stricturing behavior (OR: 4.71; 95% CI: 1.41-15.72), colonic location of disease (OR: 26.96; 95% CI: 2.68-271.14), but not with age of CD diagnosis. Current or previous smoking protected against the development of granulomas (OR: 0.16; 95% CI: 0.04-0.59). Granulomas were not associated with peri-anal involvement, extra-intestinal manifestations, anti-neutrophil cytoplasmic antibody or anti-Saccharomyces cerevisiae antibody serology, or severity of CD gauged by the requirement of major intestinal surgery or immunomodulating therapy.

Intestinal granulomas in the setting of CD may be helpful in determining phenotypic subtypes of CD, but is unhelpful in predicting disease severity. Smoking impairs the formation of granulomas in CD.